Chapter 118Neoplasms of the Breast

, MD, , MD, , MD, and , MD.

Female breast cancer is a major medical problem with significant public health and societal ramifications. Despite major advances that have been made in the past 25 years in understanding the biologic and clinical nature of the disease, and notwithstanding dramatic changes in its treatment, the problem continues to persist and has become more complex. In 1969, 66,000 new breast cancer cases were diagnosed and 29,000 deaths occurred; by 1993, 184,000 new cases and 43,000 deaths were reported.1,2 The National Institutes of Health (NIH) consensus development conference statement on early-stage breast cancer (June 1990) has emphasized that, from 1990 to 2000, more than 1.5 million women in the United States will be newly diagnosed with invasive cancer and that about 30% of them will ultimately die of the disease.3 It has now been estimated that 1 in 8 women will develop the disease in her lifetime. However, these statistics portray only one aspect of the problem. Each new advance has given rise to a new set of questions and issues to be resolved. Consequently, it is easy to understand why physicians involved with clinical practice are distressed by what might be perceived as chaos in the management of the disease. As new information accumulates, new paradigms compete for acceptance with those that have already been established. During that period of competition, physicians are expressing their uncertainty regarding the treatment strategy to be employed. However, as more data accumulate, the fitter paradigm will survive and that demonstrated to be inferior will disappear. Controversies arise from unwarranted adherence to outmoded hypotheses or from different value judgments arising from attempts to integrate results from clinical trials into practice. It is axiomatic that good scientific data remain the core of good clinical management.

Information obtained during the past decade from efforts to improve the diagnosis of the disease, from pathologic and biologic investigations that have created a shift from the status quo, and from clinical trials evaluating treatment regimens provides the major focus of this chapter. Attention will be given to the historic aspects of the breast cancer problem only insofar as they put more recent findings in proper perspective.

Pathology

Despite the biologic and clinical advances that have been made in breast cancer management, the role of the pathologist in establishing the diagnosis of a lesion has become more, rather than less, important. Today, greater expertise is required by the pathologist to establish the diagnosis of cancer from cytology specimens obtained by fine-needle aspiration and to determine the nature of the increasing number of borderline and precancerous lesions. The differentiation of microinvasive and noninvasive lesions and the understanding of atypical hyperplasias, all usually diagnosed after discovery by mammography, are new challenges. In addition, pathologic discriminants are playing a larger role in determining patient prognosis, and it is the pathologist who must provide the clinician with such data. Finally, the pathologist also provides information that can contribute to a better understanding of the biology of the disease).4–8

Histologic Types

A number of pathologic classifications of mammary carcinoma are currently in use. These are frequently confusing to the individual who is not a specialist in breast disease. If it is appreciated that morphologic studies are based on anatomic or structural units present in an organ, and that in the female breast these units consist of large, medium, and small ducts from which a variety of tumor types arise, a better understanding of breast tumor pathology may ensue. (Only during pregnancy are acinar units present.)

Tumors arising from duct epithelium may be found only within the lumen of the ducts of origin, that is, the carcinomas are intraductal and do not penetrate the basement membrane or invade surrounding stroma. Most frequently, such tumors arise from large ducts and may present as several types. If they grow into the ducts with a papillary configuration, they are recognized as papillary carcinomas (Fig. 118.1). Such lesions are rare, accounting for about 1% of breast cancers. Histologically, pleomorphic duct epithelial cells with disturbed polarity can be demonstrated, as can their “heaping up” into papillae. The basement membrane is intact. Difficulty may be encountered in differentiating a papillary carcinoma from benign atypical papillomatosis.

Figure 118.1. Papillary carcinoma of the breast.

Figure 118.1

Papillary carcinoma of the breast. This uncommon tumor, less than 1%, rarely infiltrates and has a favorable prognosis.

Papillary carcinomas rarely invade the surrounding stroma. A survival rate approaching 100% may be anticipated upon complete excision of such tumors. When these tumors do invade surrounding tissue, they grow rather slowly and attain considerable bulk. Skin and fascial attachments are unusual, and axillary node involvement is a late feature. Clinically, noninvasive tumors are found to be movable, circumscribed lesions that have a soft consistency not unlike that of fibroadenomas.

The noninvasive variety of carcinoma, often referred to as intraductal carcinoma or ductal carcinoma in situ (DCIS), is a proliferation of a subgroup of epithelial cells confined to the mammary ducts without invasion through the basement membrane into the stroma as determined by light microscopy. The histologic diagnosis of DCIS poses certain problems. It is often difficult to distinguish between benign but highly atypical hyperplasia and DCIS, and it is sometimes difficult to identify small foci of stromal invasion. Occasionally, it is difficult to distinguish between DCIS and lobular carcinoma in situ (LCIS), since DCIS may extend into breast lobules and LCIS may involve extralobular ducts. Some lesions may be intermediate between the two. A variety of histologic patterns of DCIS have been recognized. The most frequently encountered are comedo, cribriform, solid, papillary, and micropapillary (Fig. 118.2). The different histologic patterns have been associated with differences in biologic behavior. The thymidine labeling index has been found to vary according to the histologic characteristics of DCIS. A high labeling index has been observed with comedo-DCIS and a low labeling index with cribriform, papillary, and solid DCIS. A type of carcinoma known as comedocarcinoma is characterized by ducts that are dilated and filled with carcinoma cells. These are necrotic and can be expressed as semisolid necrotic plugs. Such cancers are not of special significance but represent a descriptive variant of intraductal carcinoma. Comedo-DCIS has been associated with increased rates of local recurrence and may progress more rapidly to invasive breast cancer than do the other types (Fig. 118.3). Of importance is the observation that, in DCIS with an invasive component, the thymidine labeling index was most often (90 to 95%) similar in the two components. Recently, HER 2 protein overexpression has been observed in solid and comedo types of DCIS, but not in small-cell papillary or cribriform types. No correlation between overexpression and tumor size exists. The role of assays for estrogen and progesterone receptors (ER and PgR) in DCIS has not been established.

Figure 118.2. Ductal carcinoma in situ (DCIS), cribriform type.

Figure 118.2

Ductal carcinoma in situ (DCIS), cribriform type. Duct spaces are completely involved by a proliferation of ductal cells with relatively uniform nuclei, arranged in back to back (cribriform) glands. The glands are fairly uniform in size and shape and (more...)

Figure 118.3. Ductal carcinoma in situ (DCIS), comedo type.

Figure 118.3

Ductal carcinoma in situ (DCIS), comedo type. Two duct spaces contain tumor cells with high nuclear grade, focal necrosis, and calcifications. The combination of high-grade nuclei and central necrosis is diagnostic of comedocarcinoma. (Courtesy Dr. Ira (more...)

One type of tumor that has attracted considerable attention is lobular carcinoma, which arises from the small end ducts of the breast. The noninvasive variety—the so-called lobular carcinoma in situ—is characterized by clusters of anaplastic small cells of low nuclear grade that fill and expand within lobules without penetration of their basement membrane. (Fig. 118.4). When this lesion extends beyond the boundary of the lobule or terminal duct from which it arises, it is known as invasive lobular carcinoma and may be indistinguishable from the conventional infiltrating duct carcinoma (Fig. 118.5). The true incidence of lobular carcinomas is uncertain. It has been emphasized that noninvasive mammary carcinomas make up almost 5% of all neoplastic lesions of the female breast and that LCIS accounts for about 50% of these, or 2.5 to 2.8% of all tumors. With the increased use of mammography, a much higher proportion of noninvasive cancers is being detected.

Figure 118.4. Lobular carcinoma in situ (LCIS).

Figure 118.4

Lobular carcinoma in situ (LCIS). Terminal ducts and acini are completely filled and dilated by a uniform small cell proliferation. (Courtesy Dr. Ira Bleiweiss, Mount Sinai School of Medicine.)

Figure 118.5. Infiltrating lobular carcinoma.

Figure 118.5

Infiltrating lobular carcinoma. Tumor cells with relatively uniform nuclei invade in a single file or linear pattern (so-called Indian file). (Courtesy Dr. Ira Bleiweiss, Mount Sinai School of Medicine.)

Infiltrating duct carcinomas in which no special type of histologic structure is recognized are designated “not otherwise specified” (NOS) and are the most common duct tumors, accounting for almost 80% of breast cancers (Fig. 118.6). They are clinically characterized by their stony hardness to palpation. When they are transected, a gritty resistance is encountered, and the tumor retracts below the cut surface. Yellowish, chalky streaks that represent necrotic foci are observed. Histologically, varying degrees of fibrotic response are present. As a rule, they do not become large. They frequently metastasize to axillary lymph nodes, and their prognosis is the poorest of the various tumor types. More than half (52.6%) of breast cancers are pure infiltrating duct lesions (NOS).

Figure 118.6. Infiltrating ductal carcinoma of the breast, not otherwise specified (NOS).

Figure 118.6

Infiltrating ductal carcinoma of the breast, not otherwise specified (NOS). Nearly 80% of breast cancers exhibit this histology, about one-third of the time with additional types of differentiation.

Several other types of invasive carcinomas arise from large ducts, and each has its own distinct histopathologic picture. The medullary carcinoma, composing 5 to 7% of all mammary carcinomas, is a circumscribed lesion that attains large dimensions and demonstrates low-grade, infiltrative properties (Fig. 118.7). This tumor is characterized by an extensive infiltration of the tumor by small lymphocytes. A recent reappraisal of medullary cancer was conducted using 336 typical and 273 atypical medullary breast cancers from 6,404 patients enrolled in various stage I and stage II National Surgical Adjuvant Breast Project (NSABP) trials.6 The findings indicated that the survival of patients with typical medullary cancers was better than that for patients with NOS invasive ductal carcinomas. Survival was comparable for those with atypical medullary and NOS types.

Figure 118.7. Medullary carcinoma of the breast accounts for about 5 to 7% of breast cancers.

Figure 118.7

Medullary carcinoma of the breast accounts for about 5 to 7% of breast cancers. Despite its relatively poor differentiation, this tumor has a better prognosis than does infiltrating duct carcinoma.

An invasive carcinoma in which tubule formation is highly prominent is known as tubular carcinoma. This tumor has a low nuclear grade with some cell polarity (Fig. 118.8). Its prognosis, although regarded as better than that of infiltrating duct cancers, is less favorable than that of medullary carcinoma, despite the fact that the cells of the latter tumor are more poorly differentiated than those of tubular carcinoma. Another tumor type, the mucinous or colloid carcinoma, composes about 3% of all mammary carcinomas (Fig. 118.9). This ductal carcinoma is characterized on microscopy by its nests and strands of epithelial cells floating in a mucinous matrix. It usually grows slowly and can reach bulky proportions. When the tumor is predominantly mucinous, the prognosis tends to be good.

Figure 118.8. Tubular carcinoma of the breast.

Figure 118.8

Tubular carcinoma of the breast. This tumor is rare in its pure form, less than 1%, but has a better prognosis than infiltrating duct carcinoma NOS. Partial tubular differentiation is seen in 20% of infiltrating duct carcinomas NOS.

Figure 118.9. Mucinous or colloid carcinoma of the breast.

Figure 118.9

Mucinous or colloid carcinoma of the breast. This tumor is uncommon (about 3%) but has a rather favorable prognosis.

Two entities represent special manifestations of mammary carcinoma. Paget’s disease of the breast occurs in 1 to 4% of all patients with breast cancer. Clinically, the patient presents with a relatively long history of eczematoid changes in the nipple, with itching, burning, oozing, and/or bleeding. The nipple changes are associated with an underlying carcinoma in the breast that can be palpated in about two-thirds of the patients. The subjacent tumor may be either intraductal or of the invasive duct type. Prognosis is related to the histologic type of the associated tumor. Histologically, the nipple epithelium contains nests of carcinoma cells. Inflammatory breast cancer or “dermal lymphatic carcinomatosis” of the breast is characterized clinically by skin redness and warmth, a visible erysipeloid margin, and induration of the underlying breast. The feature may be present at the time of primary diagnosis or as part of the clinical picture of recurrent breast cancer. Biopsies of the erythematous areas and adjacent normal-appearing skin reveal poorly differentiated cancer cells filling and obstructing the subdermal lymphatics.9 Inflammatory cells are rarely present. Patients typically have signs of advanced cancer, including palpable axillary nodes, supraclavicular nodes, and/or distant metastases.

Several other histologic types of mammary carcinomas have been described but are rarely encountered. Fewer than 100 cases of adenocystic carcinoma have been reported. Because of the small number of cases, no meaningful association with prognosis is available. Carcinosarcomas, pure squamous cell carcinoma, metaplastic carcinomas (carcinoma with osseous or cartilaginous stroma), basal cell carcinomas, and so-called lipid-rich carcinomas have been observed. Again, because of their rarity, clinical correlates are practically nonexistent.

The incidence of histologic types of breast cancer encountered is recapitulated in Table 118.1. Data are from 1,000 cases in NSABP B-04.5

Table 118.1. Incidence of Histologic Types of Invasive Breast Cancers (1,000 Cases).

Table 118.1

Incidence of Histologic Types of Invasive Breast Cancers (1,000 Cases).

Tumor Characteristics

A search for pathologic features that might serve as prognostic discriminants for treatment failure has been carried out using information from several NSABP trials. These trials represent the largest single aggregate of randomized patients treated by various surgical and adjuvant therapies and should serve as a model for breast cancer in general. Of the 38 pathologic features of tumors that were examined, the following have received the most consideration.

Histologic and Nuclear Grading

Attention has been directed to the possible relation between the behavior of malignant neoplasms and their degree of differentiation. Breast cancers have been categorized into three histologic grades of malignancy, depending on the degree of tubular formation, size of cells, size of nuclei, degree of hyperchromatism, and number of mitoses. Histologic grade 1 breast cancers are recognized as well-differentiated tumors, grade 2 as moderately differentiated, and grade 3 as the most poorly differentiated. Nuclear grade is similarly categorized from one for well differentiated nuclei, to three for poorly differentiated. Most are classified as two for moderate differentiation.

Tumor Necrosis

Tumor necrosis of varying degrees was encountered in 60% of 1,539 patients with invasive breast cancer in NSABP protocol B-04.8 Necrosis, particularly when observed to be of marked degree and of the noncomedo type or a combination of the latter with the comedo form, was positively correlated with increased rates of treatment failure. Although necrosis was observed to be significantly associated with a number of clinical and histopathologic features purportedly related to an ominous prognosis in this disease, it was not correlated with pathologic nodal status, and multivariate analysis revealed it to influence treatment failure independently of tumor size in lesions less than 5 cm in their greatest diameter. Extrapolation of the data fails to reveal any consistent information that might relate tumor necrosis to tumor growth per se in accounting for such a role. Although considerations suggest that this alteration might be a reflection of poor “differentiation,” it appears also to exert its effect independently of the latter, at least in tumors of the highest or most malignant grade.

Circumscription

Mammary carcinomas generally assume either a circumscribed or more infiltrative irregular or stellate configuration. A better prognosis has been ascribed to the former tumor type.

Inflammatory Cell Reaction

Some mammary tumors may have a lymphoid infiltrate (Fig. 118.10). Such a finding has been ascribed to a host response to the tumor and has been considered a favorable prognostic sign. Others have considered an absence of lymphoid infiltrate to indicate a favorable prognosis. Twenty-four percent of the 1,000 NSABP patients had an absence of cell reaction to their tumor, 59% had slight or moderate infiltration, and 17% had an intensive reaction. No association of inflammatory cell reaction with sinus histiocytosis of lymph nodes was observed, as has been suggested.10–13 The reaction seems to be more closely related to those features indicating the degree of malignancy of the cancer, that is, large tumors, blood vessel invasion, and poor histologic grade, rather than to a host response.

Figure 118.10. Cellular infiltration of breast carcinoma.

Figure 118.10

Cellular infiltration of breast carcinoma. The significance of this reaction is controversial.

Lymphatic and Blood Vessel Invasion

One-third of NSABP patients exhibited extension into lymphatics within the dominant mass and another 23% were considered questionable (Fig. 118.11). Such a finding was associated with other unfavorable characteristics. Blood vessel invasion was observed in only 5% of patients and was associated with the finding of four or more positive axillary nodes, lymphatic invasion, and certain other undesirable findings (Fig. 118.12).

Figure 118.11. Lymphatic invasion by breast cancer.

Figure 118.11

Lymphatic invasion by breast cancer. The vessel walls are thin and lined with endothelial cells.

Figure 118.12. Blood vessel invasion by breast cancer.

Figure 118.12

Blood vessel invasion by breast cancer. The vessel wall structure is recognizable, together with erythrocytes in the vessel.

Tumor Size

Tumor size is generally regarded as an important discriminant relative to prognosis. Efforts devoted to the early detection of such lesions support the impression of an inverse relationship between survival and tumor size. The designation of cancers measuring less than 5 mm as “minimal” cancer also suggests this relationship. That such a correlation is straightforward is not so. It has been observed that tumor size per se is not so much a determinant of survival as is the association with nodal metastases. Within each nodal status, however, tumor size remains an important prognostic discriminant. In general, larger tumors are more frequently associated with axillary metastases.

Multicentricity

Many, if not all, breast cancers are multicentric in origin. Although several studies have addressed this issue, the number of multicentric, independent cancers that might have been present is difficult to ascertain since no clear indication of actual site or pathologic type of lesion encountered was presented in the reports of study findings. In an examination of 904 NSABP cases, excluding those instances in which the lesion was beneath the nipple or in the tail of the breast, data were collected from only those quadrants in which the primary lesion was not encountered. This method eliminated the difficulty in distinguishing a new focus of carcinoma in the quadrant of the primary from an integral part of the primary lesion. Either invasive or noninvasive cancers regarded as independent were found in 13.4% of the 904 patients. The probability of detecting such lesions increased with the number of quadrants available for examination rather than with the study of any particular quadrant. The frequency of invasive and noninvasive multicentric cancers was 4.1% and 9.3%, respectively. The types of noninvasive cancers encountered were intraductal (66.7%), LCIS (22.6%), and a combination of both (10.7%). All of the invasive forms were of the infiltrating duct NOS type. Although the multicentricity of breast cancer is a reality, the clinical significance of such an observation remains uncertain because of the finding that lumpectomy with or without breast irradiation is as effective as a more radical procedure in terms of curability. One of the major deterrents to accepting such a limited resection was the realization that such an excision may ignore clinically and pathologically undetected de novo cancers at sites within the breast remote from the dominant mass. Results from the NSABP breast conservation study (B-06; see below) indicate that tumors that recur in the ipsilateral breast following lumpectomy are, in the vast majority of instances, found at the site of the initial operation rather than elsewhere in the breast.

Similarly, evidence indicates that the incidence of histologic cancer in the contralateral breast may be much greater than previously supposed.14,15 Urban reported an overall detection rate of 15% in biopsies performed on contralateral breasts.14 However, despite the significant incidence of multifocal lesions in both breasts in a woman with a primary breast cancer, two or more clinically overt primary cancers in the primary breast are uncommon. Similarly, synchronous bilateral tumors are uncommon, and the incidence of a second asynchronous primary tumor in the uninvolved or opposite breast (about 4 to 6% in 10 years) fails to approach the incidence predicted by the number of occult lesions detected by random biopsy or autopsy.16 It has been noted, for example, that the incidence of clinically latent intraductal carcinomas in the breasts of women over the age of 70 who died of causes other than mammary carcinoma is 19 times greater than the reported incidence of clinical breast cancer.17 Such findings strongly suggest that not all cancers progress to overt clinical lesions and that they may even undergo regression. These conclusions are similar to and gain support from evidence about neuroblastomas of the adrenal in children, from thyroid carcinomas, and from carcinomas of the prostate, which are found more frequently pathologically in randomly examined material than clinically in comparable populations.

Lymph Nodes

Sinus Histiocytosis

A great deal of attention has been directed to the occurrence and significance of sinus histiocytosis in axillary nodes draining mammary cancers (Fig. 118.13). A more or less direct relationship has been observed between the intensity of the nodal response and survival.10–13,18 The reaction has been considered to represent a manifestation of the host response to tumor growth. Others have failed to find any correlation between sinus histiocytosis and survival in breast cancer.19,20 Clinically positive lymph nodes that did not contain metastatic tumor were consistently found to show sinus histiocytosis. In nodes with metastasis, sinus histiocytosis was associated with one, two, or three affected nodes. If sinus histiocytosis was absent, the likelihood that four or more nodes contained metastasis was increased. Absence of sinus histiocytosis was associated with a greater frequency of failure during the first 12 months of observation.5

Figure 118.13. Sinus histiocytosis.

Figure 118.13

Sinus histiocytosis. Note the large mononuclear cells in the subcapsular lymphatic channels.

Prognosis and Nodal Involvement

A plot of the numbers of nodes containing tumor in surgical specimens removed from patients entered into the first NSABP protocol revealed a progressive increase in the postoperative recurrence rate as the number of positive nodes increased.21 There was an even sharper rise in the recurrence rate when four or more nodes were involved (Table 118.2).

Table 118.2. Effect of Lymph Node Involvement on Recurrence and Survival.

Table 118.2

Effect of Lymph Node Involvement on Recurrence and Survival.

Another NSABP report was directed toward determining whether an examination of more nodes in a resected specimen is more meaningful in terms of prognosis than is the recovery of only a few.22 The recurrence and survival rates of more than 2,000 breast carcinoma patients from 46 institutions have been correlated with the number of lymph nodes examined in surgical specimens. In all institutions, the range of the number of nodes examined per specimen was remarkably great, with the median number varying from a low of 7 to a high of 28. It was suggested that the wide range in the number of nodes per specimen is related to a combination of anatomic differences, errors in identification of all nodes by the pathologist, and variation in the extent of surgical dissection. A comparison of methods (such as clearing of specimens, serial section, or palpation) used for the identification of nodes in resected specimens failed to reveal a correlation between the number of nodes found and the technique used to locate them.22

The results failed to demonstrate that examining a greater number of nodes in a specimen was more meaningful in determining prognosis than the recovery of only a few. It was observed that patients having 5 or 10 nodes reported as negative had essentially the same recurrence and survival rates as did patients with 25 to 30 nodes free of tumor. Likewise, when specimens from node-positive patients contained 1 to 5 nodes or more than 30, recurrence and survival rates were similar. The patient with two positive nodes out of five examined was not found to be at greater risk than the patient who had 2 nodes with tumor out of 30 nodes recovered.

Nonepithelial Neoplasms of the Breast

A variety of nonepithelial neoplasms of the breast have been described. Various types of sarcomas predominate. Fibrosarcomas, leiomyosarcomas, rhabdomyosarcomas, and angiosarcomas are infrequent. These are ominous and usually result in rapid death as a result of widespread dissemination. Liposarcomas originating in breast tissue also occur rarely. Their prognosis is perhaps more favorable, although the number of cases is too few to be certain. Lymphomas can have their initial onset in the breast and can also occur as a focus of generalized disease. Haagensen found that they may involve both breasts, and, although they may occur initially in the breast, they rapidly become generalized.23 Haagensen, who discussed the treatment of breast lymphoma prior to the era of modern chemotherapy, recommended the use of irradiation. Only a few cases of Hodgkin’s disease and leukemia have occurred with initial manifestation in the breast; some of these have been mistaken for inflammatory carcinoma.

Phyllodes tumor (cystosarcoma) phyllodes is a neoplasm that is partially epithelial and partially mesenchymal. As Haagensen pointed out, cystosarcoma phyllodes “is a tumor of the breast with frightening clinical and microscopic characteristics which have given it prominence beyond its due. For it is in fact not only common but usually benign.”23 Such tumors are fibroepithelial in character and are often derived from fibroadenomas (Fig. 118.14). They may achieve a great size and, not infrequently, demonstrate some invasion of adjacent breast tissue. They are best handled by local excision with a rim of breast tissue. Cystosarcoma has been known to metastasize and to kill. Unfortunately, it is difficult to determine from clinical or histologic appearance which tumors behave malignantly and will metastasize.

Figure 118.14. Phyllodes tumor (cystosarcoma phyllodes).

Figure 118.14

Phyllodes tumor (cystosarcoma phyllodes). Leaf-like papillary projections, lined by benign epithelium, contain a hypercellular stroma.

Relation of Tumor Characteristics to Outcome

In a report of NSABP findings from 950 women with node-negative invasive breast cancer enrolled in NSABP study B-06, 22 pathologic and four clinical features were evaluated for their prognostic significance.24 Their assessment in a Cox regression model demonstrated that only nuclear grade, histologic tumor type, and race were prognostically important. Eighty-six percent of patients having tumors of good nuclear grade survived for 8 years as opposed to 64% in whom the nuclear grade was scored as poor. Patients with either mucinous, tubular, or papillary cancers fared significantly better than did those with NOS or atypical medullary tumors. Survival for patients with typical medullary, NOS combinations, or lobular invasive cancers was intermediate. Blacks had a worse survival rate than did whites. Survival in the NSABP was better or worse when two favorable or unfavorable characteristics were detected. In an epidemiologic study done by others, however, adjustment for stage, pathology, and co-morbid illness reduced the discrepancy in a multivariable analysis to a relative risk of 1.3, which was not significantly different. The NSABP experience suggests that, as a predictor of survival in node-negative patients, nuclear grade is as good as, if not better than, information derived from other markers, such as HER2 gene expression, cathepsin activity, S-phase fraction (SPF), ploidy, tumor size, or estrogen receptors (ER), which are discussed elsewhere in this chapter.

In another NSABP report, discriminants for 10th-year treatment failure in 614 patients treated by radical mastectomy were provided.25 Nodal metastasis was the most significant prognostic discriminant for disease-free survival in the 10th year. Histologic grade and tumor size were significant discriminants in patients with four or more positive nodes, but no additional factors were found to be significant discriminants in patients with one to three positive nodes. These findings were similar to results previously reported after 5 years of follow-up.8

Epidemiology

Breast cancer is the most common form of malignant neoplasms in North American women and for women throughout the industrialized world. Breast cancer continues to be a major public health challenge in the United States and, as measured by death rates, is even more serious a problem in other regions of the world. In the United States, it is the most common cancer in women, accounting for 30% of all cancers in this group.26 Approximately 1 of 8 American women will develop breast cancer during her lifetime.(Table 118.11) The risk might be higher for women with preexisting risk factors, such as a strong family history or older age. The American Cancer Society estimates that during 1999, 175,000 women will have been diagnosed as having breast cancer.26 The incidence of this disease has increased steadily over the past 40 years, increasing about 4% per year in the 1980s. However, breast cancer incidence rates in women have leveled off in the 1990s to about 110 cases per 100,000, and for the last 4 years for which complete statistics are available, there was a modest but continued decrease in incidence. Some experts believe that the earlier gradual increase in incidence can be explained by the more frequent and systematic use of screening mammography and the lead-time bias associated with earlier diagnosis. The several consecutive years with decreasing incidence since the early 1990s suggest that those might be the reasons, although longer follow-up would be necessary to confirm this proposed explanation. The incidence of breast cancer has also increased worldwide. In 1985, it was estimated that more than 500,000 new cases would be diagnosed, with about half of the cases occurring in the western industrialized countries and the other half occurring in developing countries.27,28 By 1990, it was estimated that close to 900,000 new cases of breast cancer would be diagnosed, and by the turn of the century, it is expected that more than 1000,000 women will develop breast cancer each year. Incidence rates vary substantially around the world. The incidence rates reported from Japan (20 new cases per 100,000 women) and other countries in the Middle and Far East contrast with incidence rates higher than 110 new cases per 100,000 women from the United States and Northern Europe.29 Some of these differences have been attributed to diet, whereas others might be related to behavioral modification associated to the changing roles of women in modern industrialized societies (earlier onset of menses, delayed parity, use of oral contraceptives and hormone replacement therapy, later onset of menopause, and increased consumption of alcohol).30–33

Table 118.11. Risk of Developing Breast Cancer.

Table 118.11

Risk of Developing Breast Cancer.

The mortality rate of breast cancer in the United States had remained essentially stable from the 1950s to 1989. According to the most recent data, however, mortality rates declined significantly during 1990–1996, with the largest decreases in younger women—both white and African American.34,35 These decreases are probably the result of earlier detection and improved treatment. The American Cancer Society estimates that in 1999, 43,700 deaths related to breast cancer will have been reported, 43,300 of them in women. That figure represents 16% of all cancer-related deaths in American women. National statistics suggest that there has been a decrease in the mortality rate of breast cancer in women younger than 65 years over the past two decades, although there has been a simultaneous increase for women over the age of 65. Similar decreases in breast cancer-related mortality obtained from population-based figures were recently released from British Columbia (Canada), Austria, Germany, Sweden and the United Kingdom.36–41 However, these favorable trends are not universal and have not been evident in Greece, Hungary, Italy, Poland, Mexico or, the Iberian Peninsula.42–45 Breast cancer is the second leading cause of cancer-related deaths in women in the United States, but it is the leading cause of cancer-related deaths in women between the ages of 15 and 54.26 The relative 5-year survival rates increased from 63 to 86% for white women between 1960 and 1993 and from 46 to 70% for black women during the same period.27,46–48

Sixty percent of new breast cancer cases are diagnosed while in the localized (node-negative) stage; another 31% are diagnosed in a regional stage, and 6% have metastasized to distant sites at the time of initial diagnosis.47 The percentage of patients with localized breast cancer is even higher among women who follow a systematic screening strategy; among these patients, between 20 and 30% of breast cancer cases are diagnosed in a noninvasive stage, and of those with invasive breast cancer, up to 79% have negative axillary lymph nodes.49 In contrast, at least 50% of breast cancer cases in Latin America and other parts of the Third World are reported in stage III or IV.50–52 This is a substantial public health challenge for these countries, and, despite lower incidence rates, it results in higher mortality rates than those observed in Western Europe and the United States.53

There have been multiple reports to suggest that there are important differences in breast cancer incidence and mortality rates among various minority groups (Table 118.3).54 The American Cancer Society estimates that the incidence rates of breast cancer for 1988–1992 were 95.4/100,000 among African Americans, 69.8/100,000 among Hispanic Americans, and 31.6/100,000 for American Indians, contrasted with 111.8/100,000 for Caucasian women.54 In contrast, the estimated mortality rates for 1988–1992 for the same ethnic groups were 31.4, 15.0, 8.7, and 27.0, respectively. Although breast cancer was diagnosed in a localized stage in 60% of Caucasian women, it was diagnosed in that stage in only 49% of African Americans. Both incidence and mortality rates are lower among Hispanic-American women or females from Oriental ethnic/cultural groups.

Table 118.3. Incidence and Mortality Rates of Breast Cancer by Race and Ethnicity in the United States, SEER, 1988–1992.

Table 118.3

Incidence and Mortality Rates of Breast Cancer by Race and Ethnicity in the United States, SEER, 1988–1992.

Risk Factors

The incidence of breast cancer varies substantially according to the presence or absence of certain well-established risk factors (Table 118.4).30,32,55–57 Among these factors, the two most prominent are gender and age.

Table 118.4. Risk Factors Associated with the Development of Breast Cancer.

Table 118.4

Risk Factors Associated with the Development of Breast Cancer.

Gender

Breast cancer is 100 to 200 times more common in women than in men, a ratio that is fairly consistent around the world.

Age

It is evident that the incidence of breast cancer increases dramatically with age, ranging from less than 10 cases per 100,000 women between the ages of 20 and 30 to more than 300 cases per 100,000 women over the age of 60.55,56 The median age at diagnosis of breast cancer in the U.S.A. is 64 years. In other parts of the world, where life expectancy might be shorter, the median age at which breast cancer develops is 10 to 15 years younger.43 Age-related mortality rates parallel this pattern.

Socioeconomic Class

Breast cancer is found more frequently in women of higher economic class and educational status. This finding is probably related to lifestyle factors such as diet, age at first childbirth, exogenous hormonal use, and alcohol consumption.

Ethnicity

Different ethnic groups have widely divergent incidence rates of breast cancer (see Table 118.3). Asian-Pacific groups have a much lower incidence of breast cancer, whereas groups of Northern European origin have the highest incidence. Studies have suggested that Jewish women, especially those with a family history of breast cancer in a first-degree relative, have a risk of breast cancer almost four times greater than that of women in other ethnic groups.58 In fact, it was recently shown that a single BRCA1 mutation can be found in as many as 1% of the Ashkenazi Jewish population.59–62 Studies of migrant populations have shown that when low-risk groups (e.g., Chinese or other Far-Eastern groups) move to high-risk regions (Hawaii or mainland U.S.A.), their incidence of breast cancer increases rapidly, approaching the rates of the host population within one or two generations.63

Family History/Genetics

Approximately one-third of women with breast cancer have one or more first-degree relatives with breast cancer.64 About 4 to 9% are considered to have hereditary breast cancer.64,65 Individuals with a first-degree relative having a history of breast cancer have a substantially increased risk of developing breast cancer themselves compared to women without such a family history.55,56,68–71 The identification and cloning of BRCA1 and BRCA2, two genes associated with familial breast (and ovarian) cancer, have highlighted the importance of taking a careful family history during the initial evaluation of breast cancer risk factors.72–76 Linkage analysis localized BRCA1 to chromosome 17q21 and loss of heterozygosity studies suggested that this gene acts as a tumor suppressor gene. BRCA2 was localized to chromosome 13q12. BRCA2 mutations are associated with early-onset breast cancer and male breast cancer but not ovarian cancer.62,73,77 The prevalence of BRCA1 mutations in high-risk families ranges from less than 20% to over 80% in different countries.78 The prevalence is higher in families with ovarian cancer or both ovarian and breast cancer. In population-based series of patients who had breast cancer diagnosed before age 35 years, BRCA1 mutations were detected in 6.2%.79 The great majority of BRCA1 mutations are found in individuals with moderate- to high-risk families. For those individuals with BRCA1 or BRCA2 mutations, the lifetime risk of developing breast cancer ranges from 40 to 80% (see Table 118.4). The characteristics of BRCA1-related breast cancers include earlier age at onset, lower diploidy rate, higher proliferative rate, higher mitotic counts, higher proportion of progesterone receptor-negative tumors, and more lymphocytic infiltration than sporadic cancers.80,81 BRCA2-associated cancers had lower mitotic counts, higher score for tubule formation, and greater proportion of continuous pushing margins than sporadic tumors.80 Despite the association with adverse prognostic characteristics, BRCA1-associated breast cancers have prognoses similar to or better than sporadic tumors of similar stage.80 Characteristic BRCA1 (185delAG, 5382insC) and BRCA2 (6174delT) mutations have been identified in Ashkenazi Jews; the combined frequency of these exceeds 2%.62,83 Familial breast cancer, however, accounts for less than 10% of all breast cancers, and BRCA1- and BRCA2-related familial breast cancers appear to be responsible for only two-thirds to three-quarters of these cases. Other genetic abnormalities and less common familial cancer syndromes (Li-Fraumeni and others) are responsible for an additional small number of breast cancers.69,84 The cloning of BRCA1 and BRCA2 and the presumed appearance of additional molecular genetic markers of risk have brought the issue of genetic screening and counseling to the forefront. Both negative and positive test results are associated with a variety of emotional, legal, economic, and work-related issues.71,86 Ongoing clinical trials are in the process of determining who the optimal subjects for screening are, how screening and counseling should be performed, and what approaches are needed to prevent unexpected risks and adverse consequences of genetic testing.

Endocrine and Reproductive Risk Factors

Numerous studies suggest a strong link between the female hormone estrogen and the development of breast cancer. In experimental, systems estrogen is required for optimal development of mammary carcinomas. Breast cancer is almost exclusively a disease of women and is rare in males. Ovarian ablation reduces dramatically the risk of mammary cancers in women and in experimental animals. Clinical reports suggest that the younger the age when ovarian ablation is performed, the greater the protective effect.87 Epidemiologic studies have demonstrated repeatedly that the absence of full-term pregnancies is a risk factor for breast cancer.32,57,70 Early onset of menarche, late onset of menopause, and greater number of years with ovulatory cycles have all been associated with an increased risk of breast cancer.88 Thus, women who start menses before the age of 12 have twice the incidence of breast cancer as do those who undergo menarche after age 12.89 This is probably related to longer exposure of the breast parenchyma to physiologic levels of estrogens. External influences that delay the onset of menses, such as poor nutrition or strenuous physical activity might, therefore, reduce the incidence of breast cancer.90,91 Some epidemiologic studies have suggested that delayed menopause is also associated with an increased incidence of breast cancer.87 Menopause occurring after age 54 increases risk of breast cancer two-fold, compared to the risk of women who have their menopause before age 45. Women who have their first full-term pregnancy before age 18 have an incidence of breast cancer that is one-third that of women who have their first pregnancy after age 35.87 In fact, women who have their first child after age 30 have a higher risk of breast cancer than nulliparous women. The probable mechanism for this apparent enhancement in risk might be the stimulatory effect of pregnancy (and its altered hormonal environment) on an otherwise involuting epithelium. Less established risk factors include the number of pregnancies, lactation, and spontaneous or induced abortion.32,92 When other important risk factors, such as age at first pregnancy, are considered, lactation has no effect on risk of breast cancer. However, epidemiologic studies have suggested that populations where long periods of lactation are customary have low risks of breast cancer. These conflicting results suggest that if lactation has an effect on risk of breast cancer, the effect is likely to be small.

Insulin-like growth factor type 1 (IGF-1) is a mitogenic peptide that enhances the proliferation of breast epithelial cells and is thought to have a role in breast cancer.93,94 A recent case-control study within the prospective Nurses’ Health Study cohort showed a positive relation between circulating IGF-1 concentration and risk of breast cancer among premenopausal women.95 This correlation was absent in the postmenopausal group. Additional studies to determine the potential clinical utility of this observation are needed.

Exogenous Hormones

The relationship of exogenous hormone replacement or oral contraceptives with risk of breast cancer has been under intense scrutiny for the past several decades.89,92,96–100 The composition of oral contraceptives has changed considerably over the years; the type and dose of estrogens, the presence or absence of a progestin, duration of administration, and age at onset all vary from study to study. Until recently, published studies have presented inconsistent and often contradictory conclusions. Both topics have been the subject of meta-analysis.

In a large meta-analysis, the Collaborative Group on Hormonal Factors in Breast Cancer found that current or recent use of hormone replacement therapy was associated with a modest increase in risk of breast cancer.101 The relative risk was 1.35 (i.e., a 35% increase) for women who had used hormone replacement therapy for 5 years or longer. On an annualized basis, this increase is comparable in magnitude with the effect on breast cancer of delaying menopause. Five or more years after cessation of hormone replacement therapy, there was no significant excess in breast cancer risk. The increase in the relative risk of breast cancer associated with long durations of use in current or recent users was greater for women of lower than of higher weight or body mass index.101 Cancers diagnosed in women who had received hormone replacement therapy tended to be less advanced clinically than those diagnosed in never-users.102 The increase in risk of breast cancer is substantially less than that for endometrial cancer associated with hormone replacement therapy. Whether hormone replacement therapy affects mortality from breast cancer is not known. These findings should be considered in the context of the known benefits (prevention of osteoporosis, reduction of cholesterol, preservation of cognitive function) and other risks (increased risk of endometrial cancer, thromboembolic complications) associated with the use of hormone replacement therapy.101,103 Over the past two decades, progestins have been added to estrogen replacement therapy to reduce the risk of developing endometrial cancer. Although this addition has succeeded in reducing the risk of endometrial cancer, the effect of this combination on breast cancer risk and cardiovascular risk factors requires further study.99,104–106

Recent, detailed analyses of the many epidemiologic studies correlating oral contraceptive use with risk of breast cancer have reached somewhat similar conclusions.107–109 Current or recent users of oral contraceptives have a small increase in the relative risk (RR) of having breast cancer (RR for current users = 1.24), but this excess risk disappears 10 years after stopping use. Women who began using oral contraceptives before age 20 had higher RRs of having breast cancer diagnosed. As was stated in relation to hormone replacement therapy, the cancers diagnosed in association with oral contraceptive use tended to be less advanced clinically than those diagnosed in never-users.108

The benefits of hormone replacement therapy are well defined and include a reduction in the risk of cardiovascular disease and osteoporosis.110–113 It has been calculated that the risk of a modest increase in breast cancer incidence is outweighed, by far, by the benefits in cardiac and osteoporotic risk.111,112 Whether such excess benefit also applies to women with a markedly increased risk of developing breast cancer, such as those with BRCA1 or BRCA2 mutations, remains to be established.

Abortion

Several recent epidemiologic studies suggested that a history of abortion correlated with a higher incidence of breast cancer.114–116 However, additional studies have not provided confirmation of these findings, and at the moment there is insufficient evidence to support the correlation of abortion with breast cancer risk.117–119

Physical Activity

Regular physical activity, especially during adolescence, has been associated with significant reductions in the risk of early onset of breast cancer in some studies.90,91,120 Strenuous exercise has profound effects on menstrual activity during adolescence.122 Exercise delays menarche and produces amenorrhea in ballet dancers and females participating in college athletic programs.122,123 Participation in even moderate levels of physical activity can significantly reduce the frequency of ovulatory cycles.91 Any factor that reduces the frequency of ovulation, and therefore the cumulative exposure to ovarian hormones, may reduce a woman’s lifetime risk of developing breast cancer. On the basis of this information, one might hypothesize that regular physical exercise during adolescence and early adulthood would be beneficial, even if its effect on reducing breast cancer risk remains unproven. The benefits of weight reduction, especially in postmenopausal women, are based on a solid hypothesis; in addition to the possible reduction in breast cancer risk, weight reduction may have other favorable effects on cardiovascular disease, osteoarthritis, and other chronic illnesses.

Environmental Factors, Obesity, and Diet

The incidence of breast cancer varies markedly throughout the world.32,53,87 There is a five- to six-fold difference in incidence between the United States and Western Europe (highest incidence) and most Asian countries (lowest incidence), with African, Latin American, and Southern European countries reporting an intermediate incidence.32,41,53 The incidence rates in some of the low-risk regions have been increasing over the past several decades. Furthermore, epidemiologic studies have indicated that immigrant groups from low- to high-risk regions evidence increasing incidence rates that approach those of the higher risk host region.63,124 These marked differences in incidence of breast cancer and the rapid changes in risk observed in migrant populations suggest that environmental factors might have a major influence on the risk of developing breast cancer; in fact, environmental factors might be more important than the influence of genetic factors, perhaps with the notable exception of the familial breast cancer syndromes.51 Variations in weight, height, and reproductive factors represent confounding variables in these studies. In addition, most confounding risk factors point to dietary differences between high- and low-risk regions.30,32,56,63,87126–128 Many studies have attempted to establish a correlation between dietary intake of animal proteins, total calories, animal fat, fiber, micronutrients, and risk of breast cancer.30,126,127,129,130–134 Most of the studies used more or less sophisticated epidemiologic techniques, but essentially all were retrospective in nature. Whereas some earlier studies suggested that increased caloric and saturated fat intake may be correlated with increased risk of breast cancer, more recent and definitive studies have failed to confirm this hypothesis.135–137 Ongoing laboratory and epidemiologic studies are attempting to assess the influence of dietary fiber intake on breast cancer risk.138–140 Studies in animal models point to the potential role of dietary fat in breast carcinogenesis.92,141–144 Even in preclinical experiments, there is ongoing controversy about the relative role of total caloric intake and saturated fat in mammary carcinogenesis.145,146 On the basis of these conflicting experimental and clinical data, one might conclude that the association between diet and risk of breast cancer is weak, at best, and possibly nonexistent. Nevertheless, substantial epidemiologic literature is the basis of the hypothesis that a high caloric intake, especially a high intake of saturated fats, might be linked to increased breast cancer risk. A corollary of such a hypothesis is that dietary modifications, which reduce the fat content of the diet substantially, will be associated with an equivalent decrease in breast cancer risk. Dietary interventions have been tested in preclinical animal experiments with mixed results. Depending on the model and animal species used, decreased caloric intake and a low-fat diet have been associated with a decreased risk of breast cancer or no change in the incidence of mammary carcinoma. Despite the lack of agreement on the impact of diet on the risk of breast cancer, there are currently several ongoing trials in which dietary interventions are being evaluated for breast cancer prevention.

Dietary interventions (mostly low-fat diets that limit daily caloric intake from fat to less than 15 to 20%) have proven feasible in preliminary or pilot studies.147–149 The lessons learned from these studies are being applied in large, controlled, multicenter cancer prevention trials.150,151 The Women’s Health Initiative is a randomized, placebo-controlled, multicenter trial involving postmenopausal women aged 50 to 79 years. Three different interventions were built into this study, one of which was designed to reduce fat intake to 20% of all caloric intake while increasing the intake of fruits and vegetables. Whether this modest reduction in dietary fat intake can result in a tangible reduction in breast cancer risk or not, the reduction in dietary fat may have salutary effects on cardiovascular disease and the prevention or control of other chronic illnesses. Because obesity in postmenopausal women is a risk factor that is associated with a greater risk of breast cancer, weight reduction should be encouraged in middle-aged and older adults, even in the absence of demonstrated clear-cut benefits in terms of reduction of breast cancer incidence because other health benefits may be associated with this intervention. These additional studies should clarify the role of diet in the etiology of breast cancer.

Obesity, which is related to diet, is associated with an increase in the frequency of estrogen-related tumors, such as cancer of the uterus and breast. The relation of body weight to breast cancer is complex. An inverse association between relative weight and breast cancer risk has been found among premenopausal women in most case-control and prospective studies.152,153 Obesity may reduce breast cancer risk slightly in premenopausal women through its association with anovulatory menstrual cycles. The relationship between body weight and postmenopausal breast cancer risk is less clear. In many case-control studies, body mass index has been positively associated with postmenopausal breast cancer.134,152,154,155 However, prospective studies have generally suggested only a weak, if any, positive association.156–158 This lack of a consistent positive association between body weight and risk of breast cancer is somewhat surprising. Postmenopausal women have higher estrogen levels resulting from greater conversion of adrenal androgens to estrogens in adipose tissue and they have lower levels of sex-hormone binding globulin, resulting in more free estrogen.159–161 Dietary fat reduction has been shown to reduce body weight and plasma estradiol concentrated in post menopausal women.162–165 This provides additional evidence in support of interventional studies to reduce chances of developing breast cancer. Other studies suggest that total body size, rather than weight-to-height ratio, and increased central-to-peripheral body-fat distribution may be more important than degree of adiposity.156,159

Alcohol Consumption

Several epidemiologic studies have found that women who drink alcohol are at increased risk of developing breast cancer.166–169 In multivariate analyses controlled for age, race, body mass, and smoking, the RR ranged from 1.5, for one to two drinks per day, to 3.3, for six or more drinks per day.170 There were no significant differences in this association depending on the type of alcoholic beverage. Early exposure to alcohol may be a key risk factor. Alcohol consumption in premenopausal women has been associated with increased total estrogen levels and bioavailable estrogens.171 The association of alcohol consumption and postmenopausal obesity with subsequent breast cancer risk might be mediated, at least in part, through alteration of plasma estrogen levels.163 Recent epidemiologic data suggested that the excess risk of breast cancer associated with alcohol consumption may be reduced by adequate folate intake.—172

Radiation Exposure

Exposure to ionizing radiation is a known risk factor for breast cancer. Atomic bomb survivors and patients treated with irradiation for postpartum mastitis, acne, hirsutism, or arthritic conditions all have an increased incidence of breast cancer, even after low or moderate radiation doses.87,173 Repeated fluoroscopic chest radiography, as used for monitoring the treatment of tuberculosis in the past, is also associated with increased risk of breast cancer.174 However, the risk of developing breast cancer as a result of common diagnostic radiologic procedures is minimal, and radiology technologists do not have an increased incidence of breast cancer.175 The incidence of breast cancer is also increased in patients who received radiotherapy with the mantle technique for Hodgkin’s disease.176,177 The adolescent and young adult breast appear most susceptible to the carcinogenic effects of ionizing radiation, but irradiation during infancy and childhood also increases breast cancer risk.178,179 The latency period between radiation exposure and the development of breast cancer is long (median 30 years). There is no evidence that therapeutic radiation administered to treat primary breast cancer would increase the risk of developing a contralateral breast cancer.

Environmental Factors

Cigarette smoking does not appear to be implicated in the development of breast cancer.180–182 Caffeine consumption may exacerbate benign breast disease, but it does not increase breast cancer risk.92 There is a substantial reduction in breast cancer risk among women with a high intake (as measured by excretion) of phytoestrogens—particularly the isoflavonic phytoestrogen equol and the lignan enterolactone.183 Although there is substantial interest in evaluating the influence of other occupational and environmental exposures on the risk of breast cancer, no definitive correlation has been found.

Benign Breast Disease

Benign breast disease includes a broad array of different, unrelated pathologic entities. However, a number of studies suggest that the presence (or history) of benign breast disease is associated with an increase in breast cancer risk.87,184–186 Other studies have found that women who have had a previous breast biopsy for benign disease are also at increased risk.187 However, this association is limited, to a large extent, to biopsy-proven lesions with histologic demonstration of atypia or proliferative lesions (atypical ductal or lobular hyperplasia)188,189 (Table 118.5). When compared with women who had never had a breast biopsy, women with benign breast disease without hyperplasia had an odds ratio of breast cancer of 1.5; women with hyperplasia without atypia had an odds ratio of 1.8, and women with hyperplasia and atypia had an odds ratio of 2.6 to 4.3.190,191 Although there has been ongoing controversy regarding the definitions used to diagnose these various pathologic entities, there has been growing consensus among pathologists to adopt the classification proposed by Page et al.184,192 In this system, the joint occurrence of family history of breast cancer and atypical hyperplasia had a strong synergistic effect on breast cancer risk. Women with papillomas with atypical hyperplasia and those with fibroadenoma also have increased risk of breast cancer.193,194 Most other forms of benign breast disease appear to be unrelated to an increased breast cancer risk. Therefore, the majority of women with lumpy breasts, and most of those with benign breast disease, do not have a significantly increased risk of breast cancer.

Table 118.5. Relative risk* of Invasive Breast Carcinoma Based on Histologic Examination of Breast Tissue Without Carcinoma.

Table 118.5

Relative risk* of Invasive Breast Carcinoma Based on Histologic Examination of Breast Tissue Without Carcinoma.

Mammographic Parenchymal Pattern

In 1976, Wolfe proposed that mammographic parenchymal patterns are predictive of breast cancer risk.195 The P2 pattern, defined as prominent ducts occupying 25% or more of the breast volume, and the DY pattern, characterized by irregular, sheet-like radiographic densities, pose the highest risk. Subsequent studies have been inconsistent in confirming this observation, perhaps because of a lack of standardization and poor reproducibility in accurately classifying mammograms.92,196,197 Nevertheless, the cumulative data suggest that the P2 and DY patterns are moderate risk factors for breast cancer.

Other Risk Factors

Several other factors that influence the risk of breast cancer have been reported.87,92,198,199 Patients with a previous history of ovarian, uterine, or bowel cancer have a higher breast cancer risk. Mothers of children with soft-tissue sarcoma have been reported to have a two- to three-fold increased risk of breast cancer.200 Caffeine consumption does not increase breast cancer risk, and its ability to exacerbate the symptoms of benign breast disease remains unproven.92 Recent studies suggesting that various psychosomatic factors increase breast cancer risk need confirmation,201 as does the recent report suggesting that exposure to extremely low-frequency electromagnetic fields causes an excess in mortality from breast cancer.202

Combinations of Factors

Although the factors described above have been shown to have an independent effect on the relative risk of developing breast cancer, their interrelationship requires further investigation. Several investigators have developed modeling techniques using statistical methodology to combine several risk factors into one model, enhancing the sensitivity and predictive value of risk assessment (Table 118.6).203–210 These models are currently being used to determine their value in the identification of high-risk patient groups for more efficient mammographic screening programs and cost-effective genetic screening programs. In the recently reported Breast Cancer Prevention Trial (BCPT), the Gail model was used for selecting eligible patients. The model accurately predicted the incidence of breast cancer in the placebo group, providing additional support to the usefulness and reproducibility of this predictive tool. These models also provide the possibility to calculate absolute benefit or risk of an intervention for individual subjects. The selection of an individual prediction method depends on characteristics of the woman’s family history and the medical decision being considered. The National Cancer Institute (NCI) is distributing the Gail model, as used in the NSABP BCPT, in an electronic format, the Risk Disc.

Table 118.6. Risk Model and Associated Relative Risks*.

Table 118.6

Risk Model and Associated Relative Risks*.

Breast Cancer Biology

Regulation of Breast Cancer Growth

The adult female breast is composed of epithelial lactiferous ducts terminating in secretory alveoli embedded in a fibrous tissue framework and fat. Normal breast growth and development are regulated by the complex interaction of many hormones and growth factors, some of which are secreted by the mammary cells themselves and may have autocrine functions. Others are produced by stromal cells and generate paracrine controls on epithelial cells.211 These hormones include estrogens, progesterone, androgens, glucocorticoids, prolactin, thyroid hormone, insulin and IGF-1 and IGF-2, fibroblast growth factors, and epidermal growth factor (EGF)/transforming growth factor alpha (TGF-α).212–216 Estradiol modulates epithelial tumor cell morphology and tumor growth. Breast growth and development may also be influenced by epithelial growth inhibitors, such as TGF-β and mammastatin.217 Estradiol regulates the expression of several genes corresponding to peptides and proteins involved in mammary cell growth control mechanisms. Effects of these growth factors and hormones are triggered by binding to specific receptors. Polypeptide hormone receptors are typically located on the cell membrane, whereas receptors of the steroid hormone family are found in the interior of the cell or nucleus. The interaction of growth factors, cytokines, and hormones with specific membrane receptors triggers a cascade of intracellular biochemical signals, resulting in the activation and repression of various subsets of genes. Several of these hormones have been shown to play an active role in breast epithelial cell growth and development and in lactation. Since normal breast tissue is regulated by these hormones and their receptors, it is not surprising that malignant cells arising from breast tissue might also express receptors for many of these hormones and might retain some degree of hormonal dependence. Numerous studies using cultured cells, as well as human breast cancer tissue, have demonstrated the presence of receptors for several of these hormones in human breast cancer cells, and investigators have begun to unravel the mechanisms by which hormones and growth factors regulate breast cancer cell proliferation. Genetic aberrations in growth factor signaling pathways are inextricably linked to developmental abnormalities and to a variety of chronic diseases, including cancer. Malignant cells arise as a result of a stepwise progression of genetic events that include the unregulated expression of growth factors or components of their signaling pathways.

Growth regulation of breast cancer cells by hormones and growth factors is shown schematically in Figure 118.15. The biological role of estrogens is mediated through high-affinity binding to the ER that belongs to a family of ligand-inducible nuclear receptors that have steroid and thyroid hormones and vitamins as known ligands.218,219

Figure 118.15. Growth regulation of breast cancer by hormones and growth factors.

Figure 118.15

Growth regulation of breast cancer by hormones and growth factors. E = Estrogen; Pg = progesterone; Pr = prolactin; I = insulin; IGF’s = insulinlike growth factors; EGF = epidermal growth factors; TGF-α = transforming growth factor alpha; (more...)

Recent studies suggest that breast cancer cells under estrogen control can synthesize and secrete their own growth factors that could autostimulate breast cancer cells or adjacent stromal tissues through autocrine or paracrine mechanisms.220 Stromal tissues may also secrete growth factors, such as IGF-1 and IGF-2, that can stimulate the breast cancer cells. Potential autocrine/paracrine growth factors identified include EGF, TGF-α, IGF-2, platelet-derived growth factor, and fibroblast growth factor. EGF, TGF-α, and IGF-2 have been found to be expressed and secreted by cultured breast cancer cells and by human breast cancer tissue specimens.221–223 They are potential mitogens for the epithelial (malignant) component of the tumor. Platelet-derived growth factor and fibroblast growth factor are secreted by breast cancer cells and may be responsible for the proliferation of the mesenchymal stromal component evident in many breast cancers.224,225

Several peptides that may have autocrine inhibitory activity are also secreted by human breast cancer cells. TGF-β is a family of growth factors that inhibit the proliferation of epithelial tissues and stimulate the proliferation of stromal tissues.226–229 Studies suggest that ER-negative breast cancer cells are more sensitive to TGF-β than are cells containing ER.230 The malignant potential of breast cancer is likely to depend on the balance between growth stimulators and growth inhibitors produced by the tumors. The epithelial and/or stromal cells within the tumor also secrete proteases, such as the cathepsins, stromelysin, gellatinases,231 or urokinase plasminogen activator, which may contribute to tumor invasiveness and metastatic potential.232–237

In ER-positive breast cancer cells, expression and secretion of certain autocrine growth factors, such as TGF-α and IGF-2, are stimulated by estrogen and inhibited by antiestrogens.216,220 In ER-negative breast cancer cells, secretion of these factors is not estrogen regulated. Investigators have hypothesized that changes in the expression of these secreted factors may mediate to some extent the growth effects of estrogens and antiestrogens. Estrogens and antiestrogens have a variety of other effects on breast cancer cells. Estrogen stimulates RNA, DNA, and protein synthesis and the activity of key regulatory enzymes.238 Antiestrogens have the opposite effects. Estrogens ultimately regulate movement of the cells through the cell cycle and mitosis. Cell kinetic studies suggest that antiestrogens, such as tamoxifen, slow the transit of cells through the cell cycle by causing a block in the G1 phase.239

Disturbance of normal growth control mechanisms within a cell can result in uncontrolled cell division and the development of cancer. Such cellular transformation occurs through the activation of oncogenes, loss or mutation of tumor suppressor genes, or both.240,241 The normal counterparts of oncogenes, termed proto-oncogenes, function as growth regulators in normal cells. Alterations of proto-oncogenes are associated with the initiation, promotion, and/or maintenance of tumors in animals and humans. In addition to polypeptide growth factors and their receptors, breast cancer cells have been shown to express several oncogenes, that is, genes involved in normal regulatory processes that, when overexpressed, can induce or promote the malignant phenotype.242–244 The products of oncogenes are frequently growth factors or growth factor receptors. Oncogenes found to be expressed in human breast cancer tissue include members of the myc and ras family (c-myc, Ha-ras-1), int-2, which is involved in mouse (and, presumably, human) mammary gland carcinogenesis; the members of the EGF receptor (EGFR, erb B) family, including erb B-2 (or HER2 or neu), HER3, and HER4. Overexpression of growth factor receptors often leads to constitutive activation of these receptors (i.e., signaling in the absence of their cognate ligands). Growth-promoting signals may be continuously transmitted into the cells, resulting in activation of multiple intracellular signal transduction pathways and unregulated cell growth. Genes normally involved in cell cycle control, especially members of the cyclin D family, may also function as oncogenes. Overexpression of these oncogenes may contribute to the initiation and maintenance of the malignant phenotype. Tissue-specific expression of myc, ras, and HER2 in mammary glands of transgenic mice has been shown to result in an increased incidence of both benign and malignant breast pathology.245–247 Altered expression of these otherwise normal genes can have profound effects on growth homeostasis of breast epithelium. Recent studies have shown that blockade of these growth factor receptors or pathways has therapeutic implications.247–255 These studies have shown that, both in preclinical models and in human breast cancer, monoclonal antibodies to EGFR or HER2 have dramatic antitumor effects. Furthermore, these antibodies have synergistic interactions with cytotoxic agents, such as the anthracyclines, the platinum analogs, and the taxanes.248,256,257 Quantification of the expression of these oncogenes in human breast cancer specimens has been shown to provide valuable information on tumor aggressiveness, prognosis, and possibly sensitivity to therapy.258–265 bcl2 is another gene frequently overexpressed in breast cancer; its overexpression is associated with unfavorable prognosis and decreased responsiveness to cytotoxic therapy.266–268

Tumor suppressor genes (or antioncogenes) may also play a role in breast carcinogenesis. Loss of the normal “suppressor” function of these genes through mutations or deletion may cause cancer. Alterations in two known suppressor genes, the retinoblastoma gene (RB1) and the human P53 gene, have been identified in human breast cancer cells, as well as in other solid tumors.269–278 Mutations in the P53 gene have been found in families with the Li-Fraumeni syndrome, who have a markedly increased incidence of breast cancer and other neoplasms.276 The two genes associated with familial breast cancer, BRCA1 and BRCA2, are also thought to function as tumor suppressor genes under normal conditions. The normal function of the protein products of these genes is to control cell proliferation (RB1 and P53) or facilitat/mediate DNA repair (P53, BRCA1, BRCA2). Mutations then lead to dysregulated transit of cells through the cell cycle. Recognition that mutational inactivation of suppressor genes is associated with breast cancer could lead to early recognition of high-risk families, as well as to new treatment strategies to reverse the malignant phenotype by introducing normal gene copies through gene therapy or by treatment with the normal suppressor protein itself. Such strategies are under active investigation, both in the laboratory and in early clinical trials.275,279,280

Estrogen and Progesterone Receptors

The human ER is located on chromosome 6q24-q27281; it is a large and complex gene, giving rise to two transcripts.282 The ER is composed of six regions. The central C region encodes a DNA-binding domain and is flanked on either side by two independent activation domains (AF-1 and AF-2).283,284 The AF-1 domain can activate transcription constitutively when bound to DNA through the DNA-binding domain of the ER or through a heterologous DNA-binding domain. In contrast, the AF-2 domain overlaps the hormone-binding domain and activates transcription only when it is bound by estradiol or another estrogen agonist. The different activities of AF-1 and AF-2 are mediated by adaptors or co-activators that are specific to one or the other of the domains.285,286 Estradiol and tamoxifen induce different conformations of the hormone responsive domain/AF-2 region of ER. This may account for the differential ability of estrogens and antiestrogens to activate the AF-2 transactivation function. A second member of the ER family (ER-β) was recently identified and cloned.287 The tissue distribution and/or the relative level of ER-α and ER-β expression seems to be quite different.288 There are also differences between the ER subtypes in relative ligand binding affinity. These differences in binding affinity and tissue distribution could contribute to the selective action of ER agonists and antagonists in different tissues. Estrogen stimulates proliferation of cells that express the ER. Estrogen diffuses freely across the cell membrane and binds ER, leading to ER dimerization and to tight binding to its specific DNA target, the estrogen responsive element (ERE). After ERE binding, transcription of new mRNA is activated. Certain estrogen-induced proteins, such as PsR, are important for specific metabolic processes in the cell. Other estrogen-induced proteins regulate events leading to cell proliferation. When receptors are bound to antiestrogens such as tamoxifen, transcription of growth-promoting genes is blocked, although other genes might be activated by tamoxifen.

Assays for ERs and PgRs are helpful in selecting the patients most likely to benefit from endocrine therapy, and they provide prognostic information on recurrence and survival, since their expression is related to the degree of tumor differentiation.

Both ER and PgR are nuclear proteins that can be measured in intact cells or tumor extracts by several assay techniques. However, most earlier techniques have been replaced by immunohistochemical (IHC) or immunocytochemical assays.289–291 The availability of monoclonal antibodies that recognize human ER or PgR circumvents many of the shortcomings from earlier biochemical assays. In addition, IHC can be performed in small tissue or cytologic specimens, is not affected by endogenous hormone levels, and displays the cellular heterogeneity of receptor expression; it can be used on fresh or archival (paraffin-embedded) tissues. The results of IHC assays correlate well with quantitative enzyme-linked immunoassay techniques and those of the older biochemical assays. More importantly,280 the results of IHC correlate well with response to hormonal therapy and prognosis.292,293 The remaining disadvantage of IHC is that it is only semi-quantitative; the scoring of slides is subjective and requires a trained histopathologist. Nevertheless, because of the simplicity and reproducibility of the assay, it is considered the assay of choice for ER and PgR today.

ERs are detected (or expressed) in 60 to 80% of breast cancer samples, depending on the assay used and the clinical characteristics of the tumor and patient.294 The ER concentration varies widely from tumor to tumor (from 0 to over 1,000 fmol/mg protein). Higher ER levels are seen in postmenopausal patients. Assays performed on primary tumors are more frequently ER positive than assays done on metastatic lesions, especially those obtained from visceral metastases. This probably reflects the greater propensity for ER-negative tumors to metastasize to visceral organs. ER positivity also correlates with histologic demonstration of differentiation (i.e., low nuclear grade), with diploid DNA content, and with low proliferative indices (low SPF or Ki-67 expression). ER expression is inversely correlated with HER2 and EGFR expression.295–300 These associations may explain the prognostic significance of ER status.

An important application of the ER assay is the selection of appropriate patients for endocrine therapy. Approximately 50 to 60% of patients with ER-positive tumors benefit from endocrine therapy.301,302 This percentage includes patients who achieve a major objective remission (partial or complete) and those who derive long-term (> 6 months) stability of the disease with endocrine therapy; both groups have equivalent survival expectations. The ER status predicts equally well for all modalities of endocrine therapy. Patients with no detectable ER in their tumors respond infrequently (<10%) to endocrine therapy. Patients who have borderline but detectable ER in their tumors have higher rates of response to endocrine therapy than do those in whom tumor ER is undetectable. This may explain why some patients with “ER-negative” tumors have been reported to benefit from adjuvant tamoxifen therapy. It is not known why 40 to 50% of ER-positive tumors fail to respond to hormonal therapy despite the presence of receptor. Quantitative ER assay and the simultaneous determination of PR expression increase the predictive accuracy of these assays. Tumors with high ER concentration (greater than 100 fmol/mg protein or strong, homogeneous staining) or those positive for both ER and PgR have the highest probability of response and clinical benefit from hormonal therapy.303,304 Tumor ER and PgR status can change over time or with intervening therapy; thus, repeat biopsies of accessible tissue may be helpful in selecting sequential therapies. However, ER status on the primary tumor still predicts reasonably well for endocrine response at the time of relapse. Although there is a modest trend for higher response rate to chemotherapy in ER-negative patients, receptor status is not helpful in predicting response to chemotherapy. Clearly, an assay that would identify truly hormone-insensitive tumors would be more clinically useful. Variant and/or mutated ERs have been identified in breast cancer tissue.305 Some of these altered receptors are constitutively active (activate transcription in the absence of estrogen), some are inactive, and some have dominant negative activity. The biologic importance of these variants and their role, if any, in hormone-resistant states remains to be clarified.

Natural History and Prognostic Markers

The natural history and prognosis for primary breast cancer vary considerably from patient to patient. Some patients present with very indolent disease and either are cured by local therapy or survive for many years even after developing metastases. A small percentage of patients survive more than 10 years without any treatment.125,306 In other patients, the disease follows an aggressive, rapidly progressive course that is refractory to treatment.

The heterogeneity in the clinical course of breast cancer is mirrored by great variability in measured doubling time and other cell kinetic parameters. In general, human breast cancer has a low growth fraction (proportion of cells in the active cell cycle) compared with many other tumors, with estimated values ranging from 5 to 30%, depending on the method used.307–310 The SPF in rapidly growing tumors, such as testicular cancer or high-grade lymphomas, may exceed 50%.

Estimated tumor volume doubling times for primary human breast tumors are also prolonged. In one retrospective study, 147 tumors observed to grow on serial mammograms were evaluated.311 Doubling times ranged from 44 to more than 1,800 days, with a mean of 212 days. Another, similar study reported a mean tumor volume doubling time of 325 days (range, 109–944 days) in 32 primary tumors.312,313 It is not possible to determine the growth rate of breast cancers in their preclinical (microscopic) stage, but if one assumes that a cancer begins with a single cell and grows with a constant doubling time of 200 days, a tumor would need about 20 years of growth to reach 1 to 2 cm in diameter. A tumor with a faster doubling time of 100 days would still require 10 years to become clinically detectable, and a remarkably fast-growing tumor (doubling time of 20 days) could possibly have originated just 2 years earlier. Similarly, a 2-mm tumor with an average doubling time would require about 4 years of growth to reach a size of 1 cm. These growth calculations assume logarithmic growth, whereas Gompertzian growth models indicate that growth rates are not constant throughout the life history of the tumor and that preclinical latency may not be so long. Metastatic lesions may have a slightly faster average rate of growth than primary tumors.314 Although these calculations demand certain assumptions, they suggest that a significant period of preclinical growth precedes the detection of most breast cancers. These observations may explain the relatively poorer prognosis recorded in several studies for very young women (less than 35 years old) with breast cancer. These women may have a higher proportion of faster growing, more aggressive tumors, since indolent, slowly growing tumors would not have had time to become clinically evident by that age. These data also suggest that, since most tumors have had a prolonged preclinical life of at least several years, delays in diagnosis of only a few months from the first symptoms of primary breast cancer are unlikely to have a major impact on the presence or absence of metastases or ultimate patient survival. It has been estimated that only 5% of patients would be adversely affected by delays longer than 3 months. Even if primary tumors were diagnosed and treated a full year earlier, only a 30% reduction in the percentage of patients with metastases would result.315,316 These estimates are compatible with the documented benefits of mammography screening programs, which detect microscopic, nonpalpable early breast cancers in many patients. Some would also argue that these data are compatible with the concept of biologic predeterminism, which states that treatment outcome is predetermined by the biologic nature of the disease and that only a small number of tumors metastasize (if they have not already done so) after they have become clinically detectable.315,317,318

The heterogeneity of breast cancer’s natural history complicates patient management. Obviously, patients with virulent, fast-growing tumors might be treated aggressively because of their poor prognosis, whereas other patients with indolent tumors might be spared the morbidity and cost of excessive interventions when their disease is unlikely to compromise survival. A major focus of research in recent years has been the identification of tumor or host factors that would accurately predict patient outcome. The ideal prognostic marker would be one that, if expressed by the tumor, signified early metastases and short survival. Tumors not expressing the marker would be associated with an indolent course, the absence of metastases, and prolonged survival in nearly all patients. Although the ideal prognostic factor does not yet exist, a number of variables have been identified that can help to identify patients according to their RR for recurrence (Table 118.7).319–322 These factors attempt to measure and quantify the degree of tumor differentiation, tumor aggressiveness or metastatic potential, rate of growth or sensitivity/resistance to planned treatment. Some of the markers shown on Table 118.7 are old and well established; others are new and must be considered investigational until definitive evidence supports their clinical utility.

Table 118.7. Prognostic Factors in Breast Cancer.

Table 118.7

Prognostic Factors in Breast Cancer.

After surgery has been completed and the total breast (or tumorectomy) and axillary dissection specimens have been examined and evaluated by the pathologist, a number of important prognostic indicators are used to determine whether additional therapy is necessary and potentially useful (see Table 118.7). Indicators that have been demonstrated to have reproducible prognostic value are defined below.

Age and Menopausal Status

Both patient characteristics have been extensively evaluated. When other, more important tumor characteristics are considered, age and menopausal status are not important prognostic indicators. A large study with long follow-up indicated that women 45 to 49 years of age had the best prognosis and that the very young (those under age 35 years) or elderly patients had the worst breast cancer survival.299,323–325

Axillary Lymph Node Involvement

Involvement of the ipsilateral axillary lymph nodes is still the most reliable and reproducible prognostic indicator for primary breast cancer (Table 118.8).327–330 In general, 50 to 70% of patients with positive lymph nodes have a relapse, whereas only 20 to 35% of patients with all lymph nodes negative for metastatic disease have a relapse after loco-regional treatments only. The risk of tumor recurrence in a patient with primary breast cancer is a continuum related to the number of positive axillary lymph nodes (see Table 118.8).327 With each additional positive lymph node found, the risk of recurrence and metastasis increases by a few percentage points. Thus, patients with 4 to 10 positive lymph nodes have a greater risk than those with 1 to 3 positive nodes, and those with 10 or more positive nodes have a greater than 80% probability of recurrence and metastasis. Because nodal status cannot be accurately assessed by clinical means, an axillary lymph node dissection, including levels I and II, is considered the standard of care. Clinical studies have demonstrated that lymph node negativity is reliable only if at least 6, but preferably 10, axillary lymph nodes were removed and examined. Both macro- and micrometastasis within the lymph nodes have similar prognostic significance.330–332 In recent years, primary breast cancer has been diagnosed in earlier and mostly localized stages. A classic axillary lymph node dissection has no therapeutic effect for patients with node-negative axilla and is associated with considerable short- and long-term morbidity. An alternative (diagnostic) staging procedure for these patients is the sentinel lymph node biopsy.333,334 This procedure limits considerably the extent of the surgical procedure in the axilla and, for the great majority of patients with negative axillary lymph nodes, precludes the need for a formal axillary dissection while providing similar (and in some cases superior) diagnostic and prognostic information. The identification of a single (or just a couple of) sentinel node also permits the pathologist to perform a more detailed assessment to detect micrometastases by combining light microscopy, IHC, and even more sensitive molecular techniques.335 The prognostic significance of identifying isolated metastatic cells in histologically negative lymph nodes by more sensitive techniques is still undetermined. Sentinel node biopsy and assessment are under extensive evaluation. The technique is making substantial inroads in the practice of breast surgery. Whether, and to what extent, it will displace or replace classic axillary dissection for early localized breast cancer remains to be determined.

Table 118.8. 5-Year Breast Cancer-Specific Mortality Rates According to Tumor Size and Axillary Lymph Node Involvement*.

Table 118.8

5-Year Breast Cancer-Specific Mortality Rates According to Tumor Size and Axillary Lymph Node Involvement*.

Although axillary lymph node status is still the most powerful prognostic indicator, 15 to 45% of patients whose lymph nodes do not contain metastases will experience a recurrence and die. Conversely, up to 15% of patients with >10 positive lymph nodes will survive without recurrence or metastases. Because of this limitation, other prognostic markers have been developed to improve prognostic accuracy, particularly in the group of patients with node-negative tumors.

Tumor Size

In addition to being a determinant for optimal local therapy, tumor size has prognostic significance in the determination of additional therapy (see Table 118.8). As the size of the tumor increases, the risk of recurrence or metastasis also increases, for both lymph node-negative and node-positive tumors. Since the risk of treatment failure is already high for patients with node-positive breast cancer, increasing tumor size adds relatively little prognostic value. However, tumor size is often the main prognostic indicator in node-negative breast cancer. This variable is particularly important in the decision to use or not to use adjuvant systemic therapy in patients with node-negative breast cancer. Tumor size refers only to the invasive component and should be determined in all three dimensions by the pathologist. Approximately 20% of patients with negative lymph nodes and a primary tumor less than 2 cm in diameter will experience a recurrence within 20 years of follow-up.316,318,336,337 Patients with tumors 1 cm or less in diameter have an excellent prognosis, with less than 10% recurring at 10 years and only 12% by 20 years.337,338 The largest database demonstrating the relationship among tumor size, lymph node status, and breast cancer survival comes from the Surveillance, Epidemiology, and End Results (SEER) program (see Table 118.8).339 Less than 2% of patients with tumors under 1 cm and negative nodes died of breast cancer within 5 years. Considering the excellent prognosis for this group of patients with very small tumors, as well as the expense and toxicity of treatment, routine use of chemotherapy is not indicated. The combination of poor nuclear grade and lymphatic vessel invasion identifies a small subset (approximately 10%) of patients with T1a, b N0 M0 breast cancer with a significant risk of relapse, in the 30 to 40% range, that warrants consideration of systemic adjuvant therapy.340

Histologic Variables

Several histologic variables have been reported to have prognostic significance (Table 118.9).118 Most invasive breast cancers are ductal (NOS)341 The prognoses of ductal and lobular carcinomas are similar enough to prompt the same treatment modalities. However, there are several cancers that are less common but have more favorable prognoses.342 These include pure tubular carcinoma, mucinous or colloid carcinoma, papillary carcinoma, and all noninvasive breast cancers. These cancers have substantially better prognoses, especially when found in a node-negative stage.337,343–345 The more favorable prognosis of these histologic types often justifies omission of adjuvant systemic treatment, especially for small tumors (less than 3 cm). Since most of these special types have small dimensions when diagnosed and are node negative, regional treatment is usually all that is required. When stringently defined, medullary carcinoma is also considered to have a better prognosis by some but not all experts.346–348 Pure or typical medullary carcinomas, when associated with negative axillary lymph nodes, have been reported to have better prognoses than ductal or lobular carcinomas. The magnitude of this difference, in terms of 10-year survival, was reported to be 17%.346 However, atypical medullary carcinomas (those that do not fulfill the necessary histological criteria) or mixed medullary and ductal carcinomas have prognoses similar to those for the common varieties of ductal and lobular breast cancers.346

Table 118.9. Histologic Variables Associated with a Lower Risk for Recurrence.

Table 118.9

Histologic Variables Associated with a Lower Risk for Recurrence.

Histologic Grade or Differentiation

In general, tumors expressing features that indicate a high degree of tumor differentiation have the most favorable prognosis. The literature is inconsistent, however, on the prognostic importance of many of these variables, possibly because of the subjectivity of histologic assessment, the retrospective nature of most studies, and the lack of sophisticated statistical analysis. The clear definition of various histologic differentiation grades led to the recognition that those grades had reproducible prognostic significance. Trained, experienced breast pathologists can recognize poorly differentiated, moderately well-differentiated, and differentiated tumors without much difficulty; the assessment of the histologic grade for those tumors is quite reproducible.349 Furthermore, although there is some variation among different pathologists, the concordance rate is quite acceptable.350 Recent reports based on the SEER tumor registry provided strong evidence supporting the prognostic value of histologic grade determined by “average” pathologists.339 Something similar can be said for nuclear grade, although some find that histologic grade is a more reliable prognostic indicator because it includes cellular and tissue-related criteria. Well-differentiated histologic types, such as tubular, papillary, or colloid (mucinous), have a lower incidence of axillary nodal metastases and a lower risk of distant recurrence than the more common infiltrating ductal carcinomas.342,351 It should be emphasized that pure noninvasive ductal (DCIS) or lobular carcinomas (LCIS) have very low risk for axillary lymph node involvement and virtually no risk for distant metastases. These lesions do not require systemic adjuvant therapy. However, recent results from clinical trials suggest that the addition of tamoxifen to optimal locoregional therapy reduces the risk of local recurrence and the incidence of second primary breast cancer after noninvasive cancers. The histologic and nuclear grades of tumors have been consistently reported to have prognostic significance, especially in patients with negative nodes.351,352 Less than 20% of such patients having well to moderately well-differentiated (grade I or II) tumors experience a recurrence in 5 years, compared with more than 30% for those with poorly differentiated tumors. Similar results have been reported with nuclear grade. Nuclear grade can be determined in cytologic specimens. Smaller tumors are more often well differentiated, whereas larger tumors are predominantly poorly differentiated. Tumor differentiation is also associated with other prognostic indicators such as ER expression, PsR expression, ploidy, and SPF.

Angiogenesis Markers

In recent years, it has become evident that angiogenesis plays a substantial role in the growth and spread of malignant tumors.353 Consequently, markers of angiogenic activity have received increasing attention. Counting the number of tumor capillaries immunohistochemically after staining for factor VIII has been shown to have major prognostic value. Tumors with fewer capillaries have a lower metastatic potential and better prognosis.354–359 Variations in methodology have led to conflicting results, although the weight of the evidence favors the strong prognostic value of angiogenesis. Markers of angiogenesis have also become putative therapeutic targets.356

Markers of Proliferative Capacity

Measurement of the proliferation rates of malignant tissues has strong prognostic value for several types of cancer, including breast cancer. Several techniques are used to evaluate the proliferative capacity of the malignant cell, including mitotic indices, thymidine labeling indices (TLIs) and SPF, and the measurement of proteins expressed preferentially during active phases of the cell cycle. The mitotic index is determined by counting mitotic figures using light microscopy on a tumor specimen stained with hematoxylin and eosin. It is a technique well within the capabilities of any surgical pathology laboratory, and it has been validated by both univariate and multivariate analyses.360–362 In addition, the mitotic index is an integral component of the Nottingham prognostic index and other successful prognostic indices of reproducible value. Although the TLI has also been proven to be effective and reproducible, it is much more labor intensive and, for this reason, has not gained general acceptance.310,363 The most commonly used method of evaluating proliferation capacity in the United States is the determination of SPF by flow cytometry.299,364 This technique can be performed in both fresh or frozen tissues and in archival material. It also provides information about DNA ploidy. For both TLI and SPF, a low value indicates a more slowly proliferating tumor and is associated with a slower rate of recurrence, regardless of axillary nodal status. A high SPF is strongly correlated with other adverse prognostic factors such as poor histologic and cytologic grades, aneuploidy, and a negative steroid receptor status. In experienced hands, when using cutoff points validated by the laboratory’s own experience, the SPF has independent prognostic value (Table 118.10). The cumulative data suggest that SPF is of greater prognostic value than ploidy status. Multivariate analyses indicate that SPF is one of the most important prognostic factors in primary breast cancer. Many experts use SPF determination for treatment-related decisions, especially in the case of axillary lymph node-negative breast cancer. However, there is no general agreement on the clinical usefulness of SPF as a criterion to determine whether adjuvant therapies are warranted.

Table 118.10. Evaluation of the Prognostic Value of S-Phase Fraction (SPF) Performed by DNA Flow Cytometry in Patients with Negative Axillary Lymph Nodes.

Table 118.10

Evaluation of the Prognostic Value of S-Phase Fraction (SPF) Performed by DNA Flow Cytometry in Patients with Negative Axillary Lymph Nodes.

Many proteins play a role in the control of the cell cycle or are expressed at higher levels during certain phases of the cell cycle. Ki-67, MIB1, and proliferating cell nuclear antigen (PCNA) are additional markers for the proliferation rate of malignant tumors.307,365–368 Of these, Ki-67 has been more extensively studied, and it correlates strongly with the results of SPF determination and therefore long-term prognosis. The usefulness of PCNA requires additional evaluation. Other proteins, including mitosin, Ki-S1, and the various cyclins, are currently under evaluation.369,370

Steroid Hormone Receptors

Both the ER and the PsR have been extensively studied in patients with primary breast cancer.302 Both clearly have prognostic value, although their ability to discriminate between low- and high-risk patients is quite limited. Patients with ER-positive tumor tend to have a more indolent course and to metastasize preferentially to soft tissue and bone; conversely, those with ER-negative tumors relapse earlier, and metastases to liver, lung, and central nervous system are more likely. ER-positive tumors are more often well differentiated and are associated with other favorable prognostic characteristics. Although patients with ER-positive tumors tend to have better short-term disease-free and overall survival rates than do patients with ER-negative tumors, the differences between the two groups tend to diminish or even disappear with time.371 Although high levels of receptor expression are predictors of a favorable response to endocrine therapy, some studies have suggested that very high levels of receptor may be associated with worse prognosis, compared to lower ER concentrations.372 In patients with negative axillary lymph nodes, ER status is a weak discriminant between high- and low-risk patients.373 The differences in outcome between the ER-negative and ER-positive, node-negative groups are of insufficient magnitude to base treatment decisions on receptor data alone. Receptor data may be of greater value when combined with other prognostic factors.

PsR appeared in some studies to be a more valuable prognostic indicator than the ER. Evaluation of both receptors, previously performed mostly by ligand binding assays, is currently done by IHC or immunocytochemical methods with a high degree of reliability. The assessment of the prognostic value of steroid hormone receptors has been complicated by the multiplicity of assay techniques used and the time dependence of their prognostic information. The best use of steroid hormone receptors is not in the determination of prognosis but in the prediction of response after systemic therapy and therefore the selection of optimal adjuvant systemic treatments.

PS-2

The presence of the PS-2 protein has been suggested to reflect the functional status of the ER and therefore the expression of an intact hormone receptor pathway.374,375 Although initial reports were encouraging, additional studies need to be performed to determine PS-2’s independent prognostic value and its usefulness when added to other known prognostic indicators. Furthermore, it remains to be proven whether PS-2 adds to the prognostic or predictive information provided by the ERs and PsRs, or if it can be a reliable substitute for the receptor assays.

Molecular Genetic Alterations

It is well accepted that malignant tumors develop as a consequence of multiple critical gene abnormalities. These occur as a consequence of oncogene activation, loss of function of tumor suppressor genes, or alterations of other genes critical for cell control mechanisms. Two members of the type I growth factor receptor family, the EGFR (or HER1) and HER2/neu, are frequently amplified and/or overexpressed in breast cancer.264,376 Overexpression of the proteins encoded by these genes is associated with a more aggressive clinical course, including a higher risk of developing metastases and more rapid growth and tumor progression.377,378 HER2 is overexpressed in 20 to 30% of breast cancers. Overexpression is inversely correlated with ER expression and associated with poorly differentiated tumors with high growth rate. Survival is shorter for patients with HER2-overexpressing tumors than for patients with normal HER2 expression. HER2 overexpression may be associated with resistance to some therapeutic agents, although there is considerable controversy about this aspect.379–382 Several recent reports suggested, however, that patients with HER2 overexpressing breast cancer derive greater benefit from anthracycline-containing adjuvant chemotherapy than from other regimens.260,262,382,383 Whereas some studies suggested that HER2 overexpression is a marker of tamoxifen resistance, other analyses have provided conflicting results.384–386 Currently, there is no reason not to use tamoxifen for the management of patients with ER-positive breast cancer, regardless of HER2 status. The most important clinical application of HER2 testing is to identify candidates for HER2-directed therapy with trastuzumab (Herceptin).249,254 The prognostic value of EGFR overexpression is less well established, and there is no Food and Drug Administration (FDA)-approved therapeutic intervention that targets this receptor.

Bone Marrow Involvement

Several investigators have presented data to suggest that the presence of microscopic involvement of the bone marrow, detectable by sensitive IHC analyses, is a major determinant of prognosis.387–392 In fact, some have suggested that this finding is superior to axillary lymph node involvement in its prognostic capability.389

Several other histologic factors, including lymphatic invasion, vascular invasion, tumor necrosis, and mononuclear cell infiltration, have been associated with better or worse prognoses in at least one report. Although extensive clinical experience supports the prognostic value of each of these factors, they have not survived the test of independence in multivariate analysis, nor have they been sufficiently evaluated to date.

Investigational Markers

Many biochemical, molecular, genetic, and immunologic markers have been under investigation for the past several years. All of them have been suggested by one or more reports to have prognostic significance. However, evaluation of these markers falls short of determining whether they are independent prognostic factors or valuable additions to other proven, commonly used prognostic indicators. Among the promising investigational markers are heat shock proteins, EGFR, p53, nm23, cathepsin D, urokinase plasminogen activators (uPA), urokinase plasminogen activator receptors (uPAR), plasminogen activator inhibitors (PAI-1, PAI-2), Bcl-2, BAX, laminin receptors, and apoptotic rate. Several of these may be shown by additional, well-designed studies to be prognostic markers of clinical relevance.

Some markers may be shown to be more relevant as predictors of response to chemotherapy or hormone therapy, whereas others may serve to identify tumors using particular targets of biologic intervention (HER2/neu, EGFR, etc.). Many genes commonly associated with cancer participate in the regulation of cell proliferation and apoptosis. Alterations in these genes may be important in determining the chemosensitivity of cancer cells. For instance, cells that express high levels of cyclin D1 mRNA and protein have increased resistance to phase-specific agents like methotrexate but not to doxorubicin or paclitaxel.370,393 Mutations or deletions of p53 are associated with resistance to various DNA-damaging drugs.394–396 There are many other factors that have been proposed by at least one report to have prognostic significance. However, either there is no biologic rationale for these observations or the observations have not been reproducible, and additional studies have failed to support the prognostic value of those factors.

Over the years, there have been numerous attempts to reach a consensus on what prognostic factors are of recognized clinical utility. However, with the exception of the basic histopathologic factors, steroid hormone receptors, markers of proliferation, and HER2 expression, the majority of proposed factors fall short of general acceptance as useful clinical tools.

Prognostic Indices

The large number of prognostic factors available and the incomplete evaluation of most of those factors lead to serious difficulties in the interpretation of prognostic information, especially when caring for an individual patient. There is no standardized method of integrating prognostic information, and attempts to develop prognostic indices have had limited efficacy. The index developed by the breast group at The University of Nottingham is based on tumor grade, axillary lymph node involvement, and hormone receptor status.397,398 It has been validated prospectively and confirmed by an independent center, but it still has limited usefulness in the determination of an individual’s prognosis.399 Multivariate analysis is helpful in determining which of several potential factors provides independent prognostic information.400,401 However, the usefulness of this analysis varies with the factors included (and not included) in the process, and to date no large-scale analysis of all or even a majority of potential prognostic factors has been performed.

Clinical Use of Prognostic Factors

The use of prognostic factors has two major objectives. One is to calculate the individual risk of recurrence and disease-related mortality for patients with primary breast cancer treated with curative intent. In this group, determination of prognosis will assist in decisions regarding the incorporation of systemic adjuvant therapies into the management of the disease. It used to be considered that patients with a risk of relapse lower than 10% would have such marginal benefit from adjuvant systemic therapies that no such intervention would be recommended. However, recent calculations of the benefits of tamoxifen administered for 5 years to patients with ER-positive breast cancer, and the demonstration that the combination of hormonal therapy and chemotherapy has at least additive effects on reduction of risk of relapse and mortality, have prompted a reassessment of these recommendations. Most patients with invasive primary breast cancer larger than 1 cm should be encouraged to receive adjuvant systemic therapy; some with tumors smaller than 1 cm should also be advised to consider adjuvant therapy, since randomized trials have not identified any subgroups that failed to derive benefit from these interventions. The use of prognostic factors, under these circumstances, serves more to place the benefit:risk ratio for individual patients in the context of their own prognosis. The identification of subgroups with a very high risk of relapse is useful to determine eligibility for novel or more aggressive interventions. However, the acceptable benefit:risk ratio varies substantially from person to person; therefore, after a best attempt to calculate individual risk of relapse and mortality, treatment options and the probability of benefit from each should be presented in the light of toxicity and cost to facilitate informed treatment decisions.

Diagnosis and Screening

Historically, the primary presenting symptom of breast cancer was a palpable mass, often first detected by the patient. Today, the increasing use of mammography, especially in screening programs, results in many cancers being found at a preclinical stage. A simple discussion of the signs and symptoms of breast cancer without consideration of these preclinical manifestations would be incomplete. To some extent, this means greater complexity in selecting for biopsy patients who are suspected of having carcinoma. The clinical and mammographic signs and symptoms are best understood against the background knowledge of the anatomy and biology of breast cancer—how it grows and extends locally.

Patient History

The patient’s history should include standard epidemiologic and reproductive information to assess the relative risk factors. Information about lumps, pain, or any changes in the breast should be obtained and correlated with physical findings. Although pain is probably the most frequent breast complaint that brings a patient to a physician’s office, it is uncommonly the presenting factor in cancer. Breast cancer, especially in its early stages, is usually painless. Most breast pain is related to hormone stimulation and swelling of breast tissue (although these symptoms may draw attention to a mass that proves to be cancer). Careful questioning of the patient usually reveals that the pain is cyclic, beginning any time between ovulation and the onset of menstruation, and that commonly it is most intense a few days before menstruation. Pain usually disappears by the first or second day of the menstrual period, only to return again at the next cycle. Frequently, patients complain of radiation toward the shoulder and arm, and a burning sensation that goes with constantly increased muscle tone can be attributed to subconscious muscle tension in this region. Cyclic pain is present at a mild level in more than 50% of women of childbearing age. Less frequently, the pain can reach intense proportions. Some patients report that, during the worst days, it is too painful to take a simple shower.

The most effective treatment is explanation and reassurance, although some patients who are extremely symptomatic and incapacitated by the pain may require treatments with hormones or hormone-blocking drugs. There are occasional reports that caffeine limitation or low-fat diets help, but relief seems to be individual, and these reports are not supported by persuasive clinical trials.402–404

A patient who reports a lump or any other physical change in her breast needs careful attention. The history should describe any change in the character or size of the lump and whether or not it has been tender. Pain should be described with respect to its timing in the menstrual cycle. Lumpy changes associated with a fibrocystic process may wax and wane, but it is distinctly unusual for a carcinoma to do anything but increase in size. If there is confusion, the patient should be re-examined after the menstrual period.

Other descriptive changes, such as skin thickening or discoloration, the presence of axillary masses, or nipple discharge, should be elicited. Nipple discharge may be serous, watery, or milk-like. It may be clear or have a yellow or greenish hue, or it may be serosanguineous or frankly bloody. Although the latter may indicate a neoplasm, this is most commonly an intraductal papilloma, which is benign. It is possible, but rare, for such a discharge to signal an intraductal papillary carcinoma; all bloody discharges require further investigation.

Clear or serous discharge, especially if it involves more than one major duct opening on a nipple, is likely to be benign. Nonbloody discharge that is not spontaneous but requires manual compression to elicit is also likely to be benign. In an apocrine system such as the breast, there is always some cell desquamation and liquefaction and, therefore, some fluid present in the duct system. If this is not well absorbed, it can make its way through the collecting ducts to the nipple and present as a discharge. Similarly, if the duct is blocked by fibrosis or inspissated material, the pressure of secretion can cause dilation and cyst formation.

Physical Examination

The patient should be examined first in a sitting, then in a supine, position. When the patient is sitting erect, more useful information is obtained visually than by palpation. When the arms are raised and stretched upward, the contour of the skin is pulled tight, allowing for easier detection of contour abnormalities in the upper half of the breast. This position also emphasizes dimpling, especially in the lower half of the breast. Because much of the breast tissue coalesces in the sitting position, it is very difficult when palpating to appreciate true masses and often easy to be confused by confluent tissue.

With the patient supine and the arm raised so that the hand is behind the head and the elbow lies flat on the pillow, the breast tissue can be spread across the chest wall, allowing for proper palpation. The patient should be slightly turned to the contralateral side to aid this process. In all but very large breasts, the tissue is now spread out across the ribs, so that there is very little tissue thickness between the examining fingers and the underlying ribs. This provides confidence that, if there is a detectable mass in this area, it will not be missed (Fig. 118.16). It is important to proceed in a pattern, but whether it be by quadrants or strips is up to the examiner. The axilla is palpated by relaxing and adducting the patient’s arm, but this is best done with the patient in the sitting position. Skin changes, such as dimpling, peau d’orange (edema), erythema, or areas of fixation and ulceration, suggest advanced cancer that has invaded the skin or the immediate subcutaneous tissue. Skin retraction is often more easily detected when the patient is sitting and the arms are raised or when the patient is leaning forward. The breast lobules are divided loosely into fascial compartments by Cooper’s ligaments, somewhat like the divisions of a grapefruit, but much less geometric. Since the fibroblastic reactions associated with cancer tend to involve and pull on these ligaments, they become shortened, and the effects can be seen on the skin with such positioning. Retraction or asymmetry of the nipple is another worrisome sign unless the patient reports that this has been present all her life. A subtle reddish thickening of the nipple may suggest Paget’s disease.

Figure 118.16. Changing shape of breast with position.

Figure 118.16

Changing shape of breast with position. Left, upright breast is rounded, tissues are pressed together. Right, CT scan showing breast flattening when supine. A palpable tumor is easier to detect in this position.

The examination is concluded with a search for axillary, infraclavicular, and supraclavicular nodes and palpation of the liver to detect enlargement. Although palpably enlarged axillary nodes raise the probability of metastases, careful studies have shown that clinical judgment is highly inaccurate. In a study conducted by the NSABP,5 a group of cancer patients were judged by their clinicians to have normal axillary nodes, but 38% showed histologic evidence of metastatic tumor when the specimens were examined pathologically. Conversely, in 25% of such cases, nodes that appeared enlarged and were judged to contain cancer were found to be normal.

The most difficult clinical decision is differentiating between a pathologic mass and a physiologic density associated with fibroglandular (or fibrocystic) changes. Many women have the latter condition, which is characterized by a rubbery density without clear margins. The process seems to blend into the surrounding breast tissue. A true lump has definite margins. Whether these are smooth, as in a gross cyst or fibroadenoma, or somewhat irregular, as in carcinoma, they delineate a discrete or dominant mass that requires further investigation. The differentiation of true masses from fibrocystic plaques is difficult to teach and is learned only with experience.

It is important to measure the size of a tumor with a ruler so that subsequent examinations can more accurately establish any change in size. Mobile lesions are usually considered benign, but this is another area of clinical uncertainty. Advanced cancers may be fixed, but early palpable lesions will certainly be mobile with respect to skin or fascia and muscle of the chest wall. There is, however, a subtle difference in mobility (better called movability) characteristic of cysts or fibroadenomas, which have capsules and move much more easily within the surrounding breast tissue. Carcinoma, on the other hand, which has no capsule and is surrounded by an infiltrating desmoplastic process, tends to move with the neighboring breast tissue rather than within it, because the process “locks” it into the stroma and surrounding glandular tissues, even when it is not fixed to surrounding structures, such as skin or muscle. Even the most experienced examiner can sometimes fail to distinguish correctly between benign and malignant lesions.

Screening

The refinement of x-ray methods to image the breast and the important clinical-pathologic correlations are best attributed to Gershon-Cohen in the 1940s and 1950s in Philadelphia. The use of screening mammograms in asymptomatic women in a prospective clinical trial aimed at reducing mortality by discovering preclinical breast cancers was first successfully reported by the Health Insurance Plan (HIP) study in 1975.405 In the trial, 31,000 women enrolled in a prepaid insurance plan were invited for screening and compared with a second group of 31,000 women in the plan who served as controls. Long-term follow-up has demonstrated a 30% reduction in mortality in favor of the screened group. The HIP study, the first of its kind, was designed to answer questions about screening among women ages 40 to 64 and does not allow for a direct answer to the age question. The study achieved its target accrual and has reported correctly that there was an overall mortality reduction from screening. The problem arises when the 40- to 49-year-old group is examined separately. This small slice of the original population was not large enough to detect a change in mortality, and the original analysis showed identical mortality for screened and control patients ages 40 to 49 at entry.406 Subsequently, a difference was detected for this age group, but only after 8 years of follow-up, in contrast to older women, where the difference became apparent within 4 years. Many of the women who were first screened at 40 to 49 years of age were older than 50 when their cancers were detected, a factor that raised confusion about how to interpret the results.

In analyzing screening studies, strict methodology must be observed in order to avoid bias. If tumors are found earlier by mammography than by clinical examination, the additional time gained is referred to as lead-time. If, however, the tumor has already metastasized out of the breast, the date of death will not be changed, but the length of survival from the time of diagnosis to death will be increased. This is called lead-time bias. Length bias is another, more subtle form of error that plagues this type of study. It is more likely that patients with slowly growing tumors will have their tumors detected on routine screening, whereas patients with more rapidly growing lesions (interval cancers) will be diagnosed at other times. Thus, at any interim point, the screened group will include more people with slower growing (more favorable biologic) tumors, and, by comparison, this group will seem to perform better.

The way to avoid these biases is simply to count the number of deaths from breast cancer in both groups. Studies that report survival rates or average survival time should be viewed with skepticism. Similarly, studies that report that screened cases had smaller tumors or earlier stages of cancer can be misleading because they may only represent lead-time biases. The use of unorthodox, or unplanned-for, methods of analysis can similarly lead to erroneous conclusions. The confusion surrounding age and screening benefit is a long way from becoming clear.

Early studies from Sweden and the Netherlands also demonstrated a reduced mortality for screened women who are postmenopausal.407,408 None of these early studies was designed specifically to measure the impact of screening in women under the age of 50. Statistical manipulations to analyze subsets separately in these studies can sometimes show a benefit for the younger age group, but caution is required in making final recommendations. The application of widespread screening in a group of patients where it is not useful would waste time and money and inhibit the broader application of screening in the older age group, where it is of proven benefit. The early days of the screening debate were not concerned with cost-effectiveness analyses, but the present concern with allocation of health care dollars throughout North America now makes this an important consideration. The literature on this subject can be somewhat arcane, but certain trends are emerging. Kattlove et al.409 have shown that the mortality reduction from screening is expensive, even for older women. More recently, Salzmann et al. have calculated that the cost effectiveness in screening women younger than 50 is five times more expensive than that in older women.410

To be effective, a screening program should seek a disease that is common, one whose effects are serious, and one for which a useful treatment is available. The incidence of breast cancer increases with each decade of life, but it is significantly more common in postmenopausal women so that, in women under 49, more negative examinations will result and fewer cancers will be found (Table 118.12).411 Breast cancer is three times more likely in 55-year-old women than in 45-year-olds, and the difference is more conspicuous at more extreme points on this spectrum. Furthermore, in the younger group, the breast is more glandular and, therefore, more radiodense, raising the chance that faint signs of carcinoma will be obscured by intervening normal tissue.

Table 118.12. TNM Classification System.

Table 118.12

TNM Classification System.

On the other hand, modern mammography equipment with high-speed film, microfocus x-ray tubes, high-speed film screen cassettes, and good selective compression techniques make the procedure more effective than it was a decade ago and increase the possibility that small carcinomas can be found in this age group. Now,larger clinical trials have attempted to answer this question. The incidence and mortality rates of breast cancer vary by ethnicity (see Table 118.3). Many clinical features influence risk of developing breast cancer (see Table 118.4).

Canadian Trial

A large prospective study from Canada,412,413 the only trial designed to address the question of screening in women ages 40 to 49, found no benefit. Despite widespread agreement that screening postmenopausal women reduces breast cancer mortality, it is not clear how much mammography, clinical examination, or the combination contributes to the outcome. The National Breast Cancer Screening Study (NBSS) of the NCI of Canada was designed to address the question of screening the group ages 40 to 49 and, second, to evaluate the separate effects of mammography and clinical examination in women ages 50 and older. A total of 50,430 women ages 40 to 49 years were randomly assigned to either annual mammography and physical examination or “usual care” after an initial physical examination. The screening techniques detected considerably more node-negative and small tumors than did “usual care” but had no impact on the rate of death from breast cancer up to 7 years following entry.412

In the group of women ages 50 and older, 39,405 participants were randomized to undergo annual mammography and physical examination or annual physical examination only. As in the first group, mammography detected more node-negative and small tumors than did screening by physical examination alone but had no impact on the rate of death from breast cancer up to 7 years’ follow-up from entry.413 This trial was meant to be the definitive study addressing two of the main points of controversy arising from the last 20 years of screening. However, these reports have been received with considerable debate and criticism. Critics contend that the quality of mammography was substandard, the follow-up time was too short, the power was insufficient, and there may have been randomization problems since there was a disproportionate number of 40- to 49-year-old women with lymph node metastases in the mammography group.

Defenders of the NBSS insist that the results are consistent with other studies. It is true that the power was low, mainly because the calculations were based on a higher expected death rate, but the authors point out the often-observed statistical maxim that if larger power is required, it must mean that the effect is smaller.

The quality of mammography in this program did improve as the trial progressed and a quality-control plan was implemented. The main argument is now over whether the defects were frequent enough or important enough to affect the outcome of the trial.414,415

The authors provide evidence that the sensitivity of mammography in the NBSS compares favorably with that from the Stockholm and the Swedish Two-County trials.414

Swedish Overview

It is clear that the debate has not been settled by the Canadian study. A reanalysis of five randomized controlled trials carried out between 1976 and 1990 in Sweden provides further insight. The Swedish studies are often individually cited in various contexts and furnish conflicting information. An overview was accomplished by merging the data from the five trials. An independent death review committee, blinded to the individual allocation, reascertained the deaths and the causes of deaths. For the total aggregate of screened women, the RRs of dying of breast cancer as compared with the control group was 0.76 (95% CIs 0.66–0.87). When analyzed for the age group 40 to 49, there was a nonsignificant reduction in risk of 13% (95% CIs 0.63–1.20).415 The patterns follow those first noted for the HIP study in that the screened group diverged from the control group after 4 or 5 years in the women older than 50, but differences did not appear in the younger group until after 8 years from entry.

The NBSS has found no benefit at 7 years in screening younger women. The Swedish overview, which excluded the NBSS results, found a statistically insignificant benefit; Elwood et al.,416 who included the NBSS in their meta-analysis, found no benefit, nor did the NIH workshop.417 The Nijmegin update407 and the meta-analysis of Kerlikowske et al.418 both support those conclusions.

Gothenburg Trial

In 1997, the Gothenburg trial reported a significant benefit for screening women aged 39 to 49 years of age at randomization.419 At the same time, an update from the Malmo420 study showed a benefit for women older than 45 years. More recently, a long-term follow-up of the Edinburgh421 trial was reported. At 14 years of follow-up, screening women biennially showed a benefit for women aged 45 to 49. The U.K. trial of early detection,422 a nonrandomized comparison of communities that did or did not offer screening, also shows a decrease in breast cancer mortality in the 45- to 46-year age group. These trials still do not clearly resolve the controversy. It is not clear how much of the mortality reduction in young women was due to screening after they had reached the age of 50 years.

Part of the controversy arises from the manner of presenting the data. It is probably correct that even in younger women, screening reduces mortality and that with more modern equipment and techniques, the figures may be improving. Accepting the best data, there is a 45% reduction in mortality. This seems impressive, but breast cancer mortality in this age group is only 30/100,000. Salzmann et al.410 estimate that screening 10,000 women annually for 10 years would extend their collective lives by 2.5 days. Harris423 has calculated that a primary care doctor who sends 1,000 40-year-old women for mammograms each year will save one life after 16 years. The point is that screening will result in benefit for individual women, but it is not clear that as a public health program that this would be worthwhile. The issues go beyond cost effectiveness. Screening will find many abnormalities, many biopsies will result, and some people will be treated for very slow-growing variants of DCIS, which may not ever have had clinical importance for that person. Nevertheless, some women will benefit and some lives will be saved. Final decisions on this topic will be made on the basis of value judgments, and it is unlikely that there will ever be a scientific consensus.

Solutions

Dichotomizing at age 50 may be somewhat arbitrary, even though it does correspond roughly to age at menopause, when cancer rates increase and changes in breast glandularity make mammography more effective in discovering small changes. It is important to realize, however, that women age 49 may be very much like women age 50 or 51. It is highly likely that there is no steep and abrupt change in the usefulness of mammography at the age of 50. So why the dispute?

To take one extreme, there is no argument that screening mammography is not a useful public health tool among 20-year-old women, for the obvious reason that they very rarely get breast cancer. Thus, a combination of increasing incidence, possible changes in the biology of breast cancer, and the sensitivity of mammography all come together somewhere between 40 and 50. We can reasonably conceive of a gradient of uncertain steepness reflecting the increasing usefulness of mammography as the age of 50 is approached.

A logical view suggests that there are individual women, especially those closer to 50 than to 40, who will benefit from screening. When examined from a public policy viewpoint, however, it will be necessary to evaluate screening programs against other yardsticks of public health and their costs. This type of approach is in its infancy, but we can expect its impact to grow more apparent and important in the future.

Guidelines for screening, which are published by the American Cancer Society (ACS), the NCI, the American College of Radiologists (ACR), and other interested organizations, were, for many years, quite similar. In the 1990s, there has been considerable controversy about screening women younger than 50. Following the recent NIH Consensus Conference,417 the NCI at first revised its guidelines to make no specific recommendation in this age group. The workshop participants confirmed the protective effect of screening in the 50- to 65-year-old group. All subgroup analyses of women younger than 50 showed either a lack of benefit or a marginal benefit of no statistical significance. The NCI advisors felt that there was not enough scientifically dependable information to support any guideline for women younger than 50 and decided to make this information available in the hope that it would help individual women make up their minds. Consequently, the NCI made no statement for or against mammography in this age group. Subsequently, the National Cancer Advisory Board took an opposite stance, and the NCI eventually recommended screening younger women, especially in certain situations such as high-risk families. The ACS and the ACR decided not to change their guidelines and still recommend mammography to screen younger women. There is still unanimity that women over 50 should receive annual screening by mammography, but uncertainty remains about whether there is any public health advantage to screening younger women and those older than 74 years.

An ongoing study of mammography in the United Kingdom will recruit 195,000 women starting at age 40. One-third will receive mammographic screening, and two-thirds will be controls. There are no other prospective studies underway that were designed to answer the question of screening in younger women. A review of all of the evidence indicates a benefit, but the extent of the benefit as a public health measure is still controversial. Decisions are probably best made on an individual basis, taking into consideration family history, body build, and previous personal history. Women closer to 50 than to 40 years of age may be more reasonable subjects for screening mammography. Women with a higher risk because of family history may sensibly be counseled to begin mammography as young as age 40. At the end of this debate, it must be remembered that there is widespread consensus as to the significant reduction in breast cancer mortality when women older than 50 are screened.

Role of Breast Self-Examination

In the HIP study, about one-third of breast cancer cases were found using mammography alone; overall, 75% were detectable on clinical examination.424 Although mammographic techniques have improved since the 1960s, the value of clinical examination and breast self-examination (BSE) seems clear. Retrospective studies show that women who perform regular BSEs detect breast cancers at an earlier clinical and pathologic stage of the disease, but most studies have not shown an increased chance of survival.

The Swedish mammography study did not include either clinical examination or BSE, which raises the question as to whether those results would have been better had these modalities been included. The Canadian NBSS included instructions in BSE, and the teaching was reinforced at subsequent annual screenings, but it is not possible to say whether the practice had any effect since all participants received instruction. It seems logical to recommend widespread use of BSE as a diagnostic tool that is free and available to everyone, but the evidence in support of it is far from solid and remains controversial. Furthermore, the same caveats exist as for mammography. BSE can be expected to prompt a significant number of unnecessary biopsies with their attendant anxiety. It is difficult to weigh anxiety about the outcome of an unnecessary biopsy against the risk of dying of breast cancer, but that is probably not the equation in this case, since there is far less evidence that BSE reduces mortality. On the other hand, most breast masses are still self-discovered by accident, indicating that systematic BSE could have diagnosed the disease earlier.

Differential Diagnosis

In performing breast examinations, the first objective is the detection of potential abnormalities. Discovery of an abnormality is followed by further investigation and evaluation to decide whether intervention is necessary. Thus, all abnormalities are first “caught in the net,” and then more refined tests can be performed to decide whether the findings are important enough to warrant a biopsy. The traditional clinical guidelines of mobility, smoothness, and discreteness of breast lumps are useful, but careful judgment is always required to make sure that the diagnosis of carcinoma is not missed. Such tests as mammography and ultrasound can provide additional information and should be used in most cases. Fibroadenomas cannot be easily distinguished from gross cysts clinically, but a needle aspiration solves the problem instantaneously, and both are benign. Ultrasound can also differentiate cysts from solid lesions and is useful when mammography detects small lesions, probably cysts, that cannot be palpated.

The most common breast lumps are caused by a process previously called fibrocystic disease or mastitis. A more modern trend is to label this condition as fibrocystic or fibroglandular changes. The process is benign, usually symmetric, and most often situated in the upper outer quadrants because that is where most of the glandular tissue is found. Microscopically, there is a combination of fibrosis and ductal swelling, which gives the process its classic “fibrocystic” name. Clinically, this is a rubbery zone, but focal areas can be quite firm or hard. If a gross cyst is present, it tends to be round, circumscribed, and somewhat movable. The process is usually accompanied by pain or tenderness and tends to be cyclic, with relief as the menstrual period begins. It affects 50% of premenopausal women but usually disappears at menopause (Fig. 118.17). Fibroadenomas are also smooth, round, and mobile and occur from adolescence to menopause. The British colloquial term is breast mouse, which signifies extreme mobility.

Figure 118.17. Comparative frequency of fibrocystic changes, fibroadenomas, and carcinomas by age groups.

Figure 118.17

Comparative frequency of fibrocystic changes, fibroadenomas, and carcinomas by age groups.

In older women, the inferior ridge of the breast may be compressed in a crescent-shape pattern due to the weight of the overlying breast. This area represents simple fat compression and is usually benign. Many poorly defined processes require surgical biopsy to distinguish them from malignancy. Among these are sclerosing adenosis, hyperplasia with or without atypia, and mammary duct ectasia. The last is the end result of the fibrocystic process, with ducts filled with liquid and cellular debris accompanied by fibrous changes and lymphocytic infiltration.

Lesions that are less smooth and less mobile with poorly defined margins raise the suspicion of carcinoma. The identification of the nature of a mass requires careful integration of all available information, including mammography. Simple catechisms, such as “always biopsy,” are not the best guidelines. The clinician’s responsibility is to establish the diagnosis of cancer when it exists but to minimize the number of unnecessary biopsies. A simplistic approach—biopsy of every clinical abnormality—would certainly identify all of the cancers but would be irresponsible, if not reckless, because of the large numbers of unnecessary operations. Similarly, abstaining from biopsy until the signs are absolutely incontrovertible would be dangerous, even though this approach would minimize unnecessary operations. The proper strategy is to apply all of the available information—history, clinical signs, mammographic and ultrasound information, and needle aspiration cytology—and to biopsy all of those lesions where a reasonable doubt as to their benign nature exists.

It is often said that mammography and needle aspiration cytology are plagued by false negatives. This view arises from an unrealistic expectation of these modalities. No single diagnostic modality is perfect, but accuracy in diagnosis improves with the integration of several tests. If the history and clinical examination suggest a benign process and a mammogram shows no abnormality, it is reasonable to integrate all of the information and use the mammogram to reinforce the clinical diagnosis of benign process. On the other hand, if the mammogram suggests suspicion for malignancy, then further steps, including biopsy, are warranted, even if the clinical examination is normal. Conversely, in a patient with a suspicious clinical mass and a normal mammogram, biopsy is necessary. Needle aspiration cytology can confirm the presence of carcinoma and allow for better planning for necessary surgery. If both the clinical and mammographic signs suggest a benign process, then a needle cytology of a fibroglandular area can add confidence to this impression and help avoid unnecessary surgery.

Diagnostic Aids: Imaging

Mammography

Although screening mammography, discussed above, is the primary indication for the use of mammography today, diagnostic mammography is often needed to clarify abnormalities discovered in the screening process. Diagnostic mammography is also useful when clinical signs and symptoms of breast disease exist. In this setting, it can bring new information to the process in question, give additional information about other areas of the breast that may be of concern, and provide information about the opposite breast. The usefulness of mammography increases in patients with heavy, lumpy, or pendulous breasts, which are difficult to examine clinically. A diagnostic mammogram should be performed whenever there is a clinical abnormality that requires diagnosis. Exceptions to this are obvious fibroadenomas or fibroglandular symptoms in very young women.

Thermography

The search for accurate imaging of the breast without ionizing radiation has persisted for three decades. Thermography measures heat radiating from breast tissue. Since tumors have increased vascularity, they often radiate more heat and can be discovered by thermography. This technique lacks precision and has never become widely used because of unacceptably high false-negative and false-positive rates.

Light Scanning

This is a modern update of simple transillumination. Infrared light is passed through the breast and read with a television camera tuned to specific frequencies. Spectroscopic analysis of absorption patterns is said to correlate well with diagnosis, but, again, a lack of specificity and sensitivity inhibits its usefulness.

Xeroradiography

This abandoned technique, popular in the 1970s, used a selenium-coated drum to receive the image. Xeroradiography was best for detecting microcalcifications but was inferior to film-screen mammography for finding small masses and was unacceptable because of its comparatively high levels of radiation.

Ultrasound

The main use of ultrasound is to establish the presence or absence of a cyst when the mammogram has revealed a mass. If the mass is palpable, this can be done more cheaply and quickly by needle puncture, but ultrasound is useful to show that nonpalpable, or scattered, small lucencies are truly cysts. Ultrasound has not become useful as a screening tool.

Magnetic Resonance Imaging (MRI)

This technique takes advantage of the zone of neovascularization that surrounds growing tumors. Although MRI alone is not useful, contrast enhancement enables visualization of small lesions. In nonrandomized trials, sensitivity is reported to range from 88 to 100%.425 MRI is especially useful for distinguishing recurrence in a previously irradiated breast from scar tissue since scar tissue does not enhance. Because MRI is expensive and time consuming, even with modern equipment, its best role may be to separate borderline lesions discovered on routine mammography. This could eliminate some false negatives. The false-positive rate in this situation would be less important since all would have been surgical candidates on the basis of mammography. Screening with MRI creates some problems. There is no way to localize the lesion precisely if it is not visible on x-ray or ultrasound, so the surgeon is uncertain where to biopsy. The specimen cannot be examined with MRI since that requires contrast infusion. At present, the technique is still developmental.

The main objective of an imaging test is to discover cancer at a preclinical stage in the hope that cure rates will be improved. Screening mammography in the postmenopausal age group has been shown to decrease mortality because of earlier diagnosis.405,406 The other imaging modalities can sometimes differentiate between benign and malignant tumors but, so far, have not contributed to early diagnosis comparable to that achieved by mammography.

Diagnostic AIDS: Fine-Needle and Core Biopsy

Both fine-needle aspirations and core needle aspiration biopsies are very useful. Both are inexpensive, easy to perform, and require no advance preparations. In experienced hands, fine-needle aspiration yields a 90% accuracy rate.426,427 Core biopsy is not always reliable for very small lesions because the spring-loaded needle may push a small tumor aside rather than penetrate it. This is not a problem in x-ray image-guided biopsy because compression of the breast stabilizes the tissue and prevents this. For lesions larger than approximately 1 cm, core needle biopsy is an excellent office procedure to obtain clear information on the nature of the lump and to differentiate invasive from noninvasive cancer when the fine-needle aspiration shows malignancy.

Any clinically suspicious mass should be aspirated. If a mass is punctured and nonbloody fluid is aspirated with disappearance of the lump, further concern is not warranted. If the mass persists in part or in whole, or if no fluid is obtained, then cytology should be obtained on that specimen (even with no gross fluid, the same needle puncture can be used for aspiration cytology). A careful follow-up within a short interval is wise. If necessary, a second fine-needle aspiration can be performed.

If surgical biopsy is considered necessary, modern concepts require a definitive approach. If patients with cancer are to be successfully treated by lumpectomy, this is best accomplished at the first intervention. The suspicious mass should be excised in its entirety with a cuff of normal tissue that can be processed by the pathologist for evaluation of margins. An incisional biopsy or casual excision of a mass without such control makes it more difficult to perform a proper localized cancer operation at a subsequent time.

Staging and Classification

The purposes of staging are to (a) plan a therapeutic strategy that is most appropriate for the patient, (b) allow for more intelligent prognostication of the disease status of the patient, and (c) permit comparison of therapeutic results obtained from different sources by different means. The common staging methods in use today are clinical and pathologic, but newer methods involving biologic assessments are appearing. Regardless of the staging method used, it is important to remember that the stage represents the state of disease or biologic potential of an individual patient’s tumor. The usefulness of a particular staging method must be judged against its accuracy in performing this task.

The TNM classification devised by the International Union Against Cancer (UICC) and accepted by the American Joint Commission on Cancer Staging is a world standard.428 Unfortunately, the classification has become burdensomely complex and is revised so frequently that it is difficult to keep the details in mind, although a small card suffices. The TNM is based on the clinical features of tumor (T), the regional lymph nodes (N), and the presence or absence of distant metastases (M). The tumor is characterized by its size, so that a T1 is a tumor under 2 cm, a T2 is 2 to 5 cm, and a T3 is over 5 cm. Similarly, N0 represents negative or normal regional lymph nodes, and so on (Table 118.12).

Another system is the Columbia Clinical Classification (CCC), formulated by Haagensen.429 Although this system was a valuable precursor and is easier to remember than the TNM, it is a less precise classification, where stage A represents a tumor confined to the breast; stage B includes tumors with clinical axillary lymph node enlargement; stage C represents the presence of grave prognostic signs in the breast, such as peau d’orange or skin fixation; and stage D indicates metastatic disease (Table 118.13). Since both systems describe essentially the same process, there is a fairly reproducible survival pattern based on stage. The UICC-TNM system is prepared so that results can be interpreted universally, but many reports on surgical and adjuvant chemotherapy trials do not use the system directly, and there may be a need for a more useful standardized system.

Table 118.13. Columbia Clinical Classification System.

Table 118.13

Columbia Clinical Classification System.

Clinical staging systems generally underestimate the extent of disease. The inclusion of pathologic information improves staging accuracy and is the basis for most modern clinical trials. In all cases, it is wise to remember that the goal is to define the biologic activity of the tumor. For example, in considering prognostic factors, the presence of intramammary lymphatic emboli is associated with higher rates of treatment failure.25 The presence of tumor in the axillary nodes is a more specific and reliable prognostic factor, however, because it indicates that those tumor cells in the lymphatic channels are biologically able to survive in the axillary nodes in the form of metastases. Cox regression statistical models confirm that the presence of nodal metastases is a more important factor than lymphatic emboli. Furthermore, the number of nodes involved can be used to further subset the prognostic groups (see Table 118.8). A group of patients treated by radical surgery with curative intent and no adjuvant therapy has demonstrated the prognostic importance of lymph node involvement.22

The reliability of axillary lymph node dissection for staging is confused by poor terminology. Axillary sampling is an undefined term that alludes to the removal of some axillary tissue, but this lack of precision prevents comparisons or evaluations. The NSABP has evaluated the complete dissection of levels I and II axillary nodes and has shown that this provides an extremely high degree of confidence in establishing whether axillary metastases exist.53,54 A comparison of protocols employing Halsted radical mastectomy, modified mastectomy, and lumpectomy with axillary dissection shows that, essentially, the same number of lymph nodes are retrieved for examination, despite the different procedures.48 Little would be gained by further dissection for staging purposes. NSABP protocol B-04 has shown that nothing is gained by any specific axillary treatment in terms of either disease-free survival or survival. Even with multiple positive nodes, axillary recurrence is not common with today’s limited axillary dissection and adjuvant chemotherapy programs, and further regional treatment, such as radiation therapy, can be withheld unless and until such recurrence is detected. More recently, identification and biopsy of the sentinal node appears to have promise as a more limited procedure with a high degree of prognostic accuracy.

In another report from the NSABP, tumor size—always considered an important prognostic factor—was seen in a regression analysis model to be closely related to axillary lymph node involvement.8,25 Tumor size is not an important discriminant within axillary node groups, except for patients with more than four involved nodes. Thus, size, which can be a function of either time or growth rate, is less useful than axillary node involvement, which is a more specific indicator of biologic aggressiveness or of host incapability of destroying cells that reach the nodes. Although tumor size does correlate with prognosis, it is less than correct and too simplistic to say that a patient has a poor prognosis because her tumor is large. A better way to characterize the relationship is to say that the patient has a large tumor because her tumor is aggressive and has a high growth rate. This is a better view of tumor biology and shows why the TNM system, which is anatomic, should eventually be supplemented with or replaced by a more dynamic system. Furthermore, some patients with large masses may have slow-growing tumors, ignored for years, that have not metastasized. A similar problem exists in classifying patients with small but aggressive tumors found by screening mammography in whom distant metastases already exist. These patients may die rapidly, despite the initial favorable local clinical features. A biologic classification would identify these women more accurately than does the TNM system. Mittra has argued that biologic determinants also select more accurately for prognosis after adjuvant chemotherapy than do clinical features.430 These concepts will provide further challenge to the TNM system in the future.

Biologic Markers: detection and Staging

Modern molecular biologic techniques will probably change the approach to detecting and staging early breast cancer. The advent of mammography resulted in a change in presenting sign from a clinical mass to a subclinical mammographic abnormality. The search is now on for biologic markers that can indicate the presence of early carcinoma or that can be used as prognostic indicators to select patients for adjuvant therapies. (Examples of such markers in node-negative patients are listed in Table 118.9). These markers are usually substances produced by a cancer cell or by the host. A classic approach in past decades was to search for abnormal hormonal products that were excreted in the urine or found in the serum and that were associated with a higher probability of cancer. The best examples are the Guernsey studies, which yielded epidemiologic information but never reached clinical usefulness.431

More recently, nonspecific antigens, such as carcinoembryonic antigen (CEA), and more characteristic antigens, such as CA15-3, were studied. These are more reliably elevated in advanced disease (stage III or stage IV) than in early stages and are more useful in following the course of a patient who has established cancer than in detecting the presence of cancer in a screening program.432 Levels of these markers do decline with a good response to chemotherapy and are a useful reflection of changing tumor burden; therefore, they help monitor response to therapy.

New markers specific for cancer cell gene products show promise, but none has yet been shown to be more useful than are established clinical and pathologic criteria for diagnosing or staging cancer. Among the newer markers of the tumor are ER- and PsR-receptor proteins, growth-factor receptors (EGFR, IGF-1R), DNA and S-phase content, HER/neu oncogenes, and cathepsin D.433–436 All of these correlate with tumor differentiation and growth rates, and some may provide more specific correlations in future evaluations, especially within subsets. None, however, can reliably replace lymph node status as a prognostic indicator.

It is of interest to attempt to measure the serum levels of these factors.437 Ongoing work in this area has concentrated on receptors for estrogen and progesterone, but EGF and IGF-1 are among other receptors now being studied.435,438 To date, findings are encouraging, but results are not currently applicable to routine clinical practice.

Current practice requires surgical axillary lymph node removal to determine nodal involvement. This information is used for prognosis and for assignment of patients to adjuvant chemotherapy treatments. Attempts to identify lymph node involvement by radio-immunoscintigraphy have, so far, been of limited usefulness because of the inability to image lesions in the microscopic range, but recent experience with removing the “sentinal node” and studying serial sections with IHC have shown a high degree of accuracy. It is not known if clinical correlations can be relied upon. NSABP protocol B-32 attempts to answer this question.

Such less invasive methodology or, better still, the advent of biologic indicators of tumor aggressiveness may well supplant surgical lymph node dissection in the future, but this procedure still provides the most reliable prognostic indicator.434

Psychosocial Aspects of Breast Cancer

The 1980s were marked by a greater awareness of the psychosocial needs of cancer patients. These issues arose in breast cancer patients, in particular, because of the many changes that occurred in therapy during that time. Radical breast surgery gave way to breast-conserving surgery at the same time that adjuvant therapies—many of them accompanied by uncomfortable side effects—were introduced. One potentially worrisome aspect of breast-conserving surgery was an anticipated rise in the fear of recurrence among patients so treated. Fortunately, most of the studies that have been done do not demonstrate such an increase. In general, lumpectomy patients report fewer feelings of unattractiveness and loss of femininity and less change in body image.439,440 When mastectomy is performed, immediate reconstruction results in a decrease in psychologic morbidity.128

Multiple surgical interventions and adjuvant chemotherapy are accompanied by an increased fear of recurrence. This fear is probably due to the perception that these additional therapeutic manipulations imply a more worrisome prognosis. Many of the adjuvant chemotherapies are accompanied by nausea and vomiting or by hair loss, and it is not surprising that these side effects have an impact on the psychosocial status of patients. Many studies indicate that breast cancer patients suffer from either increased anxiety states or depressive illness, but these analyses suggest that it is the diagnosis rather than the type of treatment that is responsible. Lumpectomy patients are not less anxious or depressed but, in general, adapt more favorably to their surgery and exhibit less functional change. There is increasing agreement that counseling services should be provided to help improve the quality of life of breast cancer patients.

Surgical Biology

In less than two decades, revolutionary changes have occurred in the locoregional management of primary breast cancer. As a result, radical and extended radical mastectomy have been relegated to the archives of surgical history. These operations are now historic milestones against which future progress can be measured.44 Total mastectomy and axillary dissection (modified radical mastectomy) can be considered the “radical” surgery of the present era. Two events, a decade apart, vividly illustrate the changes that have taken place in the surgical management of breast cancer. On June 5, 1979, an NIH-sponsored consensus development conference was held to address the question of whether there are clinical alternatives to radical mastectomy that minimize patient morbidity and do not decrease the likelihood of survival. The recommendations from that process were that total mastectomy with axillary dissection (modified radical mastectomy) should replace the Halsted radical mastectomy as the then current treatment standard and that the evaluation of procedures aimed at preserving the breast should be vigorously pursued. In repudiating the radical mastectomy, the consensus statement obviously rejected the principles that provided the basis for that operation.

On June 18, 1990, another NCI consensus meeting was convened to evaluate, among other issues, the place of breast conservation in the treatment of breast cancer.442 It was concluded that breast preservation is the preferable treatment for women with stages I and II breast cancer because it provides survival equivalent to those of total mastectomy and axillary dissection while, at the same time, preserving the breast. Aside from providing guidelines for the surgical management of primary breast cancer, that statement, like the one issued after the consensus meeting in 1979, also refuted the principles that have governed breast cancer surgery for more than three-quarters of a century.

The recommendations made at both meetings were based primarily on the findings obtained from randomized clinical trials—in particular, those conducted by the NSABP. Many have mistakenly perceived these trials merely as efforts to compare the outcomes of patients subjected to different locoregional treatments. There is less awareness that the studies actually tested two separate hypotheses associated with the biology of tumor metastases.

The Halstedian concept formulated at the end of the nineteenth century gave rise to the paradigm that governed the surgical management of breast cancer for most of this century. This paradigm was based on an anatomic and mechanistic perception of tumor spread that was in keeping with the understanding of the biology of tumor metastases at the time.443 Its tenets gave rise to the anatomic basis for cancer surgery. The Halsted radical mastectomy became the hallmark of a surgical belief that curability could be achieved more effectively with more expansive, meticulously performed operative procedures The Halstedian paradigm was related to the concept that tumor is a local phenomenon for a finite period of time and then spreads to regional lymph nodes, where it remains for another interval prior to systemic dissemination. Cure of the patient was long considered to be the result of a carefully executed surgical procedure in which all local and regional disease was eliminated. Consequently, en bloc dissection, that is, removal of the primary tumor in continuity with regional lymph nodes and all intervening and contiguous tissue, was the accepted operative procedure in breast cancer surgery. Failure to cure the patient was associated with the assumption that the disease had either extended beyond the confines of the surgical dissection or that an inadequate operation had been performed. Since it was believed that there was a certain “orderliness” to tumor spread and that clinically recognizable cancer was, in many instances, a local and regional disease, it was felt that the disease would more likely be curable if surgeons would be more aggressive in their attempt to eradicate all cancer cells. Local and regional recurrences were usually considered to be the results of inadequate application of surgical skill rather than manifestations of systemic disease.

Despite extraordinary surgical skill, noteworthy gains in disease-free survival and overall survival of patients eluded the surgeon. Partly as a result of surgeons’ disappointment with results obtained and, more significantly, as a consequence of conceptual changes that resulted from new information concerning tumor biology, a new basis for cancer surgery was formulated. This new hypothesis, synthesized from investigations conducted three decades ago, contends that breast cancer is a systemic disease involving a complex spectrum of host—tumor interrelations and that variations in locoregional therapy are unlikely to affect survival substantially.444 That premise was formulated from a series of laboratory and clinical investigations conducted from 1958 to 1970 to obtain a better understanding of the biology of metastases. Findings from all of those studies shared the same characteristic: they did not conform to the concepts that served as the basis for the principles of the Halstedian hypothesis, but, rather, provided a matrix for the formulation of an alternative thesis. This new hypothesis, synthesized in 1968, is biologic rather than anatomic and mechanistic in concept; its components are completely antithetical to those of the Halstedian thesis. The following considerations have led to a redefinition of the role of surgery in the management of breast cancer.

Breast Cancer as a Systemic Disease

Information from various sources indicates that many patients with breast cancer have disseminated disease by the time a clinical diagnosis is established. This is not surprising since a breast tumor of 1 cm (usually the minimal size capable of being clinically diagnosed and considered to be an early tumor) has already progressed through 30 of the theoretical 40 doublings that result in a tumor of approximately 1 kg, a size lethal to the patient.

Data regarding the percentage of treatment failures and survival 10 years after radical mastectomy for what were considered to be clinically “curable” breast cancers strikingly emphasize the systemic nature of the disease (Table 118.14).445 The findings that three out of four patients with positive axillary nodal involvement and almost 9 of 10 patients with four or more nodes containing tumor became treatment failures indicate the inadequacy of extensive local and regional surgery.

Table 118.14. Disease-free Survival and Survival 10 Years Following Operation (Radical Mastectomy).

Table 118.14

Disease-free Survival and Survival 10 Years Following Operation (Radical Mastectomy).

The fact that some patients are apparently cured by operation alone is no indication that the surgical procedure eradicated every cancer cell, that the disease was completely local and regional in extent, or that dissemination did not take place. The wise surgeon accepts the concept that the residual cell burden following tumor removal may have been sufficiently minimal for its eradication by host factors, which play a significant role in the success or failure of the operative procedure. The whole enterprise of adjuvant chemotherapy is built upon this concept: that it is possible to extinguish a small residual tumor load or reduce it to proportions where host mechanisms will succeed.

Effects of Primary Tumor Removal

Not only are host immunologic mechanisms affected by a growing tumor, but its removal may further alter these host functions and thus influence the patient’s course. The consequences of both tumor removal and the surgical procedure itself seem important in that regard. In addition, it has been shown that removal of a primary tumor alters the growth pattern of micrometastases.446 Increasing evidence has accumulated regarding the effect of removal of a primary tumor on the growth kinetics of metastases. Investigations of a variety of tumor-host systems demonstrate that there is an increase in the proliferation of residual tumor cells (metastases) following removal of a primary tumor.447–451 Since breast cancer, so far as is known, behaves like other cancers with regard to its effect on host immune systems, it is likely that removal of such a tumor has a variety of effects on the host. These findings are of particular significance today in view of the considerable interest in preoperative chemotherapy for the treatment of primary operable breast cancer. This aspect of tumor biology is further described below in the section on preoperative (neoadjuvant) chemotherapy for operable breast cancer.

Redefinition of the Role of Lymphatics and Lymph Nodes

Old beliefs about the role of lymph, lymph nodes, and the lymphatic system that had given rise to surgical concepts for almost a century are no longer appropriate.452 It is now known that, on gaining access to lymphatics, tumor cells may (a) be carried as emboli directly to a lymph node; (b) traverse collateral or alternative lymphatic pathways to lodge in more distant nodes rather than in proximal ones, even when the latter are not involved; (c) bypass such nodes to enter directly into the blood vascular system; or (d) gain immediate access to the blood vascular system by lymphatic venous connections occurring within nodes.453,454 Such bypasses can explain the noninvolvement of individual lymph nodes and atypical distribution of lymphogenous metastases.

The concept that lymph nodes act as an effective barrier to tumor cell dissemination has been shown to be incorrect. The lymph node is not an effective barrier to tumor cells, as was once believed, because the majority of tumor cells entering the node fail to maintain permanent residence.453,455,456 There is evidence to indicate that tumor cells that are primarily lymphborne reach the blood vascular system, through which they become further dispersed, and it has been demonstrated that tumor cells circulating in the blood vascular system may similarly find their way into the lymphatics, the thoracic duct, and back into the bloodstream.457 Thus, the two vascular systems are so unified insofar as tumor cell dissemination is concerned that it is no longer realistic to consider them independently as routes of neoplastic dissemination.

Evidence implicating immunologic mechanisms in the fate of tumors provokes other considerations. Should a human neoplasm contain tumor antigens that evoke a host immune response, cells from that tumor disseminated via lymphatics may be destroyed by immune nodes. Experimental evidence of the tumor cell destructive properties of sensitized lymphocytes supports such a possibility.

As a result of these considerations, it is unlikely that the finding of negative lymph nodes merely indicates that a given tumor has been removed prior to its lymphatic dissemination, nor is the significance of the positive lymph node related only to substantiating that tumor cells had, prior to operation, disseminated via lymphatics. The positive node may indicate that (a) the number of disseminated tumor cells exceeded the capability of the node for cell destruction, (b) there is a reduction of the immune response of the host (node), and/or (c) there is a change in the biologic nature of the tumor cell. These studies458 indicate that cells of regional lymph nodes continue to possess immunologic capabilities despite the presence of growing tumors. There is, however, a significant variation in lymphocyte transformation and thymidine uptake of cells derived from different regional lymph nodes within the same patient as well as between patients.

Thus, the significance of the positive or negative lymph node may not be that it serves to indicate whether lymphatic tumor cell dissemination has or has not taken place. Such dissemination may have occurred in all patients. In patients with negative nodes, immune competence may be entirely adequate to eliminate disseminated tumor cells in nodes and elsewhere throughout the body—hence the more favorable prognosis in patients with negative nodes. The positive lymph node may denote that host and tumor factors that permit tumor cells to grow in nodes also permit their developing metastases elsewhere, and thus the less favorable prognosis in node-positive patients.

A Biologic Basis for Breast Cancer Surgery

It would seem that breast cancer is likely to be a systemic disease at the time of diagnosis, and, if patient curability depends on the surgical removal of all cancer cells, operative intervention would need to be looked upon as a palliative procedure at best. Currently, the primary aim of oncologic surgery seems to be directed toward reducing the tumor burden of the patient to a number of viable cells that are destroyable by (a) host immunologic (and other) factors alone, (b) systemically administered anticancer agents, or (c) a combination of the two. The evidence that primary tumor removal may result in a variety of beneficial host changes, and that it may, by increasing the growth fraction, make residual tumor cells more susceptible to anticancer agents is of profound importance and provides a rational basis for cancer surgery. As a result of the improved use of systemic therapy during the past 5 to 10 years, there is evidence to support the thesis that, before long, the surgical treatment of breast cancer will become adjuvant to the use of systemic therapy.

Breast-Removal Treatment Regimens

In August 1971, the NSABP implemented the first of two clinical trials to test the validity of the principles on which the new biologic hypothesis for breast cancer management was based and to evaluate different regimens of surgical management for primary breast cancer. The results of that trial (B-04) were obtained from almost 1,700 women.459 Patients without clinical evidence of axillary node involvement were randomized among three different treatment regimens: (a) radical mastectomy; (b) total (simple) mastectomy with locoregional irradiation, but no axillary dissection; or (c) total mastectomy and removal of nodes only if they later became clinically positive. Women with clinical evidence of axillary node involvement were randomized to treatment by total mastectomy with irradiation or radical mastectomy. The significant aspect of this study is that 40% of the clinically node-negative patients treated by radical mastectomy were found to have histologically positive nodes. Thus, about 40% of the patients in the groups treated by total mastectomy alone would have had positive axillary nodes left unremoved. Despite this therapeutic nonconformity, no significant difference in overall treatment failure, distant metastasis, or survival was noted among the three groups through more than 10 years of follow-up.460 Sixty-five (17.8%) of the 365 patients with clinically negative nodes who underwent total mastectomy without irradiation subsequently had histologically confirmed, positive ipsilateral axillary nodes, which were removed by a delayed axillary dissection. A recent update through 18 years of follow-up indicates no significant difference in survival in clinically node-negative patients treated by radical mastectomy or by total mastectomy with irradiation (p = .8) and no significant difference in survival between the radical mastectomy group and the group treated by total mastectomy without irradiation (p = .5). In clinically node-positive patients, there was, likewise, no difference in survival between patients treated by radical mastectomy and those treated by total mastectomy and irradiation (p = .3) (Fig. 118.18).

Figure 118.18. Comparative survival through 18 years of clinically node-negative breast cancer patients treated by radical mastectomy, total mastectomy and regional irradiation, or total mastectomy alone and of clinically node-positive patients treated by radical mastectomy or total mastectomy and regional irradiation.

Figure 118.18

Comparative survival through 18 years of clinically node-negative breast cancer patients treated by radical mastectomy, total mastectomy and regional irradiation, or total mastectomy alone and of clinically node-positive patients treated by radical mastectomy (more...)

When patients free of disease at the end of 5 years were evaluated at between 5 and 10 years, not only was there no difference between the treatment groups, but the node-positive patients behaved similarly to those with negative nodes. Thus, patients with positive nodes have a worse prognosis for the first 5 years, but thereafter their rates of failure, locally and distantly, are similar to those of patients who had negative nodes. In patients with clinical evidence of node involvement, there was no significant difference between the group treated by radical mastectomy and the group treated by total mastectomy and locoregional irradiation. The findings also indicated that radiation of internal mammary nodes in patients with inner quadrant lesions did not improve survival and that survival results obtained at 5 years accurately predicted the outcome through 10 years.

It was concluded that variations in locoregional treatment used in the study were not important in determining survival of breast cancer patients. Since the findings did not support the efficacy of the en bloc dissection and failed to demonstrate a benefit from removal of axillary nodes with regard to the incidence of distant metastases or survival, they refuted Halstedian principles and strengthened the credibility of the alternative hypothesis. Most important, they refuted the justification for continuing to perform the radical mastectomy to treat breast cancer and indicated that axillary node dissection does not add to patient curability.

Our alternative hypothesis was tested further in other trials conducted during the 1970s. A major trial in the United Kingdom employed women with clinical stage I or stage II carcinoma of the breast.461 In this study, simple mastectomy was performed on all patients without surgical attention to the axillary nodes. Patients received either a course of regional radiotherapy or no further primary treatment (the “watch policy” group). Ten years later, no differences had been found between the two groups, thus lending support to the alternative hypothesis. These results antedated the era of chemotherapy. Recently, new reports have indicated that after mastectomy, radiotherapy and chemotherapy provide better survival than chemotherapy alone in cases of stage II or III breast cancer.

Breast Conservation

When findings from NSABP B-04 indicated that patients treated by total mastectomy without axillary node dissection or pectoral muscle removal were at no higher risk for distant disease or death than were patients who underwent a Halsted radical mastectomy, it was considered clinically and scientifically justifiable to begin a new study (NSABP B-06) to evaluate the worth of breast conservation by local tumor excision with or without radiation therapy.

Beginning in 1976, patients with T1 or T2, N0 or N1, M0 breast tumors of 4 cm or less were randomly assigned to one of three treatment groups: (a) total mastectomy, (b) lumpectomy, or (c) lumpectomy followed by breast irradiation (Fig. 118.19). Women in all treatment groups had an axillary dissection and those with positive nodes received chemotherapy. The lumpectomy operation completely challenged contemporary conventional concepts of cancer surgery by removing only enough breast tissue so that the margins of the resected surgical specimens would be tumor-free. All resected lumpectomy specimens were examined pathologically to ensure that the margins were tumor-free. The study was designed to determine the effectiveness of lumpectomy for breast preservation, whether radiation therapy reduces the incidence of tumor in the ipsilateral breast after lumpectomy, whether breast conservation results in a higher risk of distant disease and death than does mastectomy, and the clinical significance of multicentricity.

Figure 118.19. Treatment strategy of the NSABP B-06 study.

Figure 118.19

Treatment strategy of the NSABP B-06 study.

The protocol required that a total mastectomy be performed if the margins of specimens removed by lumpectomy were not tumor-free or if tumor occurred in the operated breast subsequent to lumpectomy. A tumor occurring following a previous lumpectomy was designated a tumor “recurrence” and was not considered a treatment failure unless it was so extensive that it could not be completely removed by mastectomy. Since, however, the breast was removed, the patient was regarded as having had a “cosmetic failure.” It must also be emphasized that, when disease-free survival, distant disease-free survival, and survival were determined in the three treatment groups, it was necessary that all patients in each group be included, even those in the two lumpectomy groups who had margins involved and who, consequently, had had a mastectomy. It was found that patients with tumors having margin involvement had a poorer prognosis than did those with tumors with free margins. Consequently, to have eliminated patients with margin involvement from the lumpectomy groups would have created a bias because patients with a similarly poor prognosis existed in the total mastectomy group. Their elimination would have resulted in lumpectomy-treated patients appearing to have a much more favorable outcome than those who had a total mastectomy. Recurrences of tumor in the chest wall and operative scar, but not in the ipsilateral breast, were classified as local treatment failures. Tumors in the internal mammary, supraclavicular, or ipsilateral axillary nodes were classified as regional treatment failures. Tumors in all other locations were considered distant treatment failures. Patients classified as having any distant disease included those with a distant metastasis as a first treatment failure, a distant metastasis after a local or regional recurrence, or a second cancer (including tumor in the contralateral breast). “Overall survival” refers to survival with or without recurrent disease.

Lumpectomy Technique

When NSABP B-06 was implemented, surgeons had little familiarity with conducting breast-conserving procedures. Workshops and other educational mechanisms were used to apprise participating surgeons of the methodologies mandated by the protocol. Those procedures have been used with thousands of patients entered into all NSABP trials evaluating locoregional and systemic therapy for breast cancer. The following descriptions, which are presented in more detail elsewhere, highlight the operative procedures used.462,463

It is emphasized that lumpectomy is an entirely different operative procedure from quadrantectomy as performed by the Milan Cancer Institute.442,464 The latter operation was carried out only in patients with negative axillary nodes, whereas the NSABP lumpectomy study was conducted using patients with both positive and negative nodes. In the NSABP study, lumpectomy was performed on patients with tumors less than 4 cm, whereas the Milan trial was limited to patients with tumors of less than 2 cm. In the NSABP study, skin or pectoral fascial removal, removal of the pectoralis minor muscle, and en bloc dissection were not features of the procedure, in contrast to the Milan operation.

Incisions and Skin Removal

Except in the case of true retroareolar lesions, transverse incisions are used no matter where in the breast a lesion occurs (Fig. 118.20). To achieve the best cosmetic results, radial incisions should be avoided. Curvilinear incisions except circumareolar will not heal as well. The idea that these follow Langer’s lines is incorrect. Simple inspection will show that the normal course of these lines is transverse, and old drawings of these suggesting that they curve around the breast result from a distorted perspective caused by the three-dimensional shape of the breast. Transverse incisions should be used even when tumors are in the upper outer quadrant of the breast near the axilla. A separate incision for the axillary dissection is almost always made even when a tumor is in that portion of the breast.

Figure 118.20. Recommended incisions.

Figure 118.20

Recommended incisions.

To perform a satisfactory lumpectomy, it is essential that the incision be placed directly over the tumor (Fig. 118.21). The use of a circumareolar incision for removal of a lesion that is not in proximity to the areola is inappropriate, as is tunneling through breast tissue to remove a lesion that is not beneath the incision. Tumor-free specimen margins are difficult and often impossible to obtain when such an incision is made. Re-excision of the tumor site to obtain free margins is equally difficult. The decision as to whether the patient is a candidate for lumpectomy should be made prior to operation. Consequently, the incision should not be made with concern as to how it might relate to skin removal if a conventional mastectomy is required. In those rare instances in which it is found at operation that a planned lumpectomy cannot be carried out because of the inability to obtain tumor-free margins, the mastectomy incisions are tailored to accommodate the lumpectomy incision rather than the converse. Preoperative needle biopsy can be of enormous help in planning the incision.

Figure 118.21. Nonrecommended incisions.

Figure 118.21

Nonrecommended incisions.

Since lumpectomy is not a Halstedian operation and since patients with tumor involving the overlying skin are not apt to be candidates for the operation, skin removal is not required, but a small ellipse of skin may be included to give the pathologist a chance to examine subdermal lymphatics. The quality of cosmesis is inversely related to the amount of skin removed. If a prior biopsy was performed, skin encompassing the biopsy is removed when lumpectomy is done.

Tumor Removal and Examination of Specimen Margins

The tumor is removed so that it is completely enveloped in normal fat and/or breast tissue. This procedure does not necessitate removal of a predefined amount of normal tissue around the lesion. The aim is to remove the amount adequate to achieve specimen margins grossly free of tumor, assuming that the tumor was not transected so that a portion remained in the patient (Fig. 118.22). If a prior biopsy was done and no attention given to specimen margins, it is obligatory that, at the time of node dissection, a re-resection be performed to ensure tumor-free margins. A special point to be emphasized is that skin edges should not be undermined when the excision is being performed; that is, thin skin flaps are not desirable. Undermining of skin, just as skin removal, results in an unfavorable cosmetic result. No special effort is made to include pectoral fascia in the specimen unless the lesion lies in close proximity to it. The specimen is tagged before it leaves the operating field (Fig. 118.22). Any system for doing this may be used. For example, a long silk suture is used to mark the lateral surface and a short suture to identify the superior aspect of the specimen. If so desired, additional tags may be placed to designate other margins. The specimen is immediately delivered to the pathologist, or, more ideally, he or she is present in the operating room to receive it and visualize the orientation. The pathologist’s role is to confirm or establish the diagnosis of cancer (if a needle biopsy was not done), to aid the surgeon in deciding intraoperatively whether the specimen margins are grossly free of tumor, and to take an aliquot of tumor for any special studies. It is preferable that the operative incision not be closed until the pathologist reports on the status of the specimen margins.

Figure 118.22. Technique of lumpectomy.

Figure 118.22

Technique of lumpectomy.

The pathologist receives the specimen and carefully orients it by means of the suture tags that the surgeon has placed. After measurement, the uncut specimen is inspected for gross margin involvement. If there is evidence that the tumor has been transected, the surgeon is immediately apprised of the precise location of the margin involvement so that additional tissue can be removed from that area while the pathologist is completing inspection of the specimen. The pathologist then coats the entire surface of the specimen with India ink, blots it dry, and then bisects the tumor and specimen transversely. The anteroposterior and mediolateral diameters of the tumor are measured, and the specimen is further examined to determine if the tumor is grossly close to any margin of the specimen. If there is concern about any border, the pathologist may do a frozen section to determine margin involvement. Additional breast tissue can be removed to obtain a new true margin any time that margin involvement is considered uncertain. Rarely will there be a subsequent report of microscopic tumor at margins that have been reported to be grossly free. A multiplicity of frozen sections need not be carried out to determine whether the margins are tumor-free. In fact, a frozen section need rarely be done for that purpose. If tumor is found on gross examination to be close to a portion of the resected tissue margin, the resection in that area is extended by removal of an additional rim of breast tissue and fat. The new true margin of the area that was considered to be close is identified for the pathologist by placing methylene blue or a suture on the surface of the re-resected portion of tissue that is farthest from the initial resection site. If the margin is microscopically involved following re-resection and there is no evidence that gross tumor has been transected, consideration may be given to not removing the breast and relying on radiation and systemic therapy to achieve local control. This policy may be employed whether the margins are involved with invasive or with noninvasive cancer. An update on their series of reports on margin control from the Joint Center in Boston demonstrates that recurrence rates are the same for focally positive margins as for true negative ones.465

The technique for examining the specimen for margin involvement may vary among pathologists. A detailed description of the approach established by NSABP project pathologists has been reported.5 At least 12 to 20 blocks are made from each specimen, depending on its size. Although this scheme will vary among hospital pathologists, in the NSABP study at least five lines of resection were available for review in lumpectomy patients. Pathologic assessment of lines of resection in a lumpectomy specimen is admittedly difficult because of the large surface area. This assessment is confounded by vague pathologic criteria used for making a decision about whether the tumor involves specimen margins. Many pathologists have the tendency to infer margin involvement by such subjective designations as tumor “too close” or “very close” to it. When hospital pathologists resorted to these subjective criteria, there was residual cancer in only 12% of total mastectomy specimens removed because of presumed margin involvement. Thus, it is most appropriate to regard lines of resection involved only when cancer is transected.

A new type of problem concerns the rising number of mammographically detected carcinomas that are not identifiable by gross pathologic examination and require special techniques. After x-raying the specimen to ensure the presence of the original abnormality, the tissue can be breadloafed and the slices laid out in sequence on an x-ray cassette tray. The resulting mammograph will enable the pathologist to identify the appropriate areas for microscopic examination and will provide information about margins since four of the margins are present on the periphery of the slice. The other two margins are on the slice(es) immediately preceding and following the ones with the lesion.(Figure 118.23)

Figure 118.23. Photo of gross specimen.

Figure 118.23

Photo of gross specimen.

Closure of the Lumpectomy Wound

After a decision has been made concerning the status of the specimen margins and meticulous hemostasis of the lumpectomy site has been achieved, closure of the wound is carried out. Since lumpectomy is a cosmetic procedure, meticulous attention must be given to this part of the operation. Attempts at breast reconstruction by approximating breast tissue and deep fat can lead to unfavorable cosmesis, particularly after removal of tumors in the upper half of the breast. For optimal cosmesis, no attempt should be made to obliterate the dead space in the breast by approximating breast tissue or fat, nor is a drain of any type ever placed in the wound. The skin is then carefully approximated by a single-layer continuous fine absorbable subcuticular suture.

Lumpectomy for Subareolar Tumors or for Tumors Greater Than 4cm

The aim of the NSABP lumpectomy protocol was to carry out the operation so that a normal-appearing breast resulted in all patients. Since subareolar tumors or those close to that position might require removal of the nipple and areola to ensure tumor-free specimen margins with a resultant cosmetic defect, lesions in such a location were considered not to be amenable to lumpectomy. This was particularly the case in women with large breasts and posteriorly located tumors. Experience has shown that satisfactory cosmesis can be achieved when the nipple and areola are removed for subareolar lesions and that the resultant breast shape and sensation are more nearly normal than that achieved by breast reconstruction after total mastectomy.

It is erroneously believed that lumpectomy is appropriate for only those patients with very small tumors. This misconception has arisen despite the statement that women with tumors 4 cm or smaller were eligible for the NSABP lumpectomy study. In subsequent NSABP trials, lumpectomies were performed on patients with tumors up to 5 cm if they had a breast of ample size to permit obtaining a favorable cosmetic result. Thus, patients with clinical stages I and II tumors are candidates for lumpectomy regardless of tumor location. When technically feasible, women with larger tumors and/or clinically positive nodes are better served by lumpectomy because they are at such great risk for the development of distant metastases and death regardless of what operation is performed.

The need for a mastectomy if margins are involved with tumor, despite appropriate lumpectomy by surgeons who make every effort to obtain tumor-free margins, is an issue currently being evaluated. In such circumstances, when it is clear that gross tumor has not been transected, it is likely that radiation plus systemic therapy will provide adequate locoregional tumor control.465

Similarly, when a breast tumor recurrence occurs following lumpectomy, it is likely that tumor control will be obtained by re-lumpectomy if such tumors are small and can be removed with tumor-free specimen margins. These and other issues regarding the use of breast conservation have been addressed in several reports.443,466,467

Axillary Dissection

Axillary dissection is not used with the intent of enhancing curability since regional lymph nodes are regarded as indicators of distant metastatic disease rather than as instigators of such tumor. Although the qualitative status of axillary lymph node involvement (i.e., either positive or negative) may be accurately determined by examining relatively few nodes, a more complete dissection is required for accurately determining the number of nodes involved.468 Since patient outcome is significantly related to the number of positive nodes present (i.e., 1–3, 4–9, or >10), a sufficient number must be obtained to quantify patient prognosis more accurately.469

The incision for axillary dissection should be separate from that used for removal of the tumor in the breast. A longitudinal incision placed along the posterolateral margin of the pectoralis major muscle or a transverse incision just below the axillary hairline may be used. In all NSABP breast protocols, an axillary dissection has included all nodes from at least axillary levels I and II. The anatomic delineation of this dissection is the latissimus dorsi muscle laterally, the axillary vein superiorly, and the medial border of the pectoralis minor muscle medially. Removal of the pectoralis minor muscle is not required. The nerves to the serratus anterior and latissimus dorsi muscles should be identified and preserved. The axillary vein should be visualized and followed under the pectoralis minor muscle to the medial border. These are the minimal limits for the dissection. The average number of nodes removed compares favorably with the number obtained following a radical mastectomy or a modified radical mastectomy in previous NSABP trials. In all NSABP studies since 1971, the number of axillary nodes removed—a mean number of 15—has remained remarkably constant. Although the lumpectomy site in the breast is not drained, a suction drain is present in the axilla for several postoperative days.

Sentinal Node Dissection

The use of radiotracer material or visible blue dyes to locate and remove the sentinal node (SN), (the node that drains the tumor site most directly) is rapidly gaining favor. This technique has been described for melanoma and breast cancer patients and has a high degree of accuracy once the operator has become familiar with the technique. A summary report by Krag470 indicates that SN can be successfully removed in a high percentage of cases and that the accuracy of predicting axillary metastases on this basis is very high. Approximately 11% of SN were located outside axillary level one and in 3% they were outside the axilla.

In patients with metastases to the SN, axillary lymphadenectomy will still provide quantative information that could be important in managing the patient. An unsolved problem is the issue of long-term regional control following a negative SN without a completion lymphadenectomy. The NSABP trial B-32 addresses this problem. This is a validation study to determine the usefulness of this procedure relative to treatment and outcomes. Patients with positive SNs will undergo formal axillary dissection as above, whereas those with negative SNs will be randomized to axillary dissection or no further therapy. This trial will determine the usefulness of SN surgery as a standard approach

Intraoperative frozen section has not been as accurate in detecting nodal metastases as was specific analysis done later in the laboratory. Imprint cytology has recently been reported to have a very low false-negative rate and may be the preferred method of intraoperative evaluation.

Need for Axillary Dissection

It is frequently asked whether all lumpectomy patients require an axillary dissection. If the need for systemic therapy, as well as the type of systemic therapy, can be determined by patient and tumor characteristics other than the status of the axillary nodes, then the need for axillary node dissection becomes less significant. Furthermore, if all node-negative and node-positive patients were to be given the same systemic adjuvant therapy, as is the case in trials of preoperative chemotherapy, there would seem to be no reason to know the nodal status, except for predicting patient outcome. With the demonstration that adjuvant chemotherapy benefits women with node-negative and node-positive cancers, and that the proportionate reduction in risk of treatment failure is the same for both groups,471 it seems reasonable to offer adjuvant chemotherapy to all women except those where the proportionate reduction is so low as to be of little real gain. With this approach, there is less reason to require axillary dissection, except perhaps in those cases that lie between the extremes of millimeter-sized tubular carcinomas, where no adjuvant therapy would be given, and the obvious tumors, especially those with poor nuclear grade, where all would be given adjuvant therapy. The need for axillary dissection may also be questioned specifically in elderly women, where the status of the axillary nodes does not usually alter the decision for administration of adjuvant therapy. For the present, axillary node surgery is still a standard, but with so much uncertainty, the issue remains in flux. SN biopsy may be a partial solution.

Outcome for Patients Treated by Lumpectomy

Results from 1,843 women entered into NSABP B-06 were first reported in 1985.472 Life-table estimates through 5 years of follow-up indicated that treatment by lumpectomy, with or without breast irradiation, resulted in disease-free survival, distant disease-free survival, or overall survival that was no worse than that achieved after total mastectomy. A significantly greater number of patients treated with radiation remained free of locally recurrent breast tumor as compared with those who received no radiation (p < .001). It was concluded at that time that lumpectomy followed by breast irradiation in all patients, and adjuvant chemotherapy in women with positive nodes, is appropriate therapy for patients with tumors less than 4 cm, provided that margins of resected specimens are tumor-free. Findings reported from the B-06 study through 8 postoperative years continued to support the efficacy of breast conservation..442,473 A recent update of the findings through 12 years of follow-up indicates that the findings and conclusions are in complete accord with those previously reported. The meta-analysis by Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) confirms the general proposition that local and regional therapies have little impact on overall survival.474

Breast Tumor Recurrence

Breast irradiation after lumpectomy significantly (p < .000005) decreases the likelihood of a tumor recurrence in the ipsilateral breast through 9 years of follow-up in women with specimen margins histologically free of tumor (Fig. 118.24). This benefit is observed in all women regardless of nodal status (Fig. 118.25), age (Fig. 118.26), or tumor size (Fig. 118.27). Even in the relatively few patients with tumors 1.0 cm or smaller, a benefit (p = .06) from the use of radiation is observed. When patients were evaluated relative to nodal status and tumor size, those with tumors larger than 1.0 cm (1.1–2.0, 2.1–3.0, and 3.1 cm or smaller) displayed a highly significant decrease in tumor recurrence following breast irradiation (Figs. 118.28, 118.29). However, when women were examined according to their nodal status, there were too few patients and too few events in either the node-negative or node-positive group to accurately determine the value of breast irradiation in those with tumors 1.0 cm or less in size.

Figure 118.24. Patients free of tumor in the ipsilateral breast following lumpectomy with and without breast irradiation.

Figure 118.24

Patients free of tumor in the ipsilateral breast following lumpectomy with and without breast irradiation.

Figure 118.25. Patients free of tumor in the ipsilateral breast following lumpectomy with and without breast irradiation, according to nodal status.

Figure 118.25

Patients free of tumor in the ipsilateral breast following lumpectomy with and without breast irradiation, according to nodal status.

Figure 118.26. Patients free of tumor in the ipsilateral breast following lumpectomy with and without breast irradiation, according to age.

Figure 118.26

Patients free of tumor in the ipsilateral breast following lumpectomy with and without breast irradiation, according to age.

Figure 118.27. Patients free of tumor in the ipsilateral breast following lumpectomy with and without breast irradiation, according to tumor size.

Figure 118.27

Patients free of tumor in the ipsilateral breast following lumpectomy with and without breast irradiation, according to tumor size.

Figure 118.28. Node-negative patients free of tumor in the ipsilateral breast following lumpectomy with and without breast irradiation, according to tumor size.

Figure 118.28

Node-negative patients free of tumor in the ipsilateral breast following lumpectomy with and without breast irradiation, according to tumor size.

Figure 118.29. Node-positive patients free of tumor in the ipsilateral breast following lumpectomy with and without breast irradiation, according to tumor size.

Figure 118.29

Node-positive patients free of tumor in the ipsilateral breast following lumpectomy with and without breast irradiation, according to tumor size.

A Cox regression model indicated that, regardless of nodal status, three covariates—treatment (p = <.001), tumors with poor histologic type (p = .02), and tumors with a maximum pathologic size greater than 2.0 cm (p = .007)—are significant predictors of the time to breast tumor recurrence. When examined according to nodal status, the same three variables were significant in patients with negative nodes: treatment (p < .001), histologic type (p = .02), and size (p = .01). Only two variables—treatment (p = <.001) and tumor nuclear grade (p = .03) were predictors of breast tumor recurrence in node-positive patients.

The NSABP pathologic experience following lumpectomy, particularly as it related to ipsilateral breast tumor recurrence, has been reported.475 Of all recurrences, 86% were noted within 4 years following lumpectomy, and 95% had occurred through 5 postoperative years. A review of the location of recurrences indicated that 95% involved the mammary parenchyma and the remaining 5% involved the skin and/or nipple only. Ten percent of those in the breast parenchyma were noninvasive. The most common presentation of the recurrence (86%) was as a localized mass within or close to the quadrant of the cancer removed by lumpectomy. Of the recurrences within the breast, 14% not only were in the same quadrant as the index cancer but also diffusely extended into other quadrants. In this type, intralymphatic extension was pronounced, being evident in remote quadrants and, not infrequently, in the overlying skin and/or nipple after the fashion of so-called inflammatory or occult inflammatory breast cancer.476 There were no significant differences in the time of appearance of the invasive and noninvasive breast tumor recurrences or in those invasive forms appearing locally or more diffusely in the breast. The histologic types and grades of recurrent, invasive cancers of breast parenchyma were identical in 86% of patients, whereas in 14%, their histologic type differed from that of the initial lesion. There was no relation between recurrences in the breast and level of ERs and PsRs of the index cancer. The mean largest diameters of the initial and recurrent cancers were 2.5 to 1.3 and 2.4 to 1.4 respectively.

Patterns of Local Recurrence

Two different presentations of local tumor recurrence have been identified. In the most common, the recurring lesion appears localized and probably represents residual tumor, incompletely removed at the original operation. This type of recurrence is amenable to local surgical management, often by repeat lumpectomy, or by mastectomy. In the second, more diffuse breast involvement is apparent, both clinically and pathologically. The tumor either is exceedingly multifocal, is infiltrative, or reflects the phenomenon of intramammary metastases. Intralymphatic extension is conspicuous, not only locally but in other quadrants, and often by intralymphatic extension, to dermal and/or nipple lymphatics as well as skin. The skin satellites may not necessarily be confined to the breast. This form of recurrence appears to be a local phenomenon of highly aggressive cancers rather than an induced biologic change associated with lumpectomy and may represent involvement of the breast by disseminated cancer cells. These recurrences are invariably followed in a short time by evidence of disseminated metastases and are seldom suitable for surgical management.477,478

Schnitt, Harris, Connolly, and associates related recurrence following biopsy and irradiation of breast cancer to anaplasia and an extensive intraductal component (EIC) of the initial cancer.479–481 The NSABP experience did not support this view. In later publications, they report that EIC is simply a marker for a stronger likelihood of positive margins.465 The relative infrequency of local breast tumor recurrence following lumpectomy and irradiation indicates that there are no pathologic discriminants that would appear to represent contraindications for lumpectomy and irradiation.(Fig. 118.30)

Figure 118.30. Two types of local recurrence.

Figure 118.30

Two types of local recurrence.

Analysis of the NSABP lumpectomy study, using innovative biostatistical approaches to ascertain whether a relationship exists between an ipsilateral breast tumor recurrence and metastases, indicated that such a recurrence is a highly significant independent predictor of distant disease.67 A patient’s risk of developing distant disease increases with the diagnosis of a breast tumor recurrence. That increase is not caused by metastases from the local recurrence. A patient who develops a recurrence is already at greater risk for distant disease at the time the primary tumor was removed than is a woman who subsequently remains recurrence-free. Some of the fixed covariates (risk factors) that predict for the development of distant disease also predict for a recurrence. Thus, a recurrence is a marker for a risk already present and, in fact, may be looked upon as an early manifestation, but not the source, of distant metastases. In patients treated by mastectomy, or by lumpectomy and irradiation, that marker is completely or partially prevented from expression, but the occurrence of distant disease is unaffected. Disease-free survival and overall survival are the same for all three groups, despite the fact that mastectomy patients had no local recurrences, and the lumpectomy/radiotherapy patients had only 10% rate of local recurrence.

Disease-free Survival, Distant Disease-free Survival, and Overall Survival

When three outcome parameters of women who had a total mastectomy were compared with those following treatment by lumpectomy without breast irradiation, no advantage of any of the outcome parameters was observed through 9 years of follow-up for women who had a total mastectomy (Fig. 118.31). At 9 years, the mastectomy-treated group had a disease-free survival of 55%, a distant disease-free survival of 63%, and an overall survival of 68%, compared with 51%, 59%, and 68%, respectively, for patients treated by lumpectomy alone. When a comparison was made between patients treated by lumpectomy and breast irradiation and those treated by total mastectomy, there also were no significant differences in the end points at 9 years (Fig. 118.32). When a comparison of the two lumpectomy groups was made, there were also no significant differences between the two groups through 9 years (Fig. 118.33). Similarly, no differences were noted in patients with negative or positive nodes.

Figure 118.31. Disease-free survival, distant disease-free survival, and survival of patients treated by total mastectomy versus lumpectomy.

Figure 118.31

Disease-free survival, distant disease-free survival, and survival of patients treated by total mastectomy versus lumpectomy.

Figure 118.32. Disease-free survival, distant disease-free survival, and survival of patients treated by total mastectomy versus lumpectomy plus breast irradiation.

Figure 118.32

Disease-free survival, distant disease-free survival, and survival of patients treated by total mastectomy versus lumpectomy plus breast irradiation.

Figure 118.33. Disease-free survival, distant disease-free survival, and survival of patients with negative tumor margins treated by lumpectomy versus lumpectomy plus breast irradiation.

Figure 118.33

Disease-free survival, distant disease-free survival, and survival of patients with negative tumor margins treated by lumpectomy versus lumpectomy plus breast irradiation.

Trial Evaluations the Worth of Quadrantectomy

In 1981, the first results were reported from a trial carried out at the NCI in Milan to compare radical mastectomy with quadrantectomy, axillary dissection, and radiotherapy in patients with small cancers of the breast.483 Findings from 701 randomized patients with tumors smaller than 2 cm and no palpable axillary nodes showed no difference in disease-free survival or overall survival. A more recent update of findings indicated that, through 11 years of follow-up (average 103 months), there was no difference in outcome between the radical mastectomy- and the quadrantectomy-treated groups.494 Subsequent comparison of quadrantectomy with a simpler tylectomy showed no significant differences except for a slightly higher rate of local recurrence in the tylectomy group.485

Breast Biopsy, the Two-stage Procedure and Fine-needle Aspiration

Paradoxically, just at the time when the two-stage biopsy procedure has gained acceptance, the merit of the approach needs to be reassessed and the entire method of breast cancer biopsy needs to be reappraised and modified. With the increasing use of breast-conserving operations and evidence to indicate their credibility, there is also a need to re-evaluate the surgical strategy used in breast cancer management. A detailed algorithm describing an optimal surgical strategy for the management of primary breast cancer has been described and is presented in Figure 118.34.486 It has been pointed out that, as a result of the increasing acceptance of lumpectomy, arguments for use of the two-stage procedure are essentially obsolete. The biopsy and the definitive operation are essentially the same operation and should be carried out more frequently in one stage.

Figure 118.34. Recommended surgical strategy for management of primary breast cancer.

Figure 118.34

Recommended surgical strategy for management of primary breast cancer.

Arguments about the merit of one- or two-stage approaches are becoming moot in the face of mammographically detected subclinical lesions and the widespread use of stereotactically guided core needle biopsies that provide the diagnosis before surgery.

It is an absolute dictum that all open breast biopsies be carried out as if a lumpectomy were being performed. Attention must be given to ensuring that specimen margins are likely to be free of tumor should a malignancy be encountered. Today, it is inappropriate to perform a biopsy without paying attention to specimen margins. In all circumstances where breast conservation is feasible, the operation carried out to establish the definitive diagnosis of a breast lesion becomes the definitive treatment whether axillary surgery is done at that time or later. Recent experience has shown that most breast cancer operations—biopsy, lumpectomy, axillary dissection, and even mastectomy—can be performed as out-patient procedures with comparable levels of surgical complications and equal or better personal and social adjustment to the procedure.487–491

The use of fine-needle aspiration to establish the diagnosis of a breast lesion is gaining favor and is the ideal approach, particularly for patients with clinical and/or mammographic lesions that are highly suspicious for being cancer. In Sweden, fine-needle aspiration has been the procedure of choice at the Karolinska Institute for more than 20 years. The Institute’s rate of false-negative cytologic reports is less than 10%; false-positive diagnosis almost never occurs.492 The experience is best exemplified by the report of Wallgren et al., who noted that, in a trial to evaluate preoperative radiation, the diagnosis was established by fine-needle aspiration in 960 women and that patients received preoperative radiation based on this diagnosis.493 An increasing number of reports in the American literature also describe the use of fine-needle aspiration. In a recent review, Hammond et al. describe experience with 4,943 aspirations from seven major institutions494; other findings indicate that there are only a few anecdotal reports of false-positive aspirations.495–497 The incidence of false positives is rare, far below 1%, and probably approximates the incidence of false-positive diagnoses of breast tumors by tissue examination. There is general agreement that success with this technique relates to the cumulative experience of the individual carrying out the aspiration and the pathologist interpreting the material he or she receives. The preparation of the smear is also of major importance. Core needle biopsy is in many ways simpler and provides more exact diagnoses, especially in distinguishing invasive from noninvasive cancers.

Paget’s Disease

In recent years, changes have occurred in the understanding and management of Paget’s disease of the nipple. The pathogenesis of this disease remains a matter of debate between proponents of two theories. The epidermotropic theory maintains that the Paget’s cells originate from the ductal epithelium and migrate to the epidermis of the nipple. The alternative theory considers the Paget’s cells to be malignant keratinocytes originating in the skin of the nipple. Supporters of the epidermotropic theory have advocated that mastectomy be used to treat the disease. The surgical management of the disease was also previously related to the presence or absence of a palpable mass. Radical or modified radical mastectomy was advocated in the presence of a mass, since it was shown that, with a mass, the incidence of axillary node involvement was as high as with infiltrating cancer of the breast.498,499 A simple mastectomy was reserved for patients with no mass.

In current practice, a majority of patients with Paget’s disease have a palpable mass, usually located in the vicinity of the nipple. Most patients without a palpable mass have mammographic evidence of a mass, microcalcifications, or architectural distortion indicating an underlying lesion. Since the tumor in patients with Paget’s disease is either an intraductal or an infiltrating-ductal carcinoma, the management of such patients can be similar to the management of patients with intraductal or infiltrating ductal carcinoma with nipple involvement. Thus, although traditionally a total mastectomy has been advocated, lumpectomy should be more frequently performed. After excision of the nipple—areolar complex, a subareolar lumpectomy with free margins can be performed. If infiltrating ductal carcinoma is found, an axillary dissection should be performed as well, followed by breast irradiation and adjuvant therapy according to the lymph node status and other tumor and patient characteristics. If an intraductal carcinoma is found, postoperative breast irradiation is indicated.

If no mass or mammographic lesion was demonstrated in association with nipple involvement, total mastectomy previously was the treatment of choice. However, lumpectomy of the subareolar area can be a sound alternative. If a lesion is demonstrated in the specimen, this should be further managed according to the above guidelines. If a lesion is still not demonstrated, then breast irradiation may be administered after lumpectomy. The effectiveness of radiation therapy in the presence of an intraductal cancer was recently demonstrated in a randomized trial conducted by the NSABP (B-17).500

Inflammatory Carcinoma

Other than to obtain a biopsy for establishing the diagnosis, there is no role for surgery in the initial management of these patients. At present, the initial treatment of choice for inflammatory carcinoma is chemotherapy followed by surgery or radiation therapy for local control in patients who show a response to chemotherapy. However, prolongation of survival has not been shown to be attributable either to surgery or to radiation therapy in this form of the disease.

Management of the Uninvolved Breast

Another facet of the uncertainty regarding the proper treatment of clinically curable female breast cancer is the management of the contralateral breast that does not contain a simultaneously clinically recognizable neoplasm. It has been reported that the risk of developing a cancer in the contralateral breast is four to seven times greater than the risk of developing an initial cancer by women in the general population. An NSABP evaluation of 2,734 patients revealed that the overall incidence of second primary carcinomas was 1.9% in 6 years.501

Evidence indicates that the incidence of occult cancer in the contralateral breast may be much greater than previously supposed. These data have been gathered by biopsy of the uninvolved breast at the time of management of the primary breast cancer. Such findings suggest a dichotomy between the high incidence of tumor found by random biopsy and the number of patients who develop overt cancers in the contralateral breast. This strongly suggests that not all cancers progress to overt lesions or that they may undergo regression.

Because of the high risk of cancer in the contralateral breast, prophylactic mastectomy of the uninvolved breast has been recommended.502 Others have proposed that a generous random biopsy of the unsuspicious contralateral breast be carried out and treatment determined after noting the microscopic findings. Because of the discrepancy in the incidence of positive biopsies and overt cancers that subsequently appear, a conservative approach using mammography and diligent follow-up examination seems to be more appropriate than random biopsy or prophylactic mastectomy. Results from large-scale trials support such an approach. They also indicate a ~50% reduction in the incidence of cancer of the contralateral breast in patients treated with tamoxifen in the adjuvant setting.503–505 A compilation of NSABP studies has shown that the opposite breast carries a risk equivalent to the risk borne by the participants in the prevention study, and that tamoxifen reduces this risk by similar proportions to the risk reduction in that study.506

Radiotherapy

Mastectomy and Adjuvant Radiotherapy

Modifications of the original Halsted radical mastectomy ranging from internal mammary lymph node resection to extensive dissection of the chest wall skin flaps have failed to decrease local chest wall recurrences after surgical treatment. Such recurrences are generally less than 10% in women with pathologically negative axillae and range between 20 and 30% in women with positive axillae.445,507,508

Radiation therapy has long been used as an adjuvant to mastectomy, the rationale being to decrease local and regional recurrences and thereby improve survival. There is now abundant evidence to indicate that adjuvant radiotherapy significantly reduces local and regional recurrences after mastectomy, often by a factor of 2 or more.460,461,509–512

Radiotherapy markedly reduces the incidence of local and regional recurrences; relapse-free survival of irradiated patients in randomized trials is often significantly improved when compared with that of patients treated by mastectomy alone.510,511,513 In the NSABP B-02 randomized trial, relapse-free survival was improved in the high-risk subset of patients with four or more positive axillary lymph nodes.514 A recent overview of the results of mature randomized clinical trials where adjuvant radiotherapy was an option after mastectomy not only did not find any survival differences in the first 10 years of follow-up but uncovered an excess mortality in irradiated patients followed for more than 15 years.515 Although the causes of this excess mortality were not investigated, the anterior internal mammary radiation portals used in the studies cited may have predisposed irradiated patients to an excess incidence of fatal myocardial infarctions.

Interest in local chest wall and regional lymphatic irradiation following mastectomy has been rekindled by two studies from the Danish Breast Cancer Cooperative Group.516,517 In the first study, almost 1,500 premenopausal women were randomized after mastectomy to receive cytoxan, methotrexate, and 5-fluorouracil chemotherapy with or without local chest wall and regional lymphatic (internal mammary, axillary, and supraclavicular) irradiation. Enrolled women had positive axillary nodes (92%) or T3/T4 primary tumors (14%). Overall survival at 10 years in irradiated women was 54% versus 45% in nonirradiated women, the difference being highly significant (p < .001). A major issue in the study was the high locoregional failure rate after mastectomy and chemotherapy: 17% for negative node T3/T4 patients, 30% for women with one to three positive nodes, and 42% for women with more than three positive nodes. These figures reported in contemporary series involving mastectomy and chemotherapy.518 A concurrently published report from British Columbia of similar design but randomizing about 300 patients showed similar survival rates with 15 years of follow-up but failed to reach statistical significance because of the small number of patients enrolled.517

The Danish Breast Cancer Co-operative Group very recently reported 10-year results involving some 1,400 postmenopausal women with stage II or III breast cancer randomized after mastectomy to receive 1 year of tamoxifen with or without chest wall and peripheral lymphatic irradiation.519 Interestingly enough, an identical 9% overall survival advantage was observed in favor of radiotherapy and tamoxifen: 45% for radiotherapy and tamoxifen versus 36% for tamoxifen alone. As anticipated, overall survival rates were lower for postmenopausal women compared to premenopausal women. Locoregional failure occurred in only 8% of irradiated versus 35% of nonirradiated women.

Most centers are reluctant to embrace routine chest wall and peripheral lymphatic irradiation in all women with node-positive breast cancer, especially since the complication rates, particularly arm edema, have yet to be reported by the Danish group. On the other hand, it seems prudent to irradiate women with high axillary node positively. Because the relative reduction on local recurrence appears to be independent of the absolute magnitude of such risk, four or more positive nodes or a primary tumor larger than 5 cm are reasonable thresholds for using postmastectomy irradiation.

The basic premise underlying arguments advocating adjuvant radiotherapy after mastectomy is that breast cancer spreads in an orderly fashion from the primary site in the breast to regional lymph nodes before disseminating distantly. The corollary argument that follows from this premise is that there is a subset of women whose only site of disease beyond the breast is in the regional lymph nodes and that, if these sites are sterilized, improved survival will ensue. This Halstedian view of the spread of breast cancer has been challenged by Devitt and by Fisher, both of whom have argued that breast cancer is a systemic disease from its onset and that regional lymph node involvement is only one manifestation of systemic spread.444,520,521 The extent of regional lymph node involvement is important, however, because of its prognostic significance.469,522,523 Although efforts at local control may be relevant and of clinical importance in selected subsets of high-risk women, these efforts should clearly be subordinate to systemic therapies.

Adjuvant chemotherapy by itself reduces the likelihood of local chest wall recurrences after mastectomy. Although one randomized clinical trial comparing mastectomy with and without adjuvant cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) showed no difference in local and regional recurrence rates,524 two other randomized studies have shown that adjuvant chemotherapy decreases local and regional recurrences. In the NSABP B-05 study comparing radical mastectomy with and without melphalan, melphalan-treated patients had a 14% incidence of local recurrence versus 24% for untreated women.518 Furthermore, the Ludwig Breast Cancer Study Group found an 8% incidence of local failure in women randomized to receive CMF plus prednisone and tamoxifen (CMFPT) versus 29% in untreated women.525 Chest wall irradiation may be warranted in high-risk patients (those with four or more positive axillary lymph nodes or primary lesions 5 cm or greater in size), if only to improve the local control rate without improving overall survival. At the present time, ER status, age or menopausal status, histopathologic findings, and flow cytometry data are poor discriminants for recommending adjuvant local radiotherapy.

Concerns for local and regional control after mastectomy are based on the often poor results of treating such recurrences successfully once they become manifest. Small, isolated recurrences have a good prognosis when treated by excision and chest wall irradiation. Unfortunately, other, more extensive manifestations of local and regional recurrences exhibit failure rates of 30 to 60% with radiotherapy479,526,545 and are rarely controlled with systemic therapy alone. Failure to control chest-wall disease is common even when surgical resection and systemic chemotherapy are combined with high-dose radiotherapy.546

Conservative Surgery and Radiotherapy

Despite ample data showing comparable survival between mastectomy and breast conserving therapy, wide geographic differences exist in the use of breast conserving therapy. At least 20% of eligible patients will choose mastectomy over lumpectomy and radiation.547 Multicentric disease involving more than one quadrant of the breast is the most common medical contraindication to breast-conserving therapy.548 The use of radiation therapy as the primary treatment for breast cancer evolved from the pioneering studies of Baclesse and others at the Foundation Curie in the 1930s.549 In a more recent update of this experience,550 the 10-year survival rates showed no significant differences from the radical mastectomy experience at Memorial Sloan-Kettering Cancer Center. Unfortunately, a large percentage of patients treated exclusively with radiation required subsequent surgery for persistent or recurrent disease because appropriate surgical techniques as we now know them were not used routinely to remove the breast lesions.

In 1975, Peters reported the results of excisional biopsy and radiation in patients with tumors measuring less than 5 cm and clinically negative axillae and compared them retrospectively by matched-pair analysis with the results of radical mastectomy.551 Overall survival up to 30 years was similar for both therapies. A prospective randomized clinical trial from Milan (now largely of historic interest), which compared the original Halsted radical mastectomy with quadrantectomy, axillary lymph node dissection, and breast radiotherapy in women with small tumors, showed no difference between the two groups in terms of relapse-free or overall survival.552

Two randomized trials carried out by the NSABP have resolved all major controversies about the local and regional management of breast cancer. In NSABP B-04, begun in 1971, patients with clinically negative axillae were randomized to radical mastectomy alone, total (simple) mastectomy and postoperative radiotherapy to the chest wall and regional nodes, or total mastectomy alone. Patients with clinically positive axillae were randomized either to radical mastectomy or to total mastectomy and postoperative radiotherapy. Within each group defined by the clinical axillary lymph node status at presentation, there were no differences at 10 years in disease-free, distant disease-free, or overall survival.460

Begun in 1976, the NSABP B-06 protocol evaluated breast conservation by local tumor excision with or without breast irradiation.472,473 Patients were randomly assigned to receive either total mastectomy or lumpectomy with or without breast irradiation. All women had axillary dissections, and those with positive nodes received chemotherapy. The breast operation, now commonly called a lumpectomy, abandoned traditional tenets of cancer surgery by removing only enough breast tissue to ensure free resection margins. Nonetheless, every lumpectomy should be carried out with the intent of removing the suspicious mass in its entirety and obtaining tumor-free margins.

Radiation therapy is highly efficacious in eliminating occult foci of tumor in the breast (Table 118.15)

Table 118.15. Local Recurrence Rates in Randomized Trials of Lumpectomy/Excision With or Without Radiation.

Table 118.15

Local Recurrence Rates in Randomized Trials of Lumpectomy/Excision With or Without Radiation.

The incidence of tumor foci elsewhere in the breast after lumpectomy alone is high: 24% of patients have invasive foci and 39% have noninvasive foci. Only 37% of breasts are tumor-free after lumpectomy.553 The dose level used should be cancericidal without producing distortion or fibrosis of the breast. The efficacy of 5,000 cGy in 25 fractions as used in the NSABP trials has been clearly established by the marked reduction in breast tumor recurrence after radiation, the failure to observe untoward cosmetic sequelae, and the absence of major complications, such as rib fractures and pneumonitis.

Radiation to the internal mammary lymph nodes offers no overall survival advantage. Indeed, unless an en face anterior radiation portal is used to treat this lymph node chain, many of these nodes will be missed or undertreated by tangential portals.554 Special attempts to treat internal mammary lymph nodes by increasing the tangential breast radiation portals are not justified because of the increased lung and contralateral breast tissue that is irradiated.

The NSABP results were achieved without using radiation boosts to the lumpectomy site. Since the NSABP incidence of breast tumor recurrences is similar to that observed by proponents of boost therapy,555 the need for a radiation boost to the excision may not be necessary when special attention is paid to the breast specimen margins. On the other hand, the use of such boosts is prudent if the status of the resection margins is unclear or if the margins are positive and re-excision is not performed. Boost techniques have been performed with interstitial brachytherapy, en face electrons, or cone-down photon tangential portals. Interstitial brachytherapy is no longer recommended because of the additional inpatient and operating room expenses, risks of general anesthesia, and often inferior cosmetic results compared with those obtained with electron beam or cone-down tangential photon irradiation.

Life-table analyses of the NSABP B-06 protocol through 9 years of follow-up for women whose specimen margins were histologically free of tumor revealed that 87% of women treated with lumpectomy and radiation were free of breast tumor recurrences compared with only 57% of those treated with lumpectomy alone (see Fig. 118.35).473 Breast irradiation was of significant benefit in all patients, regardless of axillary lymph node status (see Fig. 118.25). Among women with negative axillary lymph nodes, only 14% of irradiated women developed local tumor recurrence versus 40% of those treated by lumpectomy alone. The probability of recurrence among women with positive axillary nodes, all of whom received systemic chemotherapy, was only 11% with irradiation versus 46% with no irradiation. Life-table analyses in this study indicate that disease-free survival was significantly improved for women treated by lumpectomy and irradiation as compared with those treated by lumpectomy alone (see Fig. 118.33). No significant differences were observed in either distant disease-free or overall survival.

Figure 118.35. Disease-free survival (A) and survival (B) of node-positive patients with breast cancer who are 49 years old or younger, with cumulative odds ratios and cumulative p values.

Figure 118.35

Disease-free survival (A) and survival (B) of node-positive patients with breast cancer who are 49 years old or younger, with cumulative odds ratios and cumulative p values. PLAC, placebo; pts, patients.

Contingency analyses in the NSABP B-06 study demonstrated that recurrences after lumpectomy and radiation therapy were best, but not significantly, correlated with intralymphatic extension in the primary tumor.475 In those patients treated by lumpectomy alone, increasing tumor size, histologic and nuclear grade, and intralymphatic extension were all significantly associated with tumor recurrences in the breast. The presence of extensive intraductal carcinoma within or adjacent to the primary tumor is not an important risk factor for local recurrence when appropriate surgery for removal of the primary breast tumor is performed.475,556,557

The 1990 NIH Consensus Development Conference on Treatment of Early-Stage Breast Cancer concluded that breast conservation treatment is the appropriate and preferred therapy for stages I and II breast cancer because it provides survival equivalent to total mastectomy while preserving the breast. The recommended technique includes lumpectomy with clear margins, axillary dissection of level I and II nodes, and breast irradiation of 4,500 to 5,000 cGy with or without a boost. Regional lymphatic irradiation is not routinely recommended. Based on the postmastectomy radiation therapy experience of the Danish Breast Cooperative Group, however, regional lymph node irradiation may be justified in women with four or more positive axillary nodes. Prior breast augmentation or reconstruction is not a contraindication to conservative breast therapy. A recent re-evaluation of these studies has only reinforced the earlier conclusions. On the other hand, the presence of scleroderma is a contraindication because of the poor cosmetic results often observed.558

Paget’s disease of the nipple is not a contraindication to breast-conserving therapy.559 Complete resection of the nipple areolar complex followed by radiotherapy yields excellent results. A study of conservative surgery alone in early-stage breast cancer failed to identify any group of patients not benefitted by radiation after complete local excision.560 Despite the resurgence of interest in brachytherapy in recent years in a variety of cancers, brachytherapy as the sole therapy of early breast cancer remains unproven.561,562

Although the standard therapy after lumpectomy and radiation therapy is mastectomy, re-irradiation is an option in selected patients.563 Repeat lumpectomy is performed followed by 5,000 cGY in 25 fractions using electrons to the involved quadrant of the breast. In a recent update of the experience, the local recurrence rate in 33 patients was 15% (Melvin Deutsch, personal communication, 1999).

Breast cancer is one of the recently identified major late complications of mantle irradiation for Hodgkin’s disease.564,565 The cumulative incidence rises dramatically after 15 years of follow-up, especially in women treated by mantle irradiation before the age 15 to 20. These women can safely be offered lumpectomy and radiotherapy as an alternative to mastectomy.566

Locally advanced breast cancer is a loose term applied to nonmetastatic lesions of large size and poor prognosis because they invade the skin or underlying chest wall or otherwise present with fixed axillary lymph nodes or supraclavicular nodes. Inflammatory carcinomas represent a discrete subset of lesions that are characterized by a generalized erythema, warmth, and induration. Biopsy of the skin usually reveals obstruction of the subdermal lymphatics by tumor cells. Combined-modality therapy appears to be the most appropriate approach to patients with locally advanced breast cancer. The results from at least two prospectively randomized clinical trials comparing radiotherapy with mastectomy in a milieu of multiagent systemic chemotherapy showed no advantage of mastectomy over radiotherapy in terms of local control.567,568 Local control and cosmesis with radiotherapy can be good if attention is paid to technical factors.569,570 The cause of mortality from occult disseminated disease remains the major challenge in this group of patients. Many nonrandomized trials suggest that the majority of women with locally advanced breast cancer can be rendered disease-free after combined-modality therapy. Their disease-free and overall survival also appear to be substantially improved when compared with historic controls.571

Palliative Radiotherapy

The high response rates associated with hormonal therapy and systemic chemotherapy notwithstanding, there is a well-defined role for palliative radiotherapy in the treatment of metastatic breast cancer. Metastatic breast cancer is surprisingly responsive to modest doses of radiotherapy. Because radiotherapy is a local therapy, the responses to it are almost always faster than are those encountered with systemic treatments.

Painful bony metastases and simple pathologic fractures of non–weight-bearing bones respond well to short courses of radiotherapy, such as 3,000 to 3,500 cGy in 10 to 14 fractions. On the other hand, local radiotherapy is no substitute for proper orthopedic fixation in weight-bearing bones.

Radiotherapy is critical for pain relief as well as for the prevention and reversal of neurologic deficits associated with epidural spinal cord compression from metastatic breast cancer. A short course of high-dose corticosteroids and initial large radiation fractions should be used in an attempt to maximize tumor regression as soon as possible. Some authors advocate using radiotherapy alone without laminectomy in early-stage spinal cord compression and in responsive tumors, such as those in the breast.572

Treatment with radiotherapy is the mainstay for multiple intracranial metastases and is preferable to surgical treatment in the presence of widespread, poorly controlled systemic metastases. The generally accepted course of palliative brain irradiation for multiple lesions is 3,000 cGy in 10 to 12 fractions administered in conjunction with high-dose corticosteroids with or without phenytoin (Dilantin). The optimal therapy for a solitary intracranial metastasis in the absence of widespread systemic metastases is less clear. A recent randomized trial comparing surgical removal and radiotherapy with radiotherapy alone concluded that patients receiving combined therapy lived longer, had fewer recurrences, and enjoyed a better quality of life.573 Because 77% of patients in the study had metastatic lung cancer, which is not nearly as responsive to radiotherapy as is breast cancer, the value of surgical resection of brain metastases from breast cancer is certainly not established. It is possible that an external-beam radiation boost or a stereotactic radiosurgical boost might be as effective as surgical extirpation.

In patients with less than four brain metastases, none of which measures >2.5 cm, the addition of stereotactic radiosurgery boosts to these lesions after which brain irradiation significantly improves control of intracranial disease.574

Rapid and dramatic responses to stereotactic radiosurgery have been reported in patients with recurrent brain metastases from adenocarcinomas.574

Sequelae of Breast Irradiation

Skin

Erythema and dry desquamation are the most commonly encountered acute skin reactions observed with breast irradiation. Severe skin reactions were all but eliminated after the introduction of supervoltage equipment. Late fibrosis and telangiectasia are rare except when tissue-equivalent bolus material is deliberately applied to the breast to increase the cutaneous dose, as in cases of inflammatory breast cancer. Under these circumstances, moist desquamation is a desired component of the treatment in order to treat the subdermal lymphatics appropriately.

The cosmetic results after lumpectomy and breast irradiation are influenced by technique and the extent of surgery. Regardless of the technical factors involved, cosmetic results are generally poor when the biopsy procedure includes a wide resection of adjacent normal breast tissue without attempted reconstruction. Patients receiving 4,500 to 5,000 cGy in 180 to 200 cGy daily fractions rarely show long-term skin changes. On the other hand, patients receiving 6,000 cGy or more to the whole breast, regardless of the radiation technique, have significant breast retraction, fibrosis, and telangiectasia. Prolonged mild hyperpigmentation of the irradiated area is common in African Americans and in all women receiving adjuvant chemotherapy or electron beam radiation boosts to the lumpectomy site.

Rib Fractures

Rib fractures occur in up to 2% of women after breast irradiation.575 The median time to development is 1 year, and healing always takes place over the ensuing several months.

Lung

The incidence of untoward pulmonary reactions is low. Asymptomatic radiographic evidence of pneumonitis and/or fibrosis is often seen at the apex of the lung if the supraclavicular lymph nodes have been irradiated. This radiographic picture, which does not follow the architecture of normal anatomic structures, should not be confused with tuberculosis.

Heart

With the exception of en face internal mammary portals or tangential portals to the right breast, the heart is not irradiated in the treatment of breast cancer. Doses of 4,500 to 5,000 cGy via tangential portals to small volumes of the heart appear to be well tolerated despite the frequent development of nonspecific and reversible electrocardiographic changes.576 An increased incidence of myocardial infarctions has been attributed to the use of en face internal mammary portals.510,515 Modern radiotherapeutic techniques, however, are not associated with an increased risk of cardiac related mortality, at least within the first 12 years of follow-up.577

Nervous System

Irradiation of the supraclavicular fossa containing the brachial plexus is indicated only in locally advanced disease. Pure radiation-induced peripheral neuropathy is rare. The differential diagnosis of radiation-induced injury versus recurrent tumor is often difficult to resolve because supraclavicular induration, paresthesias, sensory loss, paresis of an arm, and edema occur with both entities. Most patients with brachial plexopathy after irradiation are found to have recurrent cancer rather than radiation-induced injury.578

Second Tumors

The development of a radiation-induced neoplasm is possible not only within the irradiated breast but also in the medial half of the contralateral breast, since this region almost always receives some irradiation, if not from the primary radiation beam, then from internally generated scatter. The total scatter dose to the contralateral breast can easily be several hundred centigrays.579 Fewer than 3% of all second contralateral breast tumors in a case-control study of 41,109 women from the Connecticut Tumor Registry could be attributed to prior radiotherapy.580 Although significantly increased in women irradiated before the age of 45, the risk of radiation-induced contralateral breast cancer should not be a factor in selecting treatment for breast cancer.

The major confounding variable in evaluating a local treatment failure versus a radiation-induced tumor is the high risk of developing a spontaneous second cancer. In the nonirradiated contralateral breast after a mastectomy, the risk is as high as 1% per year and remains relatively constant for 20 to 30 years.581,582 In comparison with results after mastectomy and postoperative radiotherapy, the overall incidence of local and regional recurrence after definitive breast irradiation is higher, and no plateau is observed at 5 years. In one study of breast conservation and radiotherapy, local recurrences developed at a projected constant rate of about 1.5% per year over 15 years of follow-up, emphasizing the need for careful long-term follow-up.583 The majority of early (less than 5-year) local recurrences develop in the vicinity of the original primary tumor. On the other hand, the majority of late local recurrences develop elsewhere in the breast, suggesting that late local recurrences may not be true recurrences at all but rather new tumors that arise spontaneously.584,585 To date, however, any excess risk of developing a late “second” tumor in the conserved breast does not appear to be clinically important. Furthermore, late local breast tumor recurrences after radiotherapy are not necessarily harbingers of disseminated disease. Fortunately, local recurrences in the irradiated breast are often detected at an early stage because of follow-up mammography and heightened physician and patient awareness. Local breast tumor recurrences after lumpectomy and radiotherapy can be successfully treated by mastectomy without excess morbidity.586–588

Ductal Carcinoma In Situ

DCIS is frequently multicentric and multifocal and is often associated with the concomitant presence or subsequent development of clinical disease (another DCIS or an invasive cancer). The frequency of synchronous multicentric or multifocal lesions is related to the thoroughness of pathologic examination after a mastectomy and to the quality of the mammography when breast conservation is used. Whether DCIS is an obligatory preliminary step for the development of breast cancer and whether all DCIS eventually becomes invasive is still uncertain. It appears that the rate of histopathologic multicentricity is greater than the incidence of synchronous or metachronous ipsilateral or contralateral cancers. In one study, DCIS was noted in 48% of contralateral breasts, yet the cumulative risk of opposite breast cancer 2 years after diagnosis of initial tumor was only 12.5%.589 Perhaps all in situ cancers have the capacity to become invasive, but not all actually do so. If genetic events occur in the transition of DCIS to invasive cancer, the time for this transition may be short for some tumors, long for others, and never for the remainder. The change may be related to the growth rate of DCIS cell populations, the efficiency of DNA repair, the rate of formation of new genetic variants, and exposure to external carcinogens and promoting agents. There is a need to identify markers or histopathologic types of DCIS that will indicate patients at risk for recurrent DCIS or for the development of invasive lesions after breast conservation.

Assuming that conservative surgery and radiotherapy represent the preferred treatment for early breast cancer, what is the best therapy for DCIS? NSABP protocol B-06 identified 78 examples of DCIS after pathologic review of the lumpectomy specimens.590 With an average follow-up of a little more than 3 years, 23% of women treated by lumpectomy alone developed a local failure within or close to the initial lesion, compared with only 7% of women treated by lumpectomy and radiotherapy. The therapy of DCIS is presented in detail below.

Special topics

Lobular Carcinoma In Situ

The surgical treatment of LCIS has changed drastically in recent years as a result of a better understanding of the biologic significance and natural history of this lesion. Treatment strategies for the management of LCIS evolved from considerations relative to its multicentricity, its bilaterality, and its tendency to develop into invasive breast cancer. Formerly, the recommended therapy for LCIS included bilateral total mastectomy, total mastectomy with mirror-image biopsy of the opposite breast, or total mastectomy with elective biopsy of the opposite breast.541,594–596 However, better information about the natural history of LCIS indicates that the majority of patients with the disease do not develop invasive cancer.597–601 Furthermore, the invasive cancer that develops in patients with LCIS more frequently is of ductal than of lobular origin, and both breasts are at similar risk for the development of invasive cancer. In light of these facts, it has become obvious that LCIS should be regarded as a marker that indicates an increased risk for the development of invasive breast cancer of any type in either breast rather than of a premalignant lesion that progresses to infiltrating lobular cancer. If one accepts this concept, it becomes evident that no further surgery is needed in a patient with a biopsy-proved LCIS. However, since such patients are at higher risk for developing invasive cancer (a risk estimated to be approximately 10 times the normal), close follow-up with mammography and physical examination is recommended.The NSABP currently maintains a registry of such patients in order to collect more definitive information about the natural history of the disease. To date, there is no evidence that breast irradiation is effective in preventing the development of invasive cancer in patients with LCIS.

A more rational approach to the management of LCIS would be an attempt to prevent the development of invasive breast cancer in women with this disease. The NSABP BCPT randomized women at high risk for the development of breast cancer (including those with LCIS) to 5 years of tamoxifen or placebo. Tamoxifen was shown to reduce the risk of a woman with diagnosed LCIS progressing to invasive cancer reduced by nearly 50% (see below). Since LCIS is the expression of a phenotype carrying a higher risk of breast cancer, interventions like tamoxifen represent the promise of ultimate biologic control of these conditions.

Pregnancy and Breast Cancer

Among women with breast cancer, 1 to 2% are pregnant, their average age being around 35 years.805 There is no evidence that pregnancy is associated with either the development or progression of breast cancer, since the patient’s prognosis is related to the stage of the disease rather than to the pregnancy itself. The generally worse prognosis for women diagnosed with breast cancer during pregnancy can be attributed to the fact that a diagnosis in such patients is often delayed so that by the time the disease is detected, it has already progressed to an advanced stage. Changes in the breasts during pregnancy that make cancer difficult to detect, as well as the reluctance of physicians to perform mammography in pregnant patients, may account for the delay in diagnosis. With the use of abdominal shields, however, radiation exposure to the fetus is negligible, and adverse effects to the fetus have not been observed with mammography.603 Therefore, the diagnostic procedures performed in women who present with suspected breast cancer during pregnancy should be the same as those used for nonpregnant women. Treatment is generally similar to that prescribed for nonpregnant breast cancer patients. Although modified radical mastectomy might be considered the treatment of choice in order to avoid the need for postoperative radiation, there is a role for lumpectomy followed by breast irradiation after delivery, particularly in late pregnancy. When adjuvant chemotherapy is indicated, this should also be delayed until after delivery. Consideration should be given to early cesarean section in order to facilitate the administration of adjuvant chemotherapy to patients at high risk for recurrence. For more advanced cancers discovered during early pregnancy, termination of the pregnancy may be warranted so that chemotherapy or radiation may be given. If the diagnosis occurs during late pregnancy, the patient can be treated after delivery. In a group of women with a similar stage of breast cancer, there is no significant difference in prognosis between those who are pregnant and those who are not.604 With regard to subsequent pregnancies for patients who have had breast cancer, several authors have suggested a waiting period of 3 to 5 years, depending on the nodal status of the cancer.600,606 Findings from recent studies, however, fail to show a worse prognosis in breast cancer patients who subsequently become pregnant; some have even indicated a better prognosis for such patients when compared with breast cancer patients who do not have subsequent pregnancy.607

Male Breast Cancer

Carcinoma of the breast occurs infrequently in men in the developed countries, the incidence being about 1% of that in women.608 In several African countries, the incidence in hospital registries is 5 to 15% that of female breast cancer. Breast cancer accounts for about 0.1% of all cancers in American men, and rarely occurs in males under the age of 40, with the average age at onset about 60 years, or about 10 years older than for women.609–613 Familial associations have been reported.614,615 Several factors have been implicated in the etiology of the disease, including a history of prior radiation, hyperestrogenism, and Klinefelter’s syndrome.616–618 The association between gynecomastia and male breast cancer is less clear.

Histologic tumor characteristics in males are similar to those in females, with two-thirds of patients presenting with intraductal carcinoma. LCIS, however, is not observed in males. ERs have been found in up to 84% of tumors in males who have the disease.619 The most common presenting symptoms include breast mass, bloody nipple discharge, nipple retraction, axillary mass, and distant or local pain. Breast cancer usually presents in a more advanced stage in men than in women.610,612,620 However, operability rates of from 74 to 95% have been reported.616,621–624 Radical mastectomy has been recommended because of the frequent involvement of the pectoralis major muscle; however, if the muscle is not extensively involved, a modified radical mastectomy can be performed. Some advocate excision of a portion of the underlying pectoral muscle in the latter case to ensure free margins of resection. Although some authors believe that lymph node involvement has the same prognostic significance in males that it does in females, others report that the presence of lymph node metastases has an even greater impact on prognosis in men.610,612,616,621,626 Postoperative radiation therapy to the chest wall is advocated by some for local control.613 To date, no systemic data are available on the use of adjuvant chemotherapy in male breast cancer patients. Patterns of metastasis are similar to those in females.

The treatment for metastatic breast cancer in men has changed during recent years. Although orchiectomy was once the standard therapy for advanced disease, it has been replaced by tamoxifen as the initial therapy since ER-positive tumors are predominant in males.627,628 A 71% response rate has been observed with tamoxifen in such patients.629,630 Although ER-negative tumors do not seem to respond to tamoxifen, convincing data are not yet available.619,629 In cases of progression after an initial remission with tamoxifen, orchiectomy or gonadotropin-releasing hormone agonist treatment is indicated, with other modalities such as medical (aminoglutethimide) adrenalectomy and chemotherapy being reserved for further failures. Surgical adrenalectomy and hypophysectomy are rarely performed. Chemotherapy as the initial therapy for metastatic disease has a lower overall response rate than that achieved with tamoxifen.631

The prognosis for breast cancer in men depends on lymph node status, size of the tumor, and duration of symptoms prior to diagnosis and, overall, is worse than that for women.610,622,626

Reconstruction

Although lumpectomy is accepted as the preferred operation, some patients with extensive or diffuse tumors still require mastectomy.667 For most patients, breast reconstruction is an important element in their psychosocial recovery.

Traditionally, it was thought best to wait several months and perform the reconstruction when the mastectomy site was well healed. Psychosocial studies have shown, however, that psychiatric morbidity is diminished if simultaneous reconstruction takes place.543

Today, a commonly accepted procedure is immediate reconstruction with the placement of an inflatable prosthesis at the time of mastectomy so that the skin flaps can be approximated without tension and be allowed to heal. Sterile saline can then be injected into the prosthesis through a side port, gently stretching the skin until the desired volume is obtained. The prosthesis can then be replaced with a more permanent type, or, as in some models, the side port can be removed.

When there is insufficient tissue for adequate reconstruction, myocutaneous flaps can be mobilized. An early version is the latissimus dorsi flap, which brings skin, subcutaneous tissue, and muscle on its neurovascular pedicle from the region of the scapula to the operative site at the breast to allow for adequate tissue expansion.

A more modern and cosmetically preferable operation is the transplantation of a musculocutaneous flap from the rectus abdominis muscle in the lower abdomen. Both of these procedures result in additional surgical scars at the donor site of the transplant, but the abdominal procedure provides a cosmetic result that is usually better than that achieved with the placement of a simple prosthesis. Nipple reconstruction can, in all cases, be accomplished by transplanting skin from the labia or inner thighs. Although many reconstructive efforts are quite acceptable cosmetically, with the passage of time, scarring may cause contraction and deformity, requiring additional corrective procedures in some patients.

Silicone Implants

Silicone implants antedate current FDA regulations so that present product safety testing regulations were not followed when these devices were introduced and no data are on file. When a possible carcinogenic breakdown product was found associated with the polyurethane covering of one type of prosthesis,633 there was no information to answer the many questions that arose about safety of implants. Berkel reviewed 11,676 women in Alberta who underwent breast augmentation with implants and compared them with 13,557 women with primary breast cancer. Estimating the expected number of breast cancer cases in the implant cohort by age and calendar year, they calculated the standardized incidence ratio to be 0.47. Subsequently, Berkel’s co-authors published a correction identifying methodologic problems and cautioned that a planned reanalysis was expected to show a ratio higher than 0.47.

Petit et al.635 studied 146 patients who received silicone implants after mastectomy at the Institut Gustave Roussy. They were compared with 146 control breast cancer patients who underwent mastectomy but who did not have reconstruction. The relative risks of death, relapse, and second primary cancers were, in fact, lower in the reconstruction group, which is probably not related to the use of implants but to the possible selection of more favorable cases for reconstruction. Other reviews contend that available data have not been sufficient to confirm or disprove the causal relationship.

The issue regarding carcinogenesis has not been substantiated, but the whole issue of safety has received serious attention as a result of that impetus. Although silicone implants have been used for 30 years, serious questions about their safety arose only in the 1990s. Most of the reports alleging systemic problems with silicone implants are anecdotal. A report evaluating 100 women with breast implants documented such symptoms as weakness, fatiguability, myalgia, morning stiffness, memory loss, and headache.636 Abnormalities in serum immunoglobulins or complement were noted in more than 70% of patients. No comparable investigation of women without implants or any other control was undertaken, but the authors concluded that the objective laboratory findings were important.

Although cellular and humoral immune responses to silicone can be detected, their relation to the development of connective tissue disorders has not been clearly established. Shons and Schubert collected 28 cases of systemic autoimmune disease arising in patients with silicone breast implants.637 Given the number of implants performed, they calculated that a coincidental occurrence should be of the order of 1,000 cases. Gabriel et al.638 followed all 749 women with implants in Olmsted County, Minnesota, and compared them with 1,498 controls. No association between implants and the incidence of the connective tissue disorders studied was found. The issue has been confused by the anecdotal nature of many reports, by differences between crystalline and liquid silicone performance in vivo, by combining the injected silicone cases with patients who had formal prostheses, and by the vagueness of many of the symptoms reported. Several reviews639,640–642 of published reports conclude that the bias against silicone is unfounded. In 1999, a special panel of medical experts convened by the Institute of Medicine at the request of the Court reported that there was no convincing evidence of a link between silicone implants and any systemic disease state. Largely because of media publicity and because of the lack of adequate objective data, the FDA ordered the removal of silicone implants from the market in 1992. Major class action and individual lawsuits led to the Dow-Corning Company filing for bankruptcy protection. Saline implants are still available, and silicone implants may again be so.

Systemic Adjuvant Therapy

Early Trials

One of the most important advances in oncology came out of the acceptance of evidence that most patients with primary breast cancer have disseminated tumor at the time of diagnosis and that increased survival results only from effective systemic therapy used in conjunction with operation. This consensus has led to a major change in the concept of the disease and to the implementation of clinical trials to evaluate the efficacy of various systemic treatment regimens as adjuncts to operation. The historic background that set the stage for the first trial is worth reporting.

The earliest observation of tumor cells in the blood was made by Ashworth in 1869.643 However, except for a few sporadic reports of abnormal cells in the blood of patients with tumors, investigators showed little interest in this phenomenon.644–647 In 1955, Fisher and Turnbull, and Engell reported the presence of tumor cells in the blood of cancer patients and a surge of interest ensued.648,649 Especially noteworthy are the studies that report the presence of cancer cells in the blood during pelvic and rectal examinations, uterine curettage, transurethral resection, the cleansing of the skin over a tumor prior to operation, and the operation itself.544,650–653

It was believed that, despite meticulous surgical skill, tumor cells dislodged during operations were a prime factor in the failure to effect a cure, and that improved results would follow if such hematogenous circulating tumor cells were destroyed. Following reports of favorable effects of chemotherapeutic agents on the destruction of disseminated tumor cells in experimental animals, a rationale for embarking on clinical trials of adjuvant therapy was established.538,654,655 Further support for the use of systemic therapy was obtained from early investigations in which it was noted that, although surgical removal of tumors or the use of 6-mercaptopurine failed to “cure” 15-day-old murine mammary tumors, the combination of the two resulted in a 57% cure rate.656

As a result of these and other experimental findings, in 1957, under the auspices of the NIH Cancer Chemotherapy National Service Center, a protocol for a trial was devised to determine the efficacy of administering chemotherapy in addition to cancer surgery with curative intent to decrease recurrence and to extend the survival of patients with breast cancer. Several other cancers were also studied in parallel trials. It was anticipated that such a therapeutic regimen could destroy the tumor cells dislodged into the blood and lymph during surgical manipulation. The effort was carried out by a group of clinical investigators in what eventually became known as the National Surgical Adjuvant Breast and Bowel Project (NSABP). This acronym has since been used to identify the cooperative group that for more than 40 years has conducted major clinical trials to evaluate a variety of treatment modalities in the management of patients with primary breast (and bowel) cancer. In 1958, the NSABP began the first clinical trial of adjuvant chemotherapy for breast cancer. Women entered into this study were treated by either conventional Halsted radical mastectomy and triethylene thiophosphoramide (thiotepa) or by radical mastectomy and placebo. Because of its effectiveness in the palliation of advanced mammary cancer, thiotepa was administered at the time of operation and on each of the first 2 postoperative days. The results reported in 1968 indicated a significant increase in the 5-year survival of premenopausal women who received thiotepa.21 The difference, which was seen mainly in patients with four or more positive axillary nodes, persisted after 10 years of follow-up.445 Thus, the initial avoidance of treatment failure had a lasting effect, which was reflected in patient survival. Most important, it was demonstrated for the first time that the natural history of some breast cancer patients could be altered by systemic therapy.

It soon became apparent that cells disseminated at the time of surgery were likely to be less important than micrometastases that were already established. In the 1960s, new concepts were formulated that led to a second generation of chemotherapy trials. Those principles were primarily related to tumor cell kinetics and still provide much of the biologic basis for the use of adjuvant chemotherapy.657–659 The first of this second generation of clinical trials was conducted jointly by the NSABP and the Eastern Cooperative Oncology Group (ECOG) to evaluate the use of l-phenylalanine mustard (l-Pam) administered for 24 months after radical mastectomy to patients with positive nodes. That study was the first full-scale trial in the United States to evaluate prolonged adjuvant therapy.

In 1973, a second clinical trial was begun at the NCI in Milan to evaluate the effectiveness of a three-drug combination, cyclophosphamide, methotrexate, and 5-fluorourocil (CMF) as an adjuvant.660 The patient selection and experimental design were essentially similar to the American both trials. The NSABP trial focused on a single drug, l-Pam, because it had limited toxicity, an important consideration for patients recently operated on with curative intent. It was also a drug that could be taken orally and was non cell cycle specific.

By September 1974, evidence was available to indicate that a specific aim of the NSABP study had been achieved, that is, that l-PAM administration could prolong the disease-free interval of patients. Those findings were subsequently reported.661 Data continue to indicate that the single agent is effective in significantly reducing the treatment failure rate of premenopausal patients. Extended follow-up (more than 10 years) has demonstrated not only a significant prolongation of disease-free survival but also a significant benefit in the survival of premenopausal patients.662 Although a similar trend was initially observed in postmenopausal women, that benefit has not been sustained. Minimal undesirable side effects were reported by women taking l-Pam; mild nausea and vomiting occurred in about one-third of the patients.

In the Italian trial, a significant reduction in treatment failure occurred in all subgroups of patients treated with CMF. About two-thirds of patients experienced some toxicity, indicated by nausea, vomiting, anorexia, alopecia, cystitis, or amenorrhea. The 20-year results from the Milan trial continue to indicate a benefit in premenopausal, but not postmenopausal, women.664–665

Over the next two decades, over 200 controlled clinical trials were initiated to extend the earlier results, define optimal adjuvant systemic therapy and evaluate a variety of newer treatment regimens. To summarize these results, the NIH organized two consensus development conferences.666,667 In addition, EBCTCG performed several meta-analyses of all (published and unpublished) prospective randomized trials designed and conducted for operable primary breast cancer.668–676 Review of the consensus documents and the reports of the EBCTCG’s meta-analyses shows the continuous evolution of this field, based on the maturation of clinical trial results and the availability of new data. The information obtained from the individual clinical trials, the consensus process, and the meta-analyses can be summarized as follows:

1.

Adjuvant chemotherapy effectively reduces the risk of recurrence and death from breast cancer.668–670,674

2.

Combination chemotherapy is more effective than single-agent chemotherapy.668–670,674

3.

Adjuvant chemotherapy is more effective for women younger than 50 years of age than for older women, but significant benefit is observed in women in all age groups in which chemotherapy has been adequately evaluated.669,670,674

4.

Adjuvant anthracycline-containing regimens are more effective than other combinations lacking an anthracycline.674

5.

Adjuvant chemotherapy for longer than 6 months with the same regimen is not more effective than chemotherapy for 6 months.669,670,674

6.

Adjuvant tamoxifen effectively reduces the risk of recurrence and death from breast cancer. This effect is similar for patients in all prognostic groups.668,669,671,675

7.

Adjuvant tamoxifen is effective only in patients with ER- and/or PsR-positive breast cancer.675

8.

Adjuvant tamoxifen has similar efficacy in patients in all age groups.675

9.

The efficacy of adjuvant tamoxifen increases with longer duration of therapy. At this time, data indicate that the optimal duration of adjuvant tamoxifen is 5 years.671,675

10.

Adjuvant tamoxifen significantly reduces the incidence of new or contralateral breast cancer.671,675

11.

Adjuvant ovarian ablation effectively reduces the risk of recurrence and death from breast cancer.668,669,671,673

12.

Adjuvant ovarian ablation is effective only for premenopausal women.668,669,671,673

13.

The combination of tamoxifen and adjuvant chemotherapy is more effective than chemotherapy alone or tamoxifen alone for patients with hormone receptor-positive tumors.671,673

The report of the first meta-analysis was based on 61 randomized trials among 28,896 women conducted by the Systematic overviews of the results of these trials demonstrated that mortality was reduced because of treatments that were significant when the following regimens were compared: tamoxifen versus no tam (p < .0001), any chemotherapy versus no chemotherapy (p = .003), and polychemotherapy versus single-agent chemotherapy (p = .001). In tamoxifen trials, a clear reduction in mortality was observed only among women 50 years of age or older, for whom assignment to tamoxifen reduced the annual odds of death during the first 5 years by about 20%. In chemotherapy trials, there was a clear reduction only among women under age 50, for whom assignment to polychemotherapy reduced the annual odds of death during the first 5 years by about 25%. Direct comparisons showed that combination chemotherapy was significantly more effective than single-agent therapy but suggested that administration of chemotherapy for 8 to 24 months may offer no survival advantage over administration of the same chemotherapy for 4 to 6 months. The second EBCTCG meta-analysis was based on 75,000 women included in 133 randomized trials.673 The third and most recent EBCTCG meta-analysis included 69 chemotherapy clinical trials (30,000 women), 17 ovarian ablation trials (3,456 women), and 63 tamoxifen trials (42,000 women).

Overviews or “meta-analyses” are relatively new innovations created by biostatisticians to formulate decisions regarding the worth of a particular therapy or therapies that have been evaluated in a large number of individual, heterogeneous trials.678 The aim of such an analysis is to be able to distinguish reliably between a treatment that produces a moderate effect and one that produces little or no effect. It has been pointed out that if such differences in mortality are to be assessed reliably, moderate random errors and moderate biases must both be avoided.676 Systematic overviews of all relevant randomized trials can help in both respects. First, since a greater number of patients are involved in an overview than in a single trial, the standard deviation of any apparent change in mortality is much smaller in an overview than in any individual trial contributing to the overview. Second, if many trials address related questions, then, by chance alone, some are likely to appear misleadingly positive, whereas others appear misleadingly negative. Emphasis on only the more positive (or only the negative) trial results introduces biases into the assessment of treatment. Similarly, even if all available trial results are considered together, undue emphasis on subgroups of patients among whom the effects of treatment appear particularly promising or unpromising (data-derived subgroups) may likewise be misleading. These sources of bias can be limited by cautious interpretation of the findings of an overview, with greater emphasis on overall findings than on findings in particular subgroups. The rest of this section provides findings from more recently conducted clinical trials and discusses issues that are currently being addressed in ongoing clinical trials.

Adjuvant Therapy for Node-negative Patients

Two assumptions hindered the evaluation of systemic therapy in women with primary breast cancer and negative axillary nodes. The first was that since such patients have a good prognosis, surgery alone was for their treatment. However, findings from two NSABP trials in which no treatment other than operation was used indicate that tumor recurrence and death due to breast cancer affected a significant percentage of the patients. In one study, treatment failed in approximately 25%, and 15% died during 5 years of follow-up.472 Unpublished data from the other study indicate that treatment failed in 43% of the patients; 32% had died by 10 years of follow-up.

A second assumption was that the use of alkylating agents was not warranted in patients with such a “good” prognosis because of the risk of myeloproliferative disease and other second tumors that might follow the use of these agents. It has long been recognized that there is a need for a marker (or markers) capable of identifying patients with negative nodes thus are at either good or poor risk and who may or may not be candidates for adjuvant chemotherapy or tamoxifen. The ER content of a tumor has been considered such a discriminant despite a lack of agreement about its worth.679 By using ER values to separate good- and poor-risk patients, it was considered justifiable to conduct adjuvant therapy trials using node-negative patients.

Although the 1985 NIH consensus conference counseled against the routine administration of adjuvant systemic therapy in women with histologically negative axillary nodes, 1990 NIH conference reversed this advice.680

One trial was carried out to assess the worth of sequential treatment with two antimetabolites—methotrexate and fluorouracil (M F)—followed by leucovorin (folinic acid) in node-negative women considered to be at greatest risk for treatment failure, that is, those with ER-negative (less than 10 fmol/mg protein) tumors.694 Treated patients had a significantly increased disease-free survival (p <60 .001) compared with those receiving no chemotherapy (74% vs. 59%, average time on study, 114 months).684 (Fig. 118.36). The benefit was observed in patients ages 49 and younger, as well as in those 50 years of age and older (Fig. 118.37). At 8 years, the treatment failure was reduced by 30% in the younger group and by 50% in the older group. Survival benefit in those 50 years old and older is significant (p = .03) (Fig. 118.38). Survival for patients 49 years of age or younger is not significantly different (p = .48).

Figure 118.36. Effect of M → F on disease-free survival through 8 years of all node-negative patients with ER-negative breast cancer.

Figure 118.36

Effect of M → F on disease-free survival through 8 years of all node-negative patients with ER-negative breast cancer.

Figure 118.37. Effect of M → F on disease-free survival through 8 years of node-negative patients with breast cancer, according to age.

Figure 118.37

Effect of M → F on disease-free survival through 8 years of node-negative patients with breast cancer, according to age.

Figure 118.38. Effect of M → F on survival of node-negative breast cancer patients through 8 years, according to age.

Figure 118.38

Effect of M → F on survival of node-negative breast cancer patients through 8 years, according to age.

A second NSABP randomized, double-blind, placebo-controlled trial was conducted to evaluate the worth of postoperative tamoxiten, 10 mg twice a day, in node-negative patients with ER-positive tumors (N1).670 A highly significant overall disease-free survival advantage was found for tamoxifen (p < .0001) (Fig. 118.39). That benefit was observed in patients 49 years and younger and 50 years and older (p = .0001 for both). The tamoxifen-treated patients had fewer locoregional and distant metastases. Of particular interest was the reduction by 58% in ipsilateral breast tumor recurrences in patients treated by lumpectomy and breast irradiation and the reduction by 40% in the number of contralateral breast cancers when tamoxifen was administered. A significant survival advantage was evident (p = .02).

Figure 118.39. Effect of tamoxifen on disease-free survival of all node-negative breast cancer patients with ER-positive tumors.

Figure 118.39

Effect of tamoxifen on disease-free survival of all node-negative breast cancer patients with ER-positive tumors.

Tamoxifen Toxicity

Although hot flashes, vaginal discharge, and irregular menses occurred more often in tamoxifen-treated patients than in those given placebo, the differences were not as pronounced as might have been thought if the placebo control had not been present. Thromboembolic events were more frequent in the tamoxifen-treated than in the placebo-treated group (1.3% vs. 0.1%; p < .001). Pulmonary embolism occurred in 6 of 1,422 tamoxifen-treated patients versus in 1 of 1,439 placebo-treated women (p = .06). There were two deaths in the former and none in the latter group. This excess in thromboembolic complications associated with tamoxifen administration has also been reported in other large controlled trials.685 Second primary tumors other than endometrial occurred equally in the two groups. Liver, gastrointestinal, urinary tract, and nonuterine genital cancers were not increased by tamoxifen treatment.

The relationship of tamoxifen administration to the development of endometrial cancer,686 was investigated in 2,843 node-negative, ER-positive patients in the NSABP B-14 study. The mean observation time was 8 years.

Two cases of endometrial cancer occurred in the placebo-treated group of patients, whose medical status subsequent to recurrence required tamoxifen treatment. Twenty-three endometrial cancers were seen in the tamoxifen-treated group. Twenty-one of the 24 originally reported endometrial cancers were International Federation of Gynecologic Oncology (FIGO) stage 1; 18 of 23 gradable cases were of good-to-moderate histologic grade. Four tamoxifen-treated women died either with or from uterine cancer. The average annual hazard rate of endometrial cancer as a first event within the first 5 years of follow-up in the randomized, tamoxifen-treated group was 1.2 per 1,000 patient-years; the cumulative hazard rate was 6.3 per 1,000 patients. Findings for a nonrandom registered, tamoxifen-treated group were similar. Including all reported endometrial cancers, the annual hazard rate through all follow-up was 0.2 per 1,000 in the placebo-treated group and 1.6 per 1,000 in the randomized, tamoxifen-treated group; the relative risk of endometrial cancer for the latter versus the former group was 7.5. Using population-based rates of endometrial cancer from SEER data, the RRs would be 2.2. The 5-year cumulative hazard rate for disease-free survival from breast or endometrial cancer in the randomized tamoxifen group was 38% less than that in the placebo group.

To put into proper perspective the small increase in endometrial cancer that was observed in the B-14 study, the cumulative hazard rates of that event are compared with the cumulative hazard rates of breast cancer relapses, of cancer occurring in the opposite breast, or of all events that took place (Fig. 118.40).686

Figure 118.40. Cumulative hazard rates through 5 years by type of first event in randomized placebo and tamoxifen-treated groups and in registered tamoxifen-treated group.

Figure 118.40

Cumulative hazard rates through 5 years by type of first event in randomized placebo and tamoxifen-treated groups and in registered tamoxifen-treated group.

Additional information about the risk of developing endometrial cancer for patients receiving tamoxifen can be derived from the recently published results of the BCPT.685 Between 1992 and 1997, 13,388 women at high risk for breast cancer were registered in the BCPT and randomly assigned to tamoxifen for 5 years or a matching placebo. At the time of the published analysis, the median time on study was 47.7 months. Thirty-six invasive endometrial cancers were reported on the tamoxifen arm, compared to 15 on the placebo arm. The RR was 4 for patients 50 years of age or older, whereas there was no detectable increase in risk for younger women.

Although the risk of endometrial cancer increases after tamoxifen therapy, the net benefit vis à vis breast cancer greatly outweighs the risk. Endometrial cancers occurring after tamoxifen therapy do not appear to be of a different type or of a worse prognosis than such tumors in patients who have not received tamoxifen.

In 1981, an Intergroup study was initiated by ECOG and subsequently joined by members of the Southwest Oncology Group (SWOG) and the Cancer and Leukemia Group (CALGB) for women with no histopathologic evidence of axillary node involvement.682 In that trial, 536 women who had undergone either a modified radical mastectomy or a total mastectomy with low axillary-node dissection for potentially curable breast carcinoma were randomized to receive adjuvant chemotherapy or no treatment. Patients were considered at high risk for recurrence because they had either an ER-negative tumor of any size or an ER-positive tumor at least 3 cm in diameter. The chemotherapy consisted of six 4-week cycles of cyclophosphamide, methotrexate, fluorouracil, and prednisone. The initial report of findings from that study indicated that the disease-free survival among patients treated with the four-drug regimen was significantly better than that of the control group at a median follow-up of 3 years (p = .0001) (Fig. 118.41). Treatment benefits were also observed in premenopausal and postmenopausal patients, as well as in patients with ER-positive or ER-negative tumors. Severe or life-threatening hematologic toxicity was encountered in 33% of the treated patients, with one death. No survival advantage was observed in that early report.

Figure 118.41. Disease-free survival according to treatment group among 406 high-risk patients with node-negative breast cancer.

Figure 118.41

Disease-free survival according to treatment group among 406 high-risk patients with node-negative breast cancer. CMFP denotes adjuvant therapy with cyclophosphamide, methotrexate, fluorouracil, and prednisone; OBS, observation; NED, no evidence of disease. (more...)

The 10-year analysis of this trial demonstrated highly significant improvements in disease-free survival (p = .0006) and overall survival (p = .02) for patients who received CMFP.687 A 37% reduction in risk of recurrence and a 34% reduction in risk of death was observed at 10 years. The benefit was observed in young and old, ER-negative and ER-positive.

A subsequent NSABP trial (B-19) was designed to assess the benefits and risks of cyclophosphamide in the node-negative population. In this study, 1,095 patients with ER-negative, axillary node-negative primary breast cancer were registered and randomized following appropriate regional therapy.684 The control arm received six cycles of M _ F with leucovorin, whereas the investigational arm required six cycles of CMF. After 5 years of study, there was a significant improvement in disease-free survival (82% vs 73%; p < .001) and a borderline advantage in overall survival (88% vs. 84%; p = .06) in favor of CMF. The benefits of CMF were greater for women younger than 50 years of age. With additional follow-up through 8 years, the advantage in favor of CMF became highly significant for both end points.

Other clinical trials demonstrated significant improvement in disease-free survival with perioperative or post-operative adjuvant chemotherapy.503,504,681–683,688

The highly significant disease-free and overall survival benefit in the initial trials of adjuvant chemotherapy for patients with node-negative breast cancer was subsequently corroborated and expanded in a meta-analysis of all randomized trials involving node-negative breast cancer. The mature results of these trials pointed out that these patients, previously considered to have an “excellent prognosis”, had a 30 to 50% risk of recurrence after locoregional treatment. The majority of patients with node-negative breast cancer are cured by breast-conserving treatment or total mastectomy and axillary dissection. There is clear evidence that the rate of local and distant recurrence is decreased by both adjuvant combination cytotoxic chemotherapy and by adjuvant tamoxifen. Data from the 10 randomized trials reviewed show that adjuvant systemic therapy reduces the rate of recurrence by approximately one-third, with a broad range. For example, among a group of women with a recurrence rate of 30%, adjuvant therapy would decrease the rate of recurrence to about 20%.

The EBCTCG meta-analysis and data from individual randomized trials clearly show that adjuvant chemotherapy, tamoxifen, or ovarian ablation improves survival for patients with node-negative breast cancer.673–675,684,689–692 As is true for node-positive breast cancer, the combination of tamoxifen plus chemotherapy provides incremental benefits, as compared to either treatment alone, for patients with hormone receptor-positive, lymph node-negative breast cancer.693

Several justifiable questions have been raised by physicians and their patients about the nature and extent of the population of patients with node-negative breast cancer who would be candidates for the therapies we have evaluated. Are there cohorts of node-negative patients—either ER-negative or ER-positive—who have so favorable a prognosis that chemotherapy or tamoxifen therapy is unwarranted? Second, are there identifiable subsets of patients who have shown no benefit from therapy, thus excluding them from treatment with these agents? The NSABP gathered and reported information from its studies to answer these questions.694 First, when patients with ER-negative (B-13) or ER-positive (B-14) tumors who received no systemic chemotherapy were examined according to tumor size, those with larger tumors demonstrated a poorer disease-free survival than did those with smaller tumors. In the ER-negative group, the best disease-free survival (77%) was in patients with tumors 1 cm or smaller, and the poorest (55%) was in those with tumors 4.1 cm or larger (Fig. 118.42). In patients with ER-positive tumors, the disease-free survival ranged from 82% in those with the smallest tumors to 55% in those with the largest tumors (Fig. 118.43).

Figure 118.42. Disease-free survival of node-negative breast cancer patients with ER-negative tumors (B-13) treated by operation only, according to tumor size (cm).

Figure 118.42

Disease-free survival of node-negative breast cancer patients with ER-negative tumors (B-13) treated by operation only, according to tumor size (cm).

Figure 118.43. Disease-free survival of node-negative breast cancer patients with ER-positive tumors (B-14) treated by operation and placebo, according to tumor size (cm).

Figure 118.43

Disease-free survival of node-negative breast cancer patients with ER-positive tumors (B-14) treated by operation and placebo, according to tumor size (cm).

Besides tumor size, other prognostic factors are of value in node-negative patients in predicting the risk for recurrence and, consequently, the need for therapy. SPF as determined by flow cytometry, has emerged as a strong, independent prognostic factor in such patients. Flow cytometric information was obtained in a subset of patients from protocol B-14.535 SPF was found to be an independent predictor of disease-free survival and survival in this cohort of patients. The 5-year disease-free survival in patients with low S phase and in those with high S phase was 82% and 58%, respectively (p < .001). The 5-year survival was also significantly higher in those with low S phase as compared with those with high S phase (94% vs. 83%, respectively; p = .003). When different prognostic variables found by univariate analysis were examined by multivariate analysis, SPF, tumor size, PgR, and nuclear grade were independent predictors of disease-free survival. All but nuclear grade predicted for survival. SPF and tumor size were independent prognostic markers of disease-free survival and survival in both placebo-treated and tamoxifen-treated patients. These two factors are valuable for defining low- and high-risk, node-negative, ER-positive patients and thus may also be valuable in selecting therapy.

Second, no subsets of patients existed who failed to benefit from M _ F or tamoxifen, thus excluding them from treatment. Tests for interactions failed to demonstrate an inconsistency of treatment effects within subgroups of patients.

In the previously described ECOG/Intergroup trial, patients with primary tumors <1 cm in largest diameter had a 75% 10-year disease-free survival rate and a 79% overall survival rate.687 However, other investigators have reported markedly superior survival figures for patients with primary tumors <1 cm and negative nodes, especially patients with tumors <0.5 cm, negative nodes, and no other unfavorable prognostic indicators.695 The reports of the SEER program and several single-institution reports also highlight the excellent prognosis of patients with special, favorable histologic subgroups: those with pure tubular or mucinous carcinomas.696–700 Clearly, there are subgroups of patients with excellent prognosis for whom the benefit from adjuvant chemotherapy (and even tamoxifen) might be so minimal as to be matched or exceeded by the proportion of serious or life-threatening toxicity of the interventions. The challenge is to develop reproducible methods to identify such patients prospectively. Until such predictive profiles are perfected and validated, patients with perceived borderline or excellent prognosis should be informed of the estimated risk of recurrence and the estimated benefit and toxicity of relevant adjuvant systemic therapy so that they can reach an informed decision.

The failure rates of node-negative patients despite treatment with M _ F, CMF or tamoxifen were of sufficient magnitude to justify continued effort to improve the outcome of these patient cohorts. The NSABP has concluded that the disease-free survival of all cohorts of node-negative patients with both ER-negative or ER-positive tumors was poor enough to justify systemic treatment. The benefit of the therapies used is insufficient to eliminate the need for assessing putatively better regimens.

What should the therapy of node-negative patients with subclinical invasive cancers be?

The expanding use of mammographic screening is associated with the detection of invasive cancers too small for clinical detection. A large number are found on microscopic examination of tissue removed because of abnormalities in mammograms or sonograms, as an incidental microscopic finding associated with a “benign biopsy,” or as the result of removal of a mammography-detected tumor that is too small for conventional tumor receptor analysis. Tumors obtained under these circumstances are most often associated with negative axillary nodes. The detection of these small lesions represents a triumph of technology and raises important questions regarding their management. One of the most frequently asked questions is Do patients with these lesions require systemic therapy and, if so, what therapy?

Although tamoxifen is successful in reducing local recurrence and distant disease in all categories evaluated, the proportionate reduction remains constant. Therefore, the likelihood of real clinical benefit diminishes as prognosis in general improves. With extremely small and favorable tumors, the use of systemic adjuvant therapies have as much rationale for prevention of new primary cancers as they do for treatment of the index cancer. At this point, value judgments based on scientific data can be quite individual.

The risk of tumor recurrence in these cases is very low and compares with the risk for treatment after DCIS. Until new answers come from ongoing clinical trials, it is probably best in practice to review the available data with each patient concerning whether to use systemic therapy because of their putative “good” prognosis, and it seems advisable that they all receive a lumpectomy followed by breast irradiation.

The initial node-negative trials evaluated tamoxifen alone in women with ER-positive tumors. The question of chemotherapy in this age group was not addressed. The NSABP recently published results of a trial (B-20) evaluating tamoxifen alone, tamoxifen + 6 months of CMF, and tamoxifen + 6 months of M → F. It is interesting that the tamoxifen-alone group had outcomes similar to the tamoxifen group in B-14, a cohort of patients that they resembled. The group that took tamoxifen + 6 months of CMF had significant improvement in disease-free survival.

Should tamoxifen be given to node-negative patients with ER-negative tumors? Since both the NATO and the Scottish trials have reported an overall advantage with tamoxifen that was independent of menopausal, nodal, or ER status, its use might be considered in this patient cohort.701,702 Concerns have been raised about the distribution of node-negative patients (relative to menopausal and receptor status). Because of the general lack of evidence from U.S. trials of a benefit from TAM for patients with ER-negative tumors, there has been a reluctance to use TAM for ER-negative patients in North America. In addition, the most recent EBCTCG meta-analysis failed to show a significant disease-free or overall survival benefit for the ER-poor group.675 Although new biologic information suggests that paracrine growth factors, produced by ER-positive cells, may affect the growth of ER-negative cells, and this putative mechanism seems to be justification for further evaluating the use of TAM in conjunction with chemotherapy in women with ER-negative tumors, there is no clinical support for this hypothesis.548 The NSABP is currently conducting such a study (B-23). Over 1,800 patients have been accrued to that trial. Until the results are available, the use of TAM is not recommended for women with ER-negative tumors outside of a clinical trial.

Adjuvant Therapy for Node-positive Patients

Over the past 30 years, controlled clinical trials provided compelling information in support of the use of adjuvant chemotherapy and adjuvant endocrine therapy for patients with node-positive primary breast cancer. Combination chemotherapy is superior to single-agent therapy, and adjuvant chemotherapy for 4 to 6 months appears as effective as longer treatments. Chemotherapy is considered the treatment of choice for patients with node-negative breast cancer.674,703 Although the magnitude of the benefit from chemotherapy is greater for younger women, significant reduction in risk of recurrence and death has been documented for women up to age 69 years.

Whereas CMF therapy was for several years almost universally employed as the chemotherapeutic regimen for node-positive breast cancer patients, doxorubicin (Adriamycin) combinations have become more commonly employed. Several prospective randomized trials comparing doxorubicin (or epirubicin)-containing regimens versus non–anthracycline-containing regimens in the adjuvant setting for node-positive and also node-negative breast cancer and the meta-analysis of all randomized trials have concluded that the anthracycline-containing regimens have superior efficacy.674,704–708

HER2/neu overexpression has been associated with increased relapse rates after adjuvant therapy,709–711 and apparent resistance to certain types of cytotoxic treatment—for instance, the CMF regimen.712 Several retrospective analyses of prospective clinical trials have suggested that patients with HER2/neu overexpressing breast cancer benefit more from treatment with an anthracycline than with the CMF regimen.711,713,714

There is clear evidence that more prolonged administration of tamoxifen (e.g., 5 years) is more efficacious than short-term therapy (e.g., 2 years or less).715–717 Tamoxifen administered for 5 years is equally effective in the management of women (and men) of any age with primary breast cancer with positive ER and/or PsR assays. However, there is no compelling evidence that prolonging the administration of tamoxifen for longer than 5 years provides greater benefit than administration for 5 years.718–720

There are conflicting results about whether patients with HER2/neu overexpression have associated resistance to hormonal therapy with tamoxifen710,721–723; additional prospective clinical trials are needed to clarify this issue.

Evidence from the EBCTCG meta-analysis and from large randomized trials showed that tamoxifen combined with chemotherapy provides the most effective systemic adjuvant treatment to patients with hormone receptor-positive breast cancer.674,675,693,724–726

The findings obtained from the NSABP clinical trial B-16 appear unambiguous. The study was carried out to determine whether tamoxifen used in conjunction with each of two different chemotherapy regimens is more effective in prolonging disease-free survival and survival than is tamoxifen alone in tamoxifen-responsive patients, that is, all of those 50 years of age or older, except women 50 to 59 years of age with PgR-negative tumors. Patients were randomized to receive (a) tamoxifen alone (10 mg b.i.d. for 5 years), (b) doxorubicin and cyclophosphamide (AC, 60 and 600 mg/m2 every 3 weeks × 4) given over 63 days plus tamoxifen; or (c) PFT (l-Pam, 5-fulyprouracil, and tamoxifen), which was subsequently modified by adding Adriamycin (PAFT).

Findings from the B-16 trial have been reported.727,728 Through 7 years of follow-up, there was a significantly better disease-free survival for ACT-treated patients than for those receiving tamoxifen alone (p = .0009) (Fig. 118.44). A significant survival advantage (p = .02) was also observed. Both the disease-free survival and survival of PAFT-treated patients were significantly better (p = .003 and p = .05) than in those treated by tamoxifen alone. The findings related to the use of PAFT and PFT are more of biologic than of clinical significance since l-Pam is rarely used today in the treatment of breast cancer. The major conclusion from this study is the better outcome from the use of postoperative prolonged tamoxifen and short-course AC therapy (completed in 63 days) than from prolonged tamoxifen therapy alone in node-positive breast cancer patients aged 50 years of age and older. Obviously, those patients whose general physical status would prohibit their being subjected to the toxicity of chemotherapy are best treated by tamoxifen alone. When both chemotherapy and tamoxifen are recommended, the two therapies may be given simultaneously, or chemotherapy may precede the initiation of tamoxifen. There are insufficient data to recommend one approach over the other; ongoing randomized trials may provide definitive information in this regard. Although earlier laboratory729,730 and clinical data731 suggesting unfavorable interactions between tamoxifen and chemotherapy in some subgroups have not been confirmed, some investigators have reported an increased risk of thromboembolic complications when tamoxifen and chemotherapy are administered simultaneously.732–734

Figure 118.44. Disease-free survival and survival of all women with breast cancer 50 years of age or older, except those 50 to 59 who were PgR-negative (tamoxifen vs.

Figure 118.44

Disease-free survival and survival of all women with breast cancer 50 years of age or older, except those 50 to 59 who were PgR-negative (tamoxifen vs. ACT: tamoxifen vs. doxorubicin (Adriamycin), cyclophosphamide, and tamoxifen).

As a result of the above findings indicating the worth of chemotherapy for node-positive, tamoxifen-responsive patients and the consideration undertaken relative to the use of shorter, more intense therapy, a study was designed for patients likely to be relatively nonresponsive to tamoxifen, that is, those age 49 and younger and those 50 to 59 years of age with PgR-negative tumors, by te NSABP (B-15) to determine the benefit of short-course, intensive chemotherapy administered after operation both with and withoutsame a chemotherapeutic reinduction by a different drug regimen 6 months after completion of the initial therapy. Adriamycin and cyclophosphamide (AC, 60 and 600 mg/m2 q 3 weeks × 4) given over 63 days was compared with 6 months of conventional CMF. A second aim of the study was to determine whether, in the same patient population, AC followed 6 months later by reinduction therapy with parenteral CMF (AC _ IV CMF) was more effective than AC without reinduction therapy. Findings from 2,304 patients, initially reported in 1990, through 42 months of follow-up showed no significant difference in disease-free survival (p = .8), distant disease-free survival (p = 1.0), or survival (p = .9) among the three groups. Updated findings through 7 years of follow-up continue to indicate that there is still no differences have emerged in any of those outcomes among the three groups of patients (Fig. 118.45).727,735

Figure 118.45. Disease-free survival and survival through 7 years of all women with breast cancer 49 years of age or less plus that group 50 to 59 who were PgR negative.

Figure 118.45

Disease-free survival and survival through 7 years of all women with breast cancer 49 years of age or less plus that group 50 to 59 who were PgR negative. Comparison of AC with AC × IV CMF and conventional CMF (AC, doxorubicin [Adriamycin] plus (more...)

Since the outcomes of those receiving AC and of those receiving conventional CMF were almost identical, the issue arises as to which regimen, AC or CMF, might be more appropriate for use as the control group in a new clinical trial or for the treatment of patients who do not participate in such a trial. The following points seem to justify the choice of AC: (a) when total mastectomy was performed, AC administration was completed on day 63 compared with day 154 for patients on conventional CMF; (b) patients visited health professionals three times as often for CMF as for AC; (c) women on AC received chemotherapy on each of 4 days compared to each of 84 days for conventional CMF; and (d) medication to control nausea was given for about 84 days when CMF was administered and for about 12 days to patients on AC. Although alopecia was observed in all patients following AC therapy, 71% of patients on CMF also had hair loss, and in 41% the loss was greater than 50%. Late cardiotoxic or leukemogenic events have not yet occurred.

Although this study failed to demonstrate the worth of reinduction by IV CMF, the ability to administer such therapy was demonstrated. Ninety-five percent of patients eligible for such treatment received the therapy, and compliance and toxicity were acceptable. The failure to demonstrate such benefit in one NSABP study does not nesate the concept of reinduction therapy. Bonadonna et al.736 tested, in a randomized trial in high-risk patients, sequential administration of Adriamycin at 75 mg/m2 for four courses followed by IV CMF for eight courses compared to alternating chemotherapy (two courses of IV CMF followed by one course of Adriamycin) for a total of 12 courses. Results of this study after a median follow-up of 6 years demonstrate a significant improvement in disease-free survival with the sequential regimen versus the alternating regimen (56% vs. 38% respectively, p = .0007). This difference was translated into a significant difference in survival (70% vs. 53%, respectively; p = .001) (Fig. 118.46).

Figure 118.46. Disease-free (left panel) and overall survival of patients with more than three metastatic nodes, who were less than 70 years old.

Figure 118.46

Disease-free (left panel) and overall survival of patients with more than three metastatic nodes, who were less than 70 years old. They received four courses of moderately high-dose doxorubicin followed by eight cycles of CMF, or two courses of CMF alternating (more...)

Recently, the CALGB has studied doxorubicin (A) at 60, 75, or 90 mg/m2 with cyclophosphamide (C) at 600 mg/m2 every 3 weeks for four cycles followed or not by paclitaxel (T) at 175 mg/m2 every 3 weeks for four cycles in node-positive breast cancer. ER-positive patients then receive tomoxifen. No difference has emerged from A dose escalation, making 60 mg/m2 the preferred dose. A highly significant improvement in disease-free survival and survival occurred in the group further treated with paclitaxel. This AC followed by T regimen is superior to AC alone and has been widely adopted for patients not in studies.

The clinical evaluation of taxanes (paclitaxel [Taxol] and docetaxel [Taxotere]) in patients with metastatic breast cancer indicated that both agents have marked antitumor activity.748–742 Both taxanes retain a high degree of activity in anthracycline-resistant tumors.743–748 Based on this information, clinical trials incorporating the taxanes into the adjuvant systemic therapy of high-risk primary breast cancer were initiated. The early results of the first large, multicenter, randomized clinical trial were recently reported.749 In this study (CALGB 9344), patients with lymph node-positive primary breast cancer were treated with four cycles of doxorubicin at 60, 75, or 90 mg/m2 plus cyclophosphamide at 600 mg/m2 every 3 weeks for four cycles and then randomly assigned to no additional chemotherapy or four cycles of single-agent paclitaxel at 175 mg/m2 every 3 weeks for four cycles. After a median follow-up of 18 months, no differences were seen in the doxorubicin dose escalation, making 60 mg/m2 the preferred dose. A highly significant difference emerged in patients treated with doxorubicin/cyclophosphamide followed by paclitaxel who had a 22% reduction in odds of recurrence and a 26% reduction in odds of death, translating into a 4% absolute improvement in relapse-free survival and a 2% absolute improvement in overall survival even at 18 months. A second analysis of this trial, with a median follow-up approaching 30 months, continues to show a significant benefit associated with AC followed by T. This regimen has been widely adopted in patients who were not in studies. Several additional randomized trials evaluating the contributions of either paclitaxel or docetaxel to the management of primary breast cancer are completing accrual. Among them, NSABP B-27 is an ongoing trial in which patients with operable breast cancer are randomly assigned to four cycles of AC followed by surgery, or four cycles of AC followed by four cycles of docetaxel and surgery, or four cycles of AC, followed by surgery and four cycles of docetaxel postoperatively. The target accrual for this study is 2,400 patients. Another NSABP study, B-28, has a similar design to CALGB 9344. Patients with operable breast cancer and positive axillary nodes are randomly assigned to receive four cycles of AC or fourcycles of AC followed by four cycles of paclitaxel. The targeted accrual of over 3,000 patients was recently reached. No reports of these or other ongoing trials have been presented.

Adjuvant Ovarian Ablation

Ovarian ablation lowers the odds of recurrence and death to levels that are quantitatively similar to those produced by chemotherapy, a benefit that is restricted to premenopausal women.673 Ovarian ablation is not commonly employed as adjuvant therapy in the United States, however, largely because adjuvant chemotherapy produces a chemical ovarian ablation in the majority of patients anyway and because there is a fear of the long-term effects of the premature menopause caused by ovarian ablation.750,751 The combination of chemotherapy and tamoxifen appears to provide superior disease control to patients with hormone receptor-positive breast cancer.674,675 However, the data in support of the superiority of the combination of chemotherapy and ovarian ablation for women under the age of 50 years are much less compelling.673,674 A nonsignificant trend in some studies suggests that the combination of ovarian ablation and chemotherapy might be superior to chemotherapy alone for premenopausal women with ER-positive tumors.752,753 Additional studies to clarify the role of combined hormone therapy and chemotherapy are needed in this population. The introduction of luteinizing hormone-releasing hormone (LHRH) analogues has also created new treatment opportunities. At this time, trials are evaluating the effects of LHRH analogues alone or in combination with chemotherapy and/or tamoxifen in premenopausal patients with primary breast cancer.755,756

Dose Intensification and Increased Cumulative Dose of Chemotherapy for Patients with Positive Axillary Nodes

Although evidence indicates that systemic chemotherapy after operation has benefited patients with primary breast cancer, there is agreement that a need exists for enhancing the effectiveness of postoperative chemotherapy. Despite manipulations of doses, schedules, and combinations of drugs, progressively better disease-free survival and survival have not been universally observed. Numerous hypotheses have been formulated to explain why such improvement has not generally occurred despite the major effort exerted toward accomplishing that goal. Foremost among them is the contention that inadequate drug dose administration is a major factor responsible for the failure to achieve a greater therapeutic effect in responsive tumors.

In 1984, Hryniuk and Bush presented arguments for recognizing the importance of dose intensity in the use of chemotherapy for metastatic breast cancer.759 They defined dose intensity as the amount of drug administered per unit of time, expressing intensity as milligrams per square meter per week using a single-drug regimen. For the determination of dose intensity using regimens containing several drugs, they used certain calculations and assumptions but still expressed the intensity of the regimen as milligrams per square meter per week, assuming that each of the various drugs in a combination (e.g., CMF or cyclophosphamide, Adriamycin, and 5-fluorouracil [CAF]), has equivalent activity and that the major effect of scheduling is to vary the total amount of drug delivered per unit of time.” Hryniuk and Bush considered that differences in drug scheduling could be ignored except insofar as dose intensity was varied. They concluded that the higher the dose intensity, the higher would be the remission rate of patients with advanced breast cancer. When actual rather than projected doses were used in their calculations, the relationship between response rate and dose intensity became even more evident. Their concept was established using information obtained by other investigators from nonrandomized studies that originally were not carried out to assess the issue of dose intensity. Results from several randomized trials were considered to support the Hryniuk thesis.758 A study by Tannock and colleagues is significant in that regard, in that it reports results from a prospectively randomized trial conducted to test the relationship between two dose levels of CMF and the remission rate in patients with advanced breast cancer.759 After adjustment for analysis by the Cox proportional hazards model for a chance imbalance in the time to start treatment after first relapse, a strong but not statistically significant trend favored the standard rather than the half-dose regimen.

Using the same approaches that they employed for evaluating dose intensity in advanced disease, Hryniuk and his associates correlated the dose intensity of adjuvant chemotherapy with relapse-free survival.760,761 Their retrospective review of the literature led them to conclude in 1986 that, as in advanced disease, dose intensity of chemotherapy correlated with relapse-free survival, and that this correlation was independent of the number of positive nodes or menopausal status.

Hryniuk’s concepts have provoked a great deal of controversy. The information obtained from randomized trials studying the effect of dose in patients treated with adjuvant chemotherapy is sparse.762–764

One recent randomized trial to evaluate the contribution of dose intensity to the results of adjuvant chemotherapy was conducted by the CALGB.765 In that study, CAF was administered at a high dose for 4 months, at a moderate dose for 6 months, and at a low dose for 4 months. The protocol-specified high dose for CAF is 600 mg/m2 on day 1 (C), 60 mg/m2 on day 1 (A), and 600 mg/m2 on days 1 and 8 (FU) of a 28-day cycle. Moderate and low dose rates are two thirds and one half, respectively, of the high dose for all three drugs. Because of the difference in duration, however, the 600–60–600 regimen for 4 months got the same total dose as the 400–40–400 regimen for 6 months. The results from the study indicate a significant difference in the 3-year disease-free survival between the high-/moderate-dose group and the low-dose group (high-dose group, 75 × 2%; moderate-dose group, 70 × 3%; low-dose group, 64 × 3%, p < .00001). The difference between high- and moderate-dose groups did not reach significance (p = .079). There was an overall survival difference at 3 years between the high-dose group (92 × 2%) and the low-dose group (84 × 2%, p = .0004) but not for the high-dose group when compared with the moderate-dose group (p = .085). All of the difference seen was attributable to the 30% of patients with high (50% or more of cells) expression of the c-erb B-2 gene, which correlated with chemotherapeutic sensitivity.266 It is of note that the high-dose arm in this trial (60 mg/m2) now represents CALGB standard-dose chemotherapy for this group of patients.767 Therefore, this trial, like the Tannock-led trial mentioned earlier, can also be interpreted as showing a detriment in therapeutic results resulting from decreasing the dose (or dose intensity) of chemotherapy below full therapeutic doses. In a subsequent trial described above, however, CALGB showed no advantage of Adriamycin at 75 mg/m2 or 90 mg/m2 over 60 mg/m2, suggesting a threshold effect.765

Obtaining definitive information regarding the relationship of adjuvant chemotherapy dosing to disease-free survival and survival is of the highest priority. Should definitive studies about high-dose intensity and/or cumulative dose indicate that a plateau has been reached in the benefit achieved with chemotherapy, then new considerations for therapy must be entertained. If, on the other hand, evidence is obtained to show that high-dose therapy has merit, that information can be exploited for future investigations.

In an appropriate trial to compare different dose intensities and different cumulative doses of multi-agent chemotherapy, (a) strict control over treatment delays must be maintained; (b) there must be an adequate number of patients properly selected and randomly assigned to each group receiving the same therapy, but at different dose intensities and/or cumulative doses; (c) the spread between the different dose-intensity groups must be great enough to provide a reasonable chance of detecting differences in treatment failure and survival rates; and (d) the therapy used must be one that has a demonstrated beneficial effect. In order to achieve these goals, it is necessary that sufficiently high doses of drugs be given without resorting to a variety of schedules of dose reductions and dose delays. At the same time, there must be acceptable patient morbidity and mortality.

To obtain more definitive information than currently exists regarding the relation of dose intensity and increased total dose to patient outcome, the NSABP implemented, in 1989, the first of two clinical trials (B-22 and B-25). In this three-arm study (Fig. 118.47), “standard” AC therapy was compared with AC therapy in which the cyclophosphamide was intensified but the cumulative dose remained the same, and to an arm in which both the intensity and cumulative dose of cyclophosphamide were increased. The results from this study after 5 years of follow-up indicate that there is no significant difference in the disease-free survival or survival among the three groups of patients (Table 118.16).768 As shown in Table 118.17, the amount of cyclophosphamide delivered indicates that dose intensification and increase in the total cumulative dose were achieved as planned. When outcome was related to the amount of delivered dose, there was no significant correlation between disease-free survival or survival and the amount of cyclophosphamide given. Thus, to date, this part of our evaluation of dose intensification has failed to demonstrate that intensifying the cyclophosphamide from 200 to 400 mg/m2/wk improved outcome regardless of whether the cumulative dose was increased from 2,400 to 4,800 mg/m2. In all of these regimens, the Adriamycin dose remained constant.

Figure 118.47. NSABP studies B-22 and B-25: evaluation of dose intensification and increased total dose.

Figure 118.47

NSABP studies B-22 and B-25: evaluation of dose intensification and increased total dose.

Table 118.16. Disease-free Survival and Survival After 5 Years of Follow-up Among Three Treatment Groups: Findings from NSABP B-22.

Table 118.16

Disease-free Survival and Survival After 5 Years of Follow-up Among Three Treatment Groups: Findings from NSABP B-22.

Table 118.17. Amount of Cytoxan Delivered and Dose Intensification and Increase in Total Cumulative Dose Achieved: Findings from NSABP B-22.

Table 118.17

Amount of Cytoxan Delivered and Dose Intensification and Increase in Total Cumulative Dose Achieved: Findings from NSABP B-22.

When colony-stimulating factors became widely available, even higher intensification of cyclophosphamide could be achieved. In study NSABP B-25, the arm from B-22 with a high intensification and increased cumulative dose of cyclophosphamide was used as the control arm (400 mg/m2/wk at a total dose of 4,800 mg/m2) with granulocyte colony-stimulating factor (G-CSF) support. In the second arm, cyclophosphamide was further intensified to 800 mg/m2/wk, keeping the total dose the same. In the third arm, both the dose intensity and the cumulative dose of cyclophosphamide were increased (800 mg/m2/wk and 9,600 mg/m2 respectively).769 In both arms, G-CSF support was also used. There were over 2,500 patients randomized in this study and the average time on study was 4 years; no statistically significant differences were observed for survival or disease-free survival. Toxicity information from this study indicates that the maximum acceptable dose of cyclophosphamide given in the outpatient setting has been achieved. Sixteen patients treated on protocol B-25 were diagnosed with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).770 The 4-year cumulative incidence of AML or MDS for patients on protocol B-25 was 0.87%, greater than that observed in previous NSABP studies using standard-dose cyclophosphamide (600 mg/m2).

The development of autologous bone marrow (and later, peripheral stem cell) support techniques and the recent availability of hematopoietic growth factors (G-CSF, GM-CSF, and erythropoietin) made possible, testing of the dose-outcome hypothesis along a much broader range of doses. Following the developmental trials of high-dose chemotherapy in metastatic disease and the early and apparently encouraging results in advanced breast cancer, several centers investigated the contribution of this approach to the management of patients with high-risk primary breast cancer.775–781 These results from uncontrolled trials suggested that patients with very high expected rates of recurrence had a better short-term outcome after high-dose chemotherapy adjuvant regimens than would be expected on the basis of historical experience. The results of pilot trials compared to historical controls suggested a marked improvement, in the range of 30 to 40%, in overall and relapse-free survival. Participation in high-dose chemotherapy trials followed a careful but intensive selection process, however, and comprehensive pretreatment testing eliminated from participation a substantial minority of patients with subclinical metastases.782–784

To evaluate the efficacy of high-dose adjuvant chemotherapy programs, often erroneously considered as “bone marrow ransplants,” several prospective randomized clinical trials were initiated over the past decade. The preliminary results of the largest of these trials have now been reported in abstract format (Table I).785 In this study, patients with 10 or more positive axillary lymph nodes received four postoperative cycles of CAF as adjuvant chemotherapy and then were randomly assigned to a single cycle of either an intermediate- or a high-dose combination of cyclophosphamide, carmustine, and cisplatin (STAMP I) and the high-dose patients received stem cell support. The high-dose chemotherapy arm was associated with a reduction in the number of relapses; however, this reduction was matched by a concomitant increase in treatment-related mortality (7%). After a median follow-up of 3 years, was no significant difference in overall survival in this trial has yet occurred.

The second largest trial had an entirely different design.786 Bergh and collaborators786 used an individually tailored combination of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) as their control arm; the experimental arm of this prospective randomized Scandinavian multicenter trial for patients with multiple positive axillary lymph nodes consisted of four cycles of a standard-dose FEC induction (adjuvant) regimen, followed by one cycle of high-dose chemotherapy regimen (cyclophosphamide, thiotepa, and carboplatin (STAMP V). With a 24-month median follow-up time, no apparent differences in either relapse-free or overall survival rates have been detected. Both the standard- and high-dose chemotherapy regimens were well tolerated, and there was no excess mortality in this study. There was a higher frequency of leukemia and myelodysplastic syndrome in the control arm, a previously reported association with dose-intensive anthracycline-cyclophosphamide combinations..770,772,787,788

A third trial, from South Africa, compared two cycles of high-dose adjuvant chemotherapy (without induction chemotherapy), consisting of cyclophosphamide, mitoxantrone, and etoposide, with six cycles of standard-dose FAC or FEC chemotherapy. After a median follow-up of 5 years, this trial was reported to show a marked improvement in relapse-free and a more modest but still significant improvement in overall survival rates.789 These data are unreliable because of admitted fraud.

Finally, the oldest two trials, of somewhat more modest size, compared four cycles of FEC790 or eight cycles of FAC791 with the same adjuvant chemotherapy followed by one or two cycles of high-dose combination chemotherapy. There were no apparent differences in relapse-free or overall survival after 5 and 6 years of follow-up, respectively, in these two studies.

These trials have confirmed that high-dose chemotherapy is a tolerable intervention with substantial morbidity but a generally acceptable mortality risk. These studies have also shown the power of selection: the short-and intermediate-term outcome for the control groups of all of these adjuvant trials was much better than would have been expected compared to historical experience, based on the rigid criteria of admission to the study. Several of these clinical trials have a limited follow-up, and additional follow-up may evidence significant differences between the control and experimental arms. The available evidence does not, however, support the superiority of high-dose chemotherapy for high-risk primary breast cancer. Additional studies are in progress testing two and three successive high-dose regimens with stem cell support. Until favorable results are proved in prospective trials, high-dose regimens remain investigational and should only be employed in the context of hypothesis-testing clinical trials. It is important clinical research, however, because the need is great, and the concept has not been disproved.

Monitoring Disease Status after Adjuvant Therapy

After completion of combined-modality therapy for primary breast cancer, patients are followed at regular intervals to detect recurrent disease, second primary tumors, or complications of therapy. During the first 2 years, patients are seen every 4 months, for the subsequent 3 years, every 6 months, and yearly thereafter. A careful history and a complete physical examination are performed at each visit. A complete blood count and limited biochemical profile that includes liver function tests is useful in this process. A yearly mammogram of the remaining breast(s) completes the necessary evaluation for asymptomatic patients. Other tests are performed only if symptoms or physical findings warrant them. No advantage has been demonstrated for performing frequent or extensive imaging studies or tumor markers. Controversy exists on this point, however, because its tacitly assumes that no advantage accrues from the early detection of metastatic disease. The advent of new therapies such as aromatose inhibitors, monoclonal antibodies, metaloproteinase inhibitors, and antiangiogenic compounds may change this laissez-faire attitude. Even if survival is not prolonged, maintaining an asymptomatic state by effective therapy may be possible and is worthy.

Preoperative (Neoadjuvant) Chemotherapy for Operable Breast Cancer

The demonstration of benefit from adjuvant chemotherapy in patients with operable breast cancer and the often dramatic response rates of patients with inoperable breast tumors treated with preoperative (neoadjuvant) chemotherapy have led to increased interest in evaluating preoperative chemotherapy in patients with primary operable breast cancer. From a clinical perspective, the impetus for such interest resulted from the demonstration of the efficacy of lumpectomy followed by breast irradiation in such patients. It was speculated that administering systemic therapy before surgery would reduce the size of primary tumors so that more patients could receive lumpectomy. Moreover, because less breast tissue would need to be removed, better cosmesis would result. This theory was supported by studies in which preoperative chemotherapy was used to treat head, neck, and esophageal carcinoma and sarcomas of the extremities and demonstrated that such an approach might reduce the extent of required surgical resection.519,792,793 In addition, its worth for locally advanced (stage III) breast cancer had been dramatically demonstrated.567,794,795

From a biologic standpoint, justification for the evaluation of preoperative chemotherapy was provided by hypotheses formulated from findings obtained from several laboratory studies. Noncurative reduction of tumor cell burden results in an increase in the proliferation of residual tumor cells.447,448,451 Investigations of six different tumor host systems demonstrated that, 24 hours after removal of a primary tumor, there is an increase in the labeling index (LI) of metastases and a decrease in tumor doubling time, with a measurable increase in tumor size.450 Primary tumor radiation also results in kinetic changes in distant tumors similar to those obtained following tumor removal. Studies of how a primary tumor exerts its effect on metastases indicate that the stimulation of cell growth following tumor removal or radiation is due to a growth factor. Chemotherapy (cyclophosphamide), tamoxifen or radiation therapy given prior to operation prevents the kinetic alterations, suppresses tumor growth, and prolongs survival.449 Serum from mice treated preoperatively fails to stimulate DNA synthesis, in contrast to what occurs when serum is obtained from untreated mice following tumor removal.

Probably the strongest rationale for conducting a trial to evaluate preoperative chemotherapy relates to the concepts promulgated in the 1960s by Skipper and Schabel, which have provided much of the theoretical justification for adjuvant chemotherapy. Skipper and colleagues proposed that (a) growth fractions and doubling times of primary tumors may differ from those in micrometastases and, consequently, responsiveness to chemotherapy may differ; (b) the magnitude of response of a primary tumor in the plateau of Gompertzian growth need not reflect the response of micrometastases in exponential growth; (c) first-order kinetics relative to cell kill by cytocidal agents apply to those cells with constant growth fractions in exponential growth, that is, micrometastases of 106 cells or less; (d) micrometastases may differ and may respond to cyclical chemotherapy differently; and (e) ablation of a primary tumor with a resultant decrease in total tumor cell burden may alter the growth characteristics of residual micrometastases so that there is a decrease in tumor doubling time, an increase in growth fraction, and an improved synchronization of cell cycle times, enhancing the sensitivity of micrometastases to chemotherapy.

During the 1980s, several randomized and nonrandomized studies were conducted to evaluate the worth of preoperative chemotherapy for primary operable breast cancer.796–803 Nonrandomized studies were limited to the evaluation of primary tumor response to preoperative chemotherapy and possibly to the correlation of such response to outcome. All of these studies demonstrated that preoperative chemotherapy results in a high rate of primary tumor response. Some authors indicated797,804,805 that a correlation existed between response of the primary tumor to chemotherapy and outcome. In some of these studies, large tumors were reduced in size, allowing breast-conserving surgery.

The most important assessment of preoperative chemotherapy will come from randomized trials. Scholl et al.801 from Institut Curie recently reported on a trial in which 414 premenopausal women with T2, T3, N0–N1 breast cancer were randomized to receive either four cycles of neoadjuvant chemotherapy (cyclophosphamide, doxorubicin, and 5-fluorouracil) followed by radiotherapy (with surgery reserved for women with persistent tumors) or surgery followed by four cycles of the same chemotherapy. With a median follow-up of 54 months, overall survival was significantly better in the group receiving neoadjuvant chemotherapy. No significant differences were observed, however, in either disease-free survival or local recurrence.

In a clinical trial reported from Bordeaux,800 272 women with operable breast cancer greater than 3 cm in diameter were randomized between (a) mastectomy, axillary lymph node dissection, and chemotherapy if their nodes were positive or if their hormone receptors were negative and (b) initial chemotherapy and subsequent radiation and/or mastectomy, depending on the response to chemotherapy. After 34 months of follow-up, patients receiving initial chemotherapy experienced a statistically significant improvement in overall survival despite the fact that more isolated local recurrences occurred in these patients. It is important to note, however, that, in this trial, not all patients in the initial mastectomy arm received chemotherapy, as opposed to the initial chemotherapy arm, where all patients received chemotherapy. At the same time, not all patients in the initial chemotherapy arm received surgery, as opposed to the initial mastectomy arm, where all patients underwent surgery. It is possible that some of the observed differences in survival and local recurrence could be attributed to the imbalance of systemic locoregional treatment between the two treatment arms.

The NSABP recently updated protocol B-18, a randomized trial comparing the preoperative and postoperative administration of four cycles of Adriamycin and cyclophosphamide in patients with operable breast cancer. The specific aims of this trial were to (a) determine whether preoperative chemotherapy more effectively prolong disease-free survival and survival than the same chemotherapy given postoperatively; (b) evaluate the response of the primary tumor to preoperative chemotherapy and correlate the response with disease-free survival and survival; (c) determine whether preoperative chemotherapy, by reducing the size of the primary tumor, permits more conservative surgery and decreases the frequency of ipsilateral breast tumor recurrence; and (d) determine whether patterns of DNA histograms (ploidy and S phase) and changes in them resulting from chemotherapy can be correlated with disease-free survival and survival. Patients with palpable operable (T1, T2, T3) breast cancer in whom the diagnosis had been established by fine-needle aspiration cytology were stratified by age, clinical tumor size, and clinical nodal status and randomly assigned to one of two groups (Fig. 118.48). Group I patients underwent either a total mastectomy plus axillary dissection, or a lumpectomy plus axillary dissection. They then received four cycles of Adriamycin and cyclophosphamide (60 and 600 mg/m2 every 21 days × 4). Group II patients received four cycles of Adriamycin and cyclophosphamide as in group I, followed by a total mastectomy or lumpectomy within 4 weeks of the fourth course of chemotherapy, when blood counts allowed. All patients in either group I or II who were 50 years of age or older received tamoxifen 10 mg twice daily at the completion of chemotherapy. For patients treated by lumpectomy, breast irradiation was administered after the completion of all chemotherapy. Patients in group II who had a complete response (i.e., no evidence of residual disease clinically or mammographically after four cycles of chemotherapy) underwent either a total mastectomy and axillary node dissection, or a lumpectomy, axillary node dissection, and ipsilateral breast irradiation.798

Figure 118.48. NSABP study of B-18 schema.

Figure 118.48

NSABP study of B-18 schema.

In the preoperative chemotherapy arm, 36% of patients demonstrated a clinical complete response, and 43% had a clinical partial response, for an overall response rate of 79%. Patients receiving preoperative chemotherapy were more likely to have a lumpectomy than were patients receiving postoperative chemotherapy (68% vs. 59%), but the difference was not statistically significant. Responding patients were significantly more likely to receive a lumpectomy than nonresponding patients. Preoperative chemotherapy also resulted in axillary nodal down-staging: 59% versus 42% pathologically negative axillary nodes, for a net axillary nodal down-staging of 17%. There was a highly significant correlation between tumor response to preoperative chemotherapy and pathologic nodal status. Eighty-seven percent of patients with a complete clinical response had pathologically negative nodes, versus 57% of patients with partial response, 50% of patients with stable disease, and 38% of patients with progressive disease. Overall disease-free survival and survival were no different in the preoperative chemotherapy group from the postoperative adjuvant therapy, however, thus failing to confirm the major hypothesis of this study.

One unanswered question arising from this study concerns the need for further therapy following initial treatment. Patients with a good response may be considered as not needing further therapy or, it may be speculated, that they should have further consolidating therapy. Similarly, those with a poor response would clearly not profit from more of similar treatment but may benefit from a non–cross-resistant regimen. These questions are being addressed in NSABP protocol B-27 where all patients receive an initial four courses of preoperative AC therapy. One group receives no further adjuvant treatment. Group II receives four courses of taxotere after surgery and group III receives four courses of taxotere before surgery. If the second four courses are beneficial, then the idea of consolidation therapy will be supported. If this is seen only in the group receiving taxotere after surgery, then clearly the timing will be identified as an important factor. Furthermore, questions relative to the usefulness of this second course of chemotherapy following initial good response will also be answerable.

Another NSABP protocol, B-20, has provided information that removes some possible concerns about preoperative chemotherapy. The issue is whether patients with favorable tumors such as node negative, ER positive, should necessarily receive adjuvant chemotherapy. B-20 showed that adding adjuvant chemotherapy to routine postoperative tamoxifen treatment in node-negative, ER-positive women improved disease-free survival significantly. Since any preoperative chemotherapy program will include some people with such favorable tumors, it is reassuring that results from B-20 confirm the additional value of chemotherapy over tamoxifen alone in such patients. It is possible that women with clinically undetectable tumors and favorable histology may have a prognosis so favorable that the additional chemotherapy would not benefit them. Therefore, women with clinically occult tumors are excluded from B-27. With the results from B-20, it has now been shown that essentially all patient cohorts with clinically palpable tumors have benefitted from the addition of chemotherapy, both node negative and node positive, and both ER negative and ER positive. Therefore, chemotherapy can reasonably be given preoperatively to people with clinically apparent tumors without necessarily knowing the nodal status. The use of core needle biopsy has removed some of the uncertainties associated with fine-needle aspiration cytology and enables us to be confident that people with noninvasive cancer are not being included in these studies.

A secondary part of the B-26 trial was to evaluate any possible correlation between the nature of the primary tumor response and long-term outcome. Women who had a complete clinical response had a better outcome than those who showed only partial response, and these fared slightly better than women with no response. In a multivariate analysis, breast tumor response was a significant independent predictor of patient outcome. This could provide a useful tool for future chemotherapy regimens. It may be possible to determine the effect of chemotherapy without waiting for long-term results. Assuming that a correlation exists between response to preoperative chemotherapy and disease-free survival and survival, the response to preoperative chemotherapy becomes a prognostic marker for disease-free survival and survival. Thus, response to preoperative chemotherapy can be used as an intermediate end point in testing new regimens or in testing the additional effect of new drugs administered after well-established regimens, without having to wait for several years until disease-free survival and survival end points can be compared. With the demonstration that preoperative chemotherapy is equivalent to postoperative chemotherapy for disease-free survival and survival, new chemotherapeutic regimens can be tested in this setting without fear of putting patients at a disadvantage. These findings may also help with the evaluation of other prognostic tumor markers in correlating tumor response and outcome.

Local Recurrence in Preoperative Chemotherapy

The overall rate of local recurrence in patients who had had a complete clinical response was 5%. In the group of patients who were not initially considered good candidates for lumpectomy, however, who responded well to chemotherapy in terms of down-sizing, the overall rate of local recurrence was twice as great compared to those who had a lumpectomy as initial assignment (15% in down-staged patients, 7% in planned lumpectomy patients). This appears to be an age-related phenomenon since patients with tumors smaller than 3 cm or larger than 3 cm both showed the same differential. On the other hand, patients younger than 50 years of age had similar local recurrence whether they were down-sized or not, whereas those older than 50 showed a remarkable difference (11% vs. 2%).(Table 118.18)

Table 118.18. NSABP Protocol B-18: Preoperative Local Recurrence.

Table 118.18

NSABP Protocol B-18: Preoperative Local Recurrence.

It should be noted that even with a higher rate of local recurrence, approximately 90% of women older than 50 and 83% of younger women had successful breast-conserving surgery, even with a larger initial tumor size. When tumor response is evaluated according to presenting features, it is clear that small tumors respond best. See Table 118.17.

These tumors would have been easily treated by lumpectomy without preoperative treatment. Larger tumors that may need size reduction to be considered for lumpectomy are less likely to respond completely and those that become suitable for lumpectomy are more likely to recur locally.(Table 118.19) This would weaken the argument for preoperative chemotherapy as a tumor-reducing program to increase the chance of lumpectomy. Many European studies on preoperative chemotherapy were designed with just that primary purpose since in many of those centers tumors, ≥3 cm were not considered suitable for initial lumpectomy. In NSABP experience tumors up to 5 cm were commonly treated by lumpectomy with similarly acceptable low rates of local recurrence. Therefore, the strategy behind B-27 remains the same as for B-18, to improve disease-free and overall survival. Even if preoperative chemotherapy merely results in disease-free survival and survival equivalent to the results of postoperative chemotherapy, there are several reasons why it may sometimes be preferred over postoperative chemotherapy. The administration of preoperative chemotherapy results in separating patients into five different groups according to their pathologic and clinical response to chemotherapy: (a) pathologic complete responders, (b) clinical complete responders, (c) clinical partial responders, (d) patients with clinically stable disease, and (e) patients with clinically progressive disease.

Table 118.19. NSABP Protocol B-18: Response to Chemotherapy According to Tumor size at Initial Presentation.

Table 118.19

NSABP Protocol B-18: Response to Chemotherapy According to Tumor size at Initial Presentation.

The observed reduction in the size of the primary tumor following preoperative chemotherapy, resulting in increased rates of breast-conserving surgery, constitutes an additional advantage of preoperative chemotherapy in patients with operable breast cancer when compared with standard adjuvant therapy. Another clinical advantage of preoperative chemotherapy that has strong biologic implications relates to the evaluation of many of the proven and putative prognostic tumor markers, such as ERs, PsRs, ploidy, S phase, erb B2, P53, and other oncogenes and growth factors, in material obtained by fine-needle aspiration, and the potential correlation of these markers individually or in combination with the tumor response to preoperative chemotherapy. By evaluating such markers, conclusions could be reached relative to the predictive value for clinical and pathologic tumor response as well as to the prognostic value of the markers for disease-free survival. Thus, it is conceivable that, in the future, subgroups of patients with a high likelihood of pathologic complete tumor response could be identified who could be spared surgical resection altogether. Furthermore, serially monitoring tumor marker changes while a tumor is undergoing preoperative chemotherapy may provide biologic insight into the nature and function of these markers. Knowledge may also be obtained regarding the mechanisms of action of new chemotherapy regimens or new treatment modalities—for example, antiangiogenesis factors, growth-factor inhibitors, and antihormonal agents.

A potential disadvantage of preoperative chemotherapy relates to the inevitability of the small number of false-positive diagnoses that would result from the use of a cytologic diagnosis such as fine-needle aspiration. Most false-positive fine-needle aspiration biopsies are obtained in patients with malignant conditions not requiring chemotherapy, such as, DCIS, adenoid cystic carcinoma, or tubular carcinoma, or in conditions not requiring the chemotherapy given for breast cancer, such as lymphoma of the breast. The number of false-positive fine-needle aspiration biopsies should not exceed 1 to 2%. Furthermore, the use of core needle biopsies, which provide histologic diagnosis, is rapidly becoming a standard preoperative diagnostic step and will help avoid false-positive diagnoses.

As systemic therapy improves, it is not unreasonable to speculate that the surgical and adjuvant chemotherapy paradigms currently governing breast cancer management might eventually unite and form a single paradigm. If found to be effective, preoperative therapy could transform the role of surgery in the future treatment of breast cancer to the extent that operation would aid other modalities in achieving the goal of cancer curability. The more effective those therapies become, the more likely it will be that surgery will play a decreased role in the management of patients with breast cancer. An algorithm for adjuvant treatment of breast cancer is shown in Figure 118.49. Many areas of this model are controversial. Further research will improve its precision.

Figure 118.49. Algorithm for determining risk level for patients with breast cancer.

Figure 118.49

Algorithm for determining risk level for patients with breast cancer. The adjuvant programs for patients at low and high risk are usually different and still evolving. Substantial data indicate that high-risk patients respond better to new, more intensive (more...)

Issues for Further Study Regarding Therapy

Treatment of the Elderly

Few studies have been carried out to clearly define the management of elderly women with breast cancer.527,540,806 Perhaps one of the reasons such efforts have failed relates to difficulty in defining the word “elderly.” One may relate this to chronologic age, physiologic age, or life expectancy. Some of the more commonly asked questions relate to whether axillary dissection is necessary in such patients. It is our contention that axillary dissection need be carried out only for (a) determining prognosis, (b) providing information for choosing a particular therapy, or (c) local disease control. In elderly women with clinically negative axillary nodes who will receive tamoxifen therapy, there is little justification for performing an axillary dissection.

Another issue relates to whether tamoxifen should be given to all elderly patients. At the present time, the use of tamoxifen alone has become standard therapy for the management of such women.

A question frequently asked is whether less than full-dose chemotherapy should be given to elderly patients. Unless full-dose chemotherapy can be given, no chemotherapy should be administered. The use of less than full-dose chemotherapy will usually be ineffective, at the cost of unnecessary toxicity. In the CALGB study, however, women who received doxorubicin in a CAF reion at a dose of 30 mg/m2 for 4 weeks × 4 did equally well as those who received 60 mg/m2 × 4 or 40 mg/m2 × 6 if their HER2/neu studies showed less than 50% of cells with overexpression. A question also has been raised regarding what chemotherapy is best and how long it should be used. Only recently has there been interest in devising protocols to evaluate new drugs that may be less toxic in such patients. Vinorelbine (Navelbine) is one such agent; others have considered the use of M _ F as described elsewhere (NSABP B-13).

Finding the entire sequence of a human mammary tumor virus offer many new challenges and possibilities.807

Management of Metastatic Breast Cancer

General Considerations

Patients with untreated metastatic breast cancer demonstrate considerable heterogeneity in the clinical course of their disease. Some have a rapidly progressing tumor that metastasizes to multiple vital organs and causes death within a few months after detection of the first metastasis. Other patients have an indolent disease course, with slow progression alternating with long periods of stability in metastasis to soft tissues or bone. Some of these patients survive in the absence of active treatment for more than 10 years.808,809

The tissue localization of recurrent or metastatic disease and the extent of metastatic breast cancer partially determine the long-term prognosis. The biologic characteristics of the tumor, including its growth rate and relative resistance or sensitivity to available interventions, also contribute to the outcome. Finally, the efficacy of individual treatment modalities determines the success of palliation and the duration of disease control. Most patients with overt distant metastases are presently incurable. However, among those who achieve a complete remission after standard chemotherapy, a few remain progression-free for extended periods of time, occasionally exceeding 20 years.810,811 Complete remissions of long duration have also been reported after high-dose chemotherapy programs.812,813 The median survival of patients with metastatic breast cancer is 2 to 3 years.809,814,815 It is longer for patients who present with low-volume metastases to skin, lymph nodes, or bone and shorter for patients with multiple organ involvement, especially those with visceral organ (liver, brain, lung) involvement. The survival is longer for patients with ER-positive tumors and for those who achieve a complete remission with chemotherapy (3 to 4 years), compared to patients with hormone receptor-negative tumors, or those who fail to respond to systemic treatment.

Diagnostic Evaluation

Patients with a previous diagnosis of primary breast cancer who present with findings suspicious for recurrent metastatic disease should be strongly considered for diagnostic biopsy, especially if there has been a long disease-free interval. A biopsy is helpful in excluding benign processes that frequently masquerade as metastases and in ruling out the development of other cancers. Furthermore, the tissue can be assayed for ER, PgR, HER2/neu and other markers, to assist in treatment decisions.

Metastases from breast cancer are usually multiple and frequently involve more than one organ site. Thus, surgical resection of metastatic lesions is not usually indicated for therapeutic purposes in breast cancer patients. However, it is advisable to remove resectable chest wall recurrences, a solitary brain metastasis in the patient with a long disease-free survival, or when histologic confirmation of a recurrence requires an open biopsy.

Diagnostic tests and staging procedures are directed by the organ sites most frequently involved in metastatic breast cancer and by patient signs and symptoms. Documentation of initial metastatic sites is helpful in treatment planning and in later assessment of response to treatment. History and physical examination should focus on the detection of metastases on the chest wall, skin, remaining breast, regional and distant lymph nodes, axial skeleton, lungs, liver, and central nervous system. Laboratory evaluation should include a complete blood count, a platelet count, serum calcium, and liver and renal function studies. A chest x-ray and bone scan are obtained in most patients because these sites are commonly involved with metastatic breast cancer. Suspicious lesions on bone scan need confirmation by x-ray or by other diagnostic tests because of the high false-positive rate. In the presence of bone pain unexplained by results of the bone scan, radiographs or MRI of the symptomatic area should be performed. Although bone scans are quite sensitive, they are of limited use in assessing treatment response in the first 2 to 4 months after the start of a new therapy. Increased intensity of uptake in existing lesions or even new lesions can signify either disease progression or disease regression with active bone healing.816–818 Bone scan changes must be corroborated by other information. Routine brain and liver imaging procedures are expensive and are not indicated in the absence of symptoms, physical findings, or laboratory values suggesting involvement. Patients with ER-positive tumors are especially unlikely to suffer recurrence initially in the brain or liver.302 Serial blood tumor markers are recommended by some clinicians as an aid for monitoring disease status. The most frequently used markers are CA 15-3, CA 27-29, and CEA. CA 15-3 and CA 27-29 are more sensitive than CEA and are elevated in more than 70% of metastatic breast cancer patients, compared with 55% for CEA.819,820 All three markers can be increased in certain benign diseases, especially liver disease, and with other neoplasms, including lung, gastrointestinal, and genitourinary cancers. Levels of all three markers do correlate significantly, although not absolutely, with changing disease status. Increasing levels may signal the need to perform more objective diagnostic tests to confirm worsening of the disease. Decreasing levels may provide greater confidence that a treatment is working. Modifying treatment based solely on changing marker levels, however, is often hazardous and should, in general, be avoided. For optimal utilization of markers, the clinician must be aware of the normal variations in measurements in the laboratory used (i.e., the coefficient of variation) and confirm decreasing or increasing values with additional measurements over time. These markers are of limited value in following patients for recurrence after treatment of primary breast cancer. The average lead-time in the diagnosis of a recurrence is only 4 to 6 months, and there are no data to suggest that early institution of presently available systemic therapy at the time the marker rises affects survival.

General Therapeutic Guidelines

Over the past four decades, systemic therapy with endocrine therapy or cytotoxic chemotherapy became the fundamental treatment approach of the management of metastatic breast cancer.821 Treatment decisions can be complicated because of the varied clinical courses among different patients and because many different therapies of apparently similar efficacy are available. Upon diagnosis of metastatic disease, the first task is to assess the extent of metastasis and to determine, based on available clinical information, the likelihood of rapid progression, which could cause vital organ failure or other catastrophic complications. In this sense, patients are often divided into low- and high-risk groups. Those at low risk include patients who have had a long disease-free interval and have limited metastatic disease, often located in soft tissues or osseous sites. Some patients with limited visceral disease may also qualify. More often than not, low-risk patients are older and postmenopausal, and their tumors are hormone receptor positive. Other than bone pain, symptoms attributed to the disease are minimal. The age of the patient, the presence of co-morbid conditions, the organ distribution and extent of metastatic disease, abnormalities in vital organ function, and the likelihood of hormone responsiveness all influence the selection of treatments. Patients with these characteristics are excellent candidates for hormone therapy as the first intervention for metastatic breast cancer.

Once the decision to use hormone therapy is made, tamoxifen or one of the newer aromatase inhibitors is the first hormonal therapy of choice. Patients who achieve an objective regression or longstanding disease stability after first- hormone therapy often benefit from second-line and sometimes third- and fourth-line hormonal interventions. With the hormonal treatments available today, if an antiestrogen is chosen for first-line therapy, an aromatase inhibitor or progestin is chosen for second- and third-line therapy; androgens are usually chosen for fourth-line interventions or beyond. Eventually, even patients with hormone-responsive breast cancer develop resistance to endocrine manipulation and become candidates for cytotoxic chemotherapy. Whereas some oncologists elect to treat selected patients with solitary lesions with locoregional therapy, the great majority of patients receive systemic therapy from the onset of overt metastatic disease.821 Certainly, symptomatic patients with widespread disease or aggressive visceral metastases should receive chemotherapy. In addition to bone pain, common symptoms include anorexia, weight loss, and reduced performance status. The disease-free interval for patients with high-risk or aggressive metastatic disease is typically short (less than 2 years), and the tumor is frequently ER negative. Carcinomatous meningitis, extensive liver metastases, lymphangitic lung metastases, or brain metastases almost always signify aggressive disease that is unresponsive to endocrine therapy. Patients who have been diagnosed with aggressive disease should be treated with combination chemotherapy, even if the tumor contains ER and PgR. Endocrine therapy is less likely to induce remission in this setting, and the more rapid response usually seen with chemotherapy is highly desirable. Patients with receptor-positive tumors can be considered for endocrine therapy at a later date or if they fail to respond to chemotherapy. Patients with brain metastases should also receive regional therapy, usually brain irradiation, which is very effective in palliating symptoms of central nervous system involvement.

Patients with more indolent disease are best treated initially with an endocrine therapy, in some cases even if the tumor is receptor negative.301 Although the probability of obtaining a response in this setting is less than 10%, false-negative receptor assays do occur, especially if the assay was performed on a biopsy specimen from a small tumor.822 In patients with slow-growing disease and other clinical characteristics suggestive of hormone-responsive tumor (soft-tissue or bone metastases, older postmenopausal patient) and especially if the patient is a poor candidate for chemotherapy, a 6- to 8-week therapeutic trial of endocrine therapy is worthwhile and appropriate. Fifty to 60% of patients with indolent disease and ER-positive tumors benefit from endocrine therapy.302,823

The hormonal interventions used in the 1950s, 1960s, and 1970s have been almost completely replaced by modern endocrine interventions that are more specific and better tolerated.823,824 Thus, hypophysectomy and bilateral adrenalectomy are of historical interest only, having been replaced first by aminoglutethimide,825–827 and, more recently, specific aromatase inhibitors such as formestane, letrozole, and anastrozole.828 Although oophorectomy is still practiced by a few surgeons, it has largely been replaced by antiestrogens (tamoxifen, toremifene) and LHRH analogues (goserelin, leuprolide), which provide an effect equivalent to chemical ovarian ablation. Progestins such as megestrol acetate and medroxyprogesterone acetate are also well tolerated when administered at the usual dose and schedule and have replaced estrogens, androgens, and corticosteroids. In addition to patient and tumor characteristics that are helpful in the determination of whether a tumor is likely to respond to hormonal manipulation (such as age, disease-free interval, menopausal status, and location and extent of tumor deposits), sophisticated assays for the determination of ER and PsR expression have facilitated the selection of patients for endocrine intervention. Patients with ER-positive metastatic tumors have a 50% or greater probability of clinical benefit from hormone therapy, whereas those with clearly ER-negative tumors have less than a 10% probability of response. Those with high ER concentrations (exceeding 100 fmol/mg) have even higher probabilities of an objective response than do patients with both ER and PsR expression.302,823 However, findings from recently conducted prospective, randomized clinical trials comparing different hormonal agents as first-line therapy for metastatic breast cancer revealed that overall response rates, using strict definitions of complete and partial remission, were closer to 13% or 40% than to 50%, even in patients with ER-positive tumors.829–835 Prolonged disease stability (including minor responses) was achieved in an additional 20 to 30% of patients during hormonal therapy. Stable disease for longer than 6 months is associated with survival durations similar to those of patients who achieve a partial or complete response with endocrine therapy.836 Over the past two decades, the antiestrogen tamoxifen became the most commonly used agent for first-line endocrine therapy of metastatic breast cancer. Tamoxifen is at least as effective as other endocrine interventions for both premenopausal and postmenopausal breast cancer.839–832,834,835,837,838 ovarian ablation is also useful for ER-positive tumors.839–842 This effect is permanent, sometimes inducing a menopausal state that permits the use of other endocrine therapies, including the selective aromatase inhibitors, for second- and third-line therapy. Although tamoxifen is an effective alternative to surgical ovarian ablation,843,844 the two treatments can be used in sequence, since response to one often predicts a high response rate to the other.845,846 The LHRH agonists offer another alternative for premenopausal patients by causing a chemical (or medical) castration.847–849 Results to date suggest that serum estrogen concentrations are suppressed to postmenopausal levels, and that response rates in advanced breast cancer are similar to those obtained after surgical ovarian ablation.848–851 The time to obtain maximal response with endocrine therapy can be quite prolonged, and treatment should not be abandoned prematurely. Patients should be continued on a therapeutic trial for 6 to 12 weeks in the absence of progressive disease, before other therapies are used. Prolonged stable disease, without objective regression, is one form of clinical benefit associated with endocrine therapy. This effect is particularly acceptable in patients with minimal or no disease-related symptoms. A “tumor flare” with increased bone pain, swelling, or erythema of superficial lesions or hypercalcemia during the first week or two of therapy should not be confused with disease progression. Tumor flare is seen occasionally with endocrine treatments such as high-dose estrogens, tamoxifen, androgens, and progestins, and it frequently reflects hormone-sensitive disease. If tumor flare occurs early, endocrine therapy should continue under close observation and appropriate symptomatic support unless life-threatening conditions exist. Management of hypercalcemia with hydration and bisphosphonate therapy and liberal use of analgesics should be applied until the flare resolves.823,824,852,853

For patients who initially respond to endocrine therapy, additional responses with second- and third-line endocrine interventions are common.823,824 This is especially the case for patients with indolent or hormone receptor-positive tumors. These patients should be offered additional endocrine therapies, in the absence of life-threatening disease, before changing to chemotherapy. Some patients derive many months or even years of high-quality life with sequential endocrine therapies. Few patients who fail to benefit from the initial endocrine treatment will respond to second- or third-line hormonal interventions. These patients, those who develop endocrine resistance, and those who manifest life-threatening disease should be offered chemotherapy.

Specific Endocrine Therapies

Interference with Steroid Hormone Production

This therapeutic objective can be accomplished by the surgical removal of organs that produce and secrete hormones involved in breast cancer growth or chemical inhibition of hormone synthesis.

Ovarian Ablation

Ovarian ablation is the oldest form of endocrine therapy, first described in 1896. It remains an effective, although infrequently employed, hormonal treatment of premenopausal women.823 It is ineffective for postmenopausal patients. Ovarian ablation can be performed by surgical removal of the ovaries or by radiotherapy. The latter requires 2 to 3 months for maximal ablation of ovarian function, which is a disadvantage in the treatment of symptomatic patients. Ovarian ablation by radiotherapy is noninvasive, but its effects may not be permanent. Ovarian ablation produces major objective tumor regressions in one-third of unselected patients with metastatic breast cancer and in about 60% of those with positive ERs. The average duration of response is 1 year, although a few patients derive long-term benefits, lasting for several years. Over the short term, ovarian ablation is a safe, well-tolerated procedure. Acute side effects include hot flashes, alterations in mood, and other symptoms of estrogen deprivation. Long-term consequences include accelerated loss of bone mineral density and alterations in the blood lipid profile that indicate an increased risk of coronary artery disease.854 Ovarian ablation has been largely displaced by antiestrogens and LHRH agonists.

In the United States, surgical ablation is preferred over radiotherapy. Since the appearance of antiestrogens, ovarian ablation has been used less commonly because its therapeutic effects are transient, whereas the estrogen deprivation it causes is permanent. However, ovarian ablation is an inexpensive, safe, and effective procedure and is a useful endocrine maneuver when there are questions about the possibility of close follow-up or of compliance with oral medication regimens.

Surgical Adrenalectomy and Hypophysectomy

These two major surgical ablative procedures are of historical interest only because they are no longer performed for breast cancer therapy. Previously they had been used as second-line endocrine manipulations after ovarian ablation. Their purpose was to eliminate adrenal steroidogenesis. Following either procedure, lifetime mineralocorticoid and glucocorticoid replacement therapy was required. In addition, even in expert hands, both procedures were associated with a small, but definite, mortality rate. They have been totally replaced by inhibitors of steroid synthesis and of aromatase.

Medical Adrenalectomy

Aminoglutethimide suppresses adrenal steroid synthesis by inhibiting the conversion of cholesterol to pregnenolone.855 Administered at doses of 500 to 1,000 mg per day orally, it is also a moderately effective aromatase inhibitor. Aminoglutethimide is effective in patients with absent or inactive ovaries.856 Because it also inhibits glucocorticoid synthesis, hydrocortisone replacement usually is administered to prevent the development of an adrenocorticotropic hormone override mechanism. Direct comparisons between aminoglutethimide and surgical adrenalectomy have documented, at the very least, equivalence, and even a suggestion of superiority for medical adrenalectomy.856 Surgical adrenalectomy is associated with a small, but definite, mortality rate. Aminoglutethimide can be administered to any patient without risk of mortality. The common side effects of aminoglutethimide include nausea, somnolence, and a mucocutaneous rash. Aminoglutethimide often was used as second- or third-line hormonal therapy before the advent of selective aromatase inhibitors for women after natural or iatrogenic menopause.

Aromatase Inhibitors

  Aromatase is an enzyme needed for the conversion of androstenedione to estrone and subsequently to estradiol at peripheral tissues.826 Aromatase is substantially concentrated in adipose and hepatic tissues and is also found in elevated concentrations in breast cancer.857,858 The enzyme has no effect on glucocorticoid, androgen, or mineralocorticoid production. Aromatase inhibitors lower serum and tumor estrogen levels in postmenopausal patients. Therefore, aromatase inhibition is applicable only to postmenopausal (or oophorectomized) women in whom estrogen production is predominantly from peripheral sources. Two types of aromatase inhibitors have been developed: type 1 aromatase inhibitors are exclusively steroidal and bind the enzyme covalently and irreversibly; type 2 inhibitors (such as aminoglutethimide) reversibly inhibit cytochrome P-450.857–860 The first aromatase inhibitor discovered, aminoglutethimide, has a double mechanism of action: inhibition of the conversion of cholesterol to pregnenolone and inhibition of androgens to estrogens by inhibition of aromatase. Because its aromatase-inhibiting activity is modest and produces multiple side effects, it has been totally displaced by new aromatase inhibitors.860

Type 1 Aromatase Inhibitors

The earliest of the new inhibitors, formestane (or 4-hydroxyandrostenedione), has no estrogenic properties and is rapidly metabolized by the liver.861,862 By intramuscular administration, its half-life is 5 to 10 days. It has an excellent therapeutic index and requires no glucocorticoid replacement. It is commercially available in several European countries.

The primary action of trilostane is aromatase inhibition, but it also inhibits the 3-hydroxysteroid dehydrogenase. Its level of activity is similar to that of aminoglutethimide.863,864 However, this drug also causes nausea, vomiting, lethargy, and diarrhea, side effects that result in poorer tolerance than formestane. This agent is not used for the management of breast cancer, although it is approved by the FDA for the management of Cushing’s disease.

Type 2 Aromatase Inhibitors

Two agents of this category were recently approved by the FDA: anastrozole and letrozole.865–867 Both agents were shown to have excellent antitumor activity and excellent tolerance profile, similar to the SERMs. Both anastrozole and letrozole were shown to have superior efficacy, in terms of higher response rates and longer survival, compared to megestrol acetate.868–872 In one randomized trial, letrozole showed similar superiority over aminoglutethimide. Based on these results, anastrozole and letrozole have replaced the progestins and aminoglutethimide in second-line therapy of metastatic breast cancer. Both agents are currently under evaluation for first-line therapy of metastatic breast cancer and, in comparison with tamoxifen, in the adjuvant setting for primary breast cancer. The preliminary results of two randomized trials comparing tamoxifen (20 mg daily) with anastrozole (1 mg daily) in first-line therapy of metastatic breast cancer suggested that the two agents had similar therapeutic efficacy, although in one of the trials, anastrozole was superior, in terms of time to progression. Fadrozole demonstrated antitumor efficacy similar to that of established aromatase inhibitors or other hormonal agents.873 It is well tolerated, although nausea, vomiting, anorexia, headache, rash, and other minor adverse effects have been reported. Pyridoglutethimide is an aminoglutethimide analogue with encouraging preliminary results in early clinical trials. However, neither of these latter two drugs will undergo additional development. The major advantage of the selective aromatase inhibitors over their predecessors is a better therapeutic index.

Inhibitors of Pituitary Function

LHRH agonists (buserelin, goserelin, leuprolide) produce long-lasting inhibition of luteinizing hormone and follicle-stimulating hormone release after a transient initial increase. Their action also could be described as pharmacologic ovarian ablation because they inhibit ovarian estradiol release by about 90%.848–850 In addition, some authors have hypothesized that LHRH analogues may have direct effects on breast cancer cells; however, this action remains speculative. LHRH analogues are primarily effective in premenopausal women. Approximately 10% of postmenopausal women respond to this therapy.874 LHRH analogues also are active in male breast cancer.875

Interference with Hormonal Action

The endocrine therapies described in this section act not by inhibiting or preventing hormonal production or release but by interfering with the effects of hormones on the end organ (i.e., the breast cancer cell).

Selective Estrogen Receptor Modulators (SERMs, or Antiestrogens)

Antiestrogens initially were developed in the search for better contraceptives.876 Although their efficacy as antifertility drugs was limited, they were found to cause regression of breast cancer cells. Tamoxifen is known to bind competitively to the ER, but it also has multiple additional effects on the cancer cell.877 It can lower the production of IGF-I and TGF-ω; it blocks angiogenesis and induces the production of TGF-ω, calmodulin, and protein kinase C. It also has been reported to increase natural killer cell activity. Tamoxifen has a multitude of actions, all of which affect breast cancer cells unfavorably. The effects of tamoxifen have been studied mostly in postmenopausal women, although its effects have also been examined in younger patients. The serum estrogen level rises dramatically in some premenopausal patients, but this effect does not mediate tamoxifen resistance. The usual dose of tamoxifen is 20 to 40 mg daily. Higher doses do not appear to be more effective. Tamoxifen and its active metabolites have a prolonged serum half-life (7 days) after reaching steady-state levels.878 Thus, once-a-day dosing is sufficient, and missing an occasional dose will not alter serum levels dramatically. Clinical trials have demonstrated that tamoxifen, administered orally at 20 to 40 mg on a daily basis, produces tumor regression of established metastatic breast cancer in about 30% of unselected patients and in 50 to 60% of patients with ER-positive tumors.833,879,880 The responses last 12 months, on average. In addition, another 20 to 30% of women have stable disease for periods that exceed 3 to 6 months and, in some cases, even longer. Numerous randomized trials in postmenopausal patients have shown that tamoxifen is therapeutically equivalent to other endocrine therapies, including the surgical ablative interventions, megestrol acetate, aminoglutethimide, and high-dose estrogens (DES).833,881–885 Because tamoxifen has excellent tolerance, it has become the front-line hormonal treatment of choice for untreated metastatic breast cancer.

Two recent reports suggested that the selective aromatase-inhibitor, anastrozole, is at least as effective and possibly more effective and equally well tolerated as tamoxifen. There is no apparent dose-response correlation for tamoxifen, and the drug has been administered safely for periods that exceed 5 years.886–889 Patients who have previously undergone tamoxifen adjuvant therapy may still respond later to tamoxifen rechallenge when they develop metastases.890

Tamoxifen is also active as second-line endocrine therapy in patients responding to, and then progressing after, ablative surgery, DES, and progestins. In a small percentage of patients (< 10%), there may be an initial, short-lasting tumor flare, starting within the first week or two of administration of this agent. This may be manifested as increased bone pain, development of hypercalcemia, or, occasionally, even a slight increase in tumor dimensions. Flare usually predicts response to therapy, and close follow-up with active symptomatic support is appropriate. If tumor flare symptoms appear late (> 3 weeks after initiation of therapy), they represent progression of disease and should prompt the discontinuation of tamoxifen and a change in therapy.

Tamoxifen is a mixed estrogen agonist and antagonist. The tumor flare reaction probably is secondary to its agonist activity. Other agonist effects of tamoxifen include the preservation or enhancement of bone mineral density, a decrease in cholesterol level, and additional modifications of the serum lipid profile that may lead to a reduction in the risk of coronary artery disease. Tamoxifen also has been associated with endometrial hyperplasia, an increased frequency of ovarian cysts, and an increased incidence of endometrial carcinomas and thromboembolic events (other manifestations of its estrogen agonist effects).891

Several new SERMs have been extensively tested. Toremifene was recently approved by the FDA for the management of metastatic, ER-positive breast cancer, whereas raloxifene was approved for the prevention of osteoporosis.829,892 Both agents are under additional evaluation in comparison with tamoxifen in randomized clinical trials. Other SERMs (idoxifene, droloxifene, etc.) are under development. However, these agents appear to be no more effective, nor less toxic, than tamoxifen.

The SERMs, along with the selective aromatase inhibitors, are the least toxic endocrine treatments currently available. Very few patients discontinue SERM treatment because of intolerance, mostly menopausal symptoms or nausea.823,834 Reports of tamoxifen-related depressive disorders remain unconfirmed; leukopenia and thrombocytopenia are rarely seen.

Estrogens

Second to ovarian ablation, estrogens are probably the oldest form of hormonal therapy for breast and other hormone-responsive tumors.893,894 It appears paradoxical that both reduction of estrogen levels by ablative therapies and the administration of high doses of estrogen can cause tumor regression. The mechanism by which high doses of estrogen induce tumor regression are not known, but this therapy is as effective as other first-line hormonal therapies of postmenopausal patients.881 High-dose estrogen therapy was also reported to have therapeutic activity in premenopausal women with breast cancer.895 Diethylstilbestrol 15 mg/d or ethinyl estradiol 1.5 to 3 mg/d are the most common preparations used. The major drawback of estrogen therapy is toxicity. Common side effects include nausea, vomiting, fluid retention, increased risk of thrombotic phenomena, tumor flare, urinary incontinence, and vaginal bleeding. When compared to tamoxifen, estrogens were found to be more toxic and less well tolerated, but also less expensive than tamoxifen or several of the other modern hormonal therapies. They were used as the first modality of hormonal therapy for postmenopausal women for many years but were displaced by SERMs and aromatase inhibitors. For postmenopausal women who have responded to several lines of hormonal therapy (SERMs, aromatase inhibitors, progestins, and perhaps androgens), estrogen therapy is a viable therapeutic alternative. Starting at a lower dose, and escalating to the full therapeutic dose over a 2- to 3-week period lessens gastrointestinal toxicity and improves tolerance.

Progestins

The development of synthetic progestational agents led to their evaluation for the treatment of breast cancer.823,896–898 Numerous clinical trials demonstrated that these agents are effective in producing tumor regression in 20% to 40% of patients with metastases and, in general, are well tolerated. In the United States, the most commonly used progestational agent for this purpose is megestrol acetate (Megace, 40 mg PO q.i.d.), whereas in Europe and South America, it is medroxyprogesterone acetate (Provera, 400 mg/d). Other progestational agents are of historical interest only. Although responses to progestin therapy correlate with ER content, there is no evidence that PsR content is a better predictor of response for this group of agents than for other hormonal treatments. Toxicity is clearly dose related. At high doses, substantial weight gain, fluid retention, and other toxicities become prominent. Some studies have suggested that higher doses of progestins are more effective in the treatment of breast cancer than are lower doses, but there is ongoing controversy about this dose-response correlation.897,899,900 At low doses, the efficacy and tolerance of progestins appear similar to those of tamoxifen. Based on these studies, progestins were frequently used as first- or second-line therapy for metastatic breast cancer until they were rapidly displaced by selective aromatase inhibitors over the past few years.823 High-dose progestins stimulate appetite and weight gain and have been used with some success for cancer cachexia.901 For palliative treatment of patients with advanced cancer, progestins can decrease or reverse a decreasing sense of well-being.

Androgens

Androgen therapy also is an effective approach to the endocrine treatment of breast cancer, but the virilizing effects make it intolerable to many women. Newer semisynthetic testosterone derivatives, such as fluoxymesterone (10 mg orally b.i.d.) and danazol, are better tolerated, with fewer virilizing effects. Nevertheless, with long-term therapy, all of these agents can produce hirsutism, deepening of the voice, clitoral hypertrophy, male pattern alopecia, and increased libido. Like other hormonal agents, androgens also can cause tumor flare. Androgens are generally considered somewhat less effective than other additive hormonal therapies, such as antiestrogens and progestins.902,903 Although this is not clearly established, the therapeutic index of the new antiestrogens, aromatase inhibitors, and LHRH analogues is clearly superior to that of androgens. Through their anabolic activity, androgens exhibit an important palliative effect, even in the absence of tumor regression. Increased appetite and weight gain are common. Androgens, like estrogens, can be valuable therapeutic tools when cost is an important consideration, especially when good tolerance can be established in an individual patient.

Corticosteroids

The antitumor efficacy of corticosteroids is poorly documented for metastatic breast cancer but is considered to be about 10%.902–904 In some trials, no antitumor activity has been documented. More importantly, the long-term administration of glucocorticoids is associated with potentially severe and intolerable side effects. Therefore, glucocorticoids are not recommended as antitumor agents for metastatic breast cancer.

Glucocorticoids have a specific role in the management of well-defined complications of breast cancer, however. High-dose glucocorticoid therapy is administered for short periods to patients with central nervous system metastases and for spinal cord compression, and some experts also use it during the management of acute hypercalcemia of malignancy. This latter indication has been relegated to the management of bisphosphonate-refractory cases in recent years. Its antiemetic effects are also well known.

Antiandrogens

Flutamide and cyproterone acetate have been evaluated in a few clinical trials.908 Their efficacy against metastatic breast cancer appears limited.905–907 At this point, there is no role for these agents in the standard treatment of breast carcinoma.

Antiprogestins

Mifepristone (RU 486) has had limited evaluation in metastatic breast cancer.909 Although antitumor activity has been demonstrated (approximately 10%), the drug also is accompanied by antiglucocorticoid activity, which limits its long-term administration. Newer antiprogestins with limited or no antiglucocorticoid effects are being developed.

Hormone Withdrawal

After the administration of estrogens, androgens, and antiestrogens, withdrawal of the hormonal agent upon the appearance of progressive disease can induce an (additional) objective regression of tumor deposits.823,910–913 The mechanism of this phenomenon is poorly understood, although laboratory experiments with tamoxifen have suggested that, after long-term suppression of breast cancer cell lines by this agent, some cells become dependent on (or stimulated by) continued exposure to tamoxifen.914 If, at the time of tumor progression, tamoxifen is removed, a secondary inhibition of these tumor cells can be observed. The hormone withdrawal response has been poorly documented in the literature and is based mostly on retrospective reports that suggest a frequency of 10 to 20%; however, its occurrence is considered real by most experts. In at least one prospective trial of tamoxifen withdrawal, up to 40% of patients progressing on tamoxifen had a response or prolonged stability after antiestrogen withdrawal.913 Importantly, a hormone withdrawal response is reported almost exclusively in patients with a preceeding response to hormonal therapy. The occurrence of a hormone withdrawal response after clear failure of hormonal therapy is negligible. For patients with indolent metastatic disease, especially those who have no symptoms at the time of secondary progression after an intervening response to additive hormonal therapy, a period of 2 or 3 months of observation to detect a hormone withdrawal response might be appropriate.

Combination Hormonal Therapy

Many attempts have been made to combine hormonal therapies for breast cancer, based on the hypothesis that blocking different pathways of the hypothalamic–hypophysial–gonadal–breast cell pathway may produce a more complete hormonal blockade and, therefore, increase therapeutic efficacy. Although initial reports regarding the addition of corticosteroids to oophorectomy or tamoxifen suggested a higher response rate,915–917 these results could not be confirmed by larger prospective, randomized trials.918,919 There have been reports of higher response rates when an androgen was added to tamoxifen.920 However, these results remain largely unconfirmed.921,922 Similarly, combinations of tamoxifen with aminoglutethimide did not produce better results than tamoxifen alone. More recently, preliminary reports of several prospective randomized trials strongly suggest that combinations of LHRH analogues with tamoxifen might be more effective than either agent alone among premenopausal patients.831,847,923,924 The mature results of these trials and the results of larger confirmatory studies are awaited with interest. Until then, there is no role for the routine use of combined hormonal therapy for the treatment of primary or metastatic breast cancer.

Hormonal Therapy for Male Breast Cancer

As noted earlier, breast cancer is more often hormone receptor—positive in men than in women.925 This also has been confirmed clinically by the more frequent observation of responses to hormonal therapy in men as compared to women.926,927 Gonadal ablation (orchiectomy) has demonstrated efficacy against metastatic breast cancer and was (until the appearance of tamoxifen and other SERMs) the hormonal therapy of choice.927–931 Orchiectomy has been reported to produce overall response rates of 30 to 80% in men with metastatic breast cancer.932,933 The median duration of response after orchiectomy was 22 months in one collective series, which is almost twice as long as for women treated with ovarian ablation. Adrenalectomy also has been used in men with breast cancer, with a high response rate and response duration.933 However, as in women with breast cancer, adrenalectomy has been displaced by noninvasive hormonal manipulations.927

Tamoxifen is the hormonal treatment of choice for male breast cancer today. More than 50% of unselected patients with metastatic breast cancer respond, as do 80% of patients with ER—positive tumors. The experience with other SERMs in male breast cancer is quite limited. Other hormonal agents with demonstrated efficacy against metastatic breast cancer in men are progestins, aminoglutethimide, estrogens, and antiandrogens. Anecdotal reports have shown antitumor activity of androgens and corticosteroids in men with breast cancer. However, these reports are based on only a few patients. Combined hormonal therapy has not been extensively evaluated in males.

Optimal Sequencing of Hormonal Treatments

Patients with metastatic breast cancer often respond to more than one hormonal manipulation. It is evident that there is no complete cross-resistance between the various endocrine interventions in use today. This points to the existence of multiple, different mechanisms of action. Consequently, sequential hormonal manipulations have been successful in offering quality palliation for these patients.823

Table 118.20 documents the recommended sequence of hormonal treatments. For premenopausal women, tamoxifen, toremifene, or ovarian ablation appears to be the treatment of choice. LHRH analogues can substitute for ovarian ablation. The selection between these two modalities depends on patient preference, cost, possibility of follow-up, and predicted compliance with treatment.

Table 118.20. Selection of Optimal Hormonal Therapy in the Management of Metastatic Breast Cancer.

Table 118.20

Selection of Optimal Hormonal Therapy in the Management of Metastatic Breast Cancer.

After a response to tamoxifen, ovarian ablation can be an effective second-line therapy. Conversely, after an objective response to ovarian ablation, tamoxifen can be an effective second-line regimen. As an alternative, progestins can serve as second- or third-line therapy, or, after ovarian ablation, selective aromatase inhibitors also might serve this purpose. Androgens can be used as third- or fourth-line therapy for premenopausal patients.

For postmenopausal patients, either antiestrogens (SERMs) or selective aromatase inhibitors are the hormonal therapy of choice. Either of these agents also can serve as effective second-line therapy after the other, whereas progestins are usually reserved for third-line endocrine treatment.

It used to be generally accepted that these endocrine manipulations had equal efficacy. However, recent clinical trials have demonstrated the therapeutic superiority of aromatase inhibitors over progestins and aminoglutethimide.823,870,934,935 Therefore, the selection of hormonal therapy or sequence of administration of hormonal therapies is now based not only on the toxicity profile of the various treatments but also on a rationale ranking by efficacy.

Cytotoxic Chemotherapy

Chemotherapy is used in patients with aggressive disease who are not candidates for endocrine therapy and in those with tumors that no longer respond to endocrine therapy. Breast cancer is moderately sensitive to a large number of cytotoxic agents.936 These agents belong to several molecular families with different mechanisms of action and only partially overlapping toxic effects. Traditionally, the most active agents included the anthracyclines (doxorubicin and epirubicin), alkylating agents (cyclophosphamide, l-Pam and thiotepa), the anthraquinones (mitoxantrone), antimetabolites (methotrexate and 5-fluorouracil), and the Vinca alkaloids (vinorelbine, vinblastine, and vincristine). Forty to 50% of previously untreated patients with metastatic breast cancer achieve an objective regression after single-agent anthracycline therapy. Mitoxantrone and the alkylating agents would produce partial or complete responses in 30 to 40% of patients, whereas the other drugs are estimated to have a 20 to 30% response rate. Cisplatin was also reported to produce response rates of around 50%, but this information is based on two small studies937,938; the reported response rate with carboplatin was around 30%.939,940 Mitomycin is another effective agent, although its use has decreased markedly since the development of the taxanes, vinorelbine, and some of the other new drugs.941 Response durations after single-agent therapy are short, and there is no noticeable impact on survival. For this reason, combination chemotherapy is a preferred approach to the management of advanced breast cancer.

Combination Chemotherapy

Combination chemotherapy was developed based on the rationale that combining agents with different mechanisms of action and different toxicities would increase treatment benefit without significantly worsening morbidity or quality of life (Table 118.21). Thus, combination chemotherapy regimens consisting of cyclophosphamide, methotrexate, 5-fluorouracil (CMF); cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, prednisone (CMFVP); and 5-fluorouracil, doxorubicin [Adriamycin], cyclophosphamide (FAC) produce higher overall response rates, exceeding 50% in most reports, with remission durations that range from 8 to 12 months and survival that approaches 2 years. Randomized trials demonstrated that these combinations were more effective than single agents such as 5-fluorouracil, cyclophosphamide, and melphalan.942–944 Anthracycline-based combinations appear to be more effective than CMF and CMFVP in several randomized trials, producing not only higher overall and complete remission rates but, in some studies, significant prolongation of survival as well.945–947 These studies suggest, however, that the additional benefit gained with combinations over single-agent therapy and with anthracycline-containing regimens over non–anthracycline-containing regimens is modest, and although toxicity has been generally tolerable, there is still insufficient information about the effects of these various interventions on quality of life. There is also some controversy about the relative efficacy of these combinations when compared to full-dose doxorubicin alone. Some contend that high-dose doxorubicin (60 to 90 mg/m2) is as effective as most combination regimens available prior to the development of the taxanes.

Table 118.21. Commonly Used Combination Chemotherapy Regimens for Metastatic and High-Risk Primary Breast Cancer.

Table 118.21

Commonly Used Combination Chemotherapy Regimens for Metastatic and High-Risk Primary Breast Cancer.

Resistance to anthracycline therapy is associated with poor prognosis. A recent review indicated that patients who initially failed to respond to an anthracycline-containing regimen had a 7% response rate to additional chemotherapy with any of the cytotoxic drugs available prior to 1990 (the pre-taxane era); the median survival for this group of patients was 4 months.948

An unresolved issue in the cytotoxic therapy of breast cancer relates to the optimal duration of treatment. Initially, treatment was continued until the development of progressive disease or intolerable toxicity. In recent years, there has been a concerted effort to determine the optimal duration of therapy based on the best balance between therapeutic effect and quality of life. Several prospective randomized trials comparing shorter versus longer durations of therapy have been reported.949 In general, treatment regimens shorter than six to eight cycles were associated with lower response rates and shorter durations of response (or time to progression).950–952 In at least one of the studies, the continuous rather than periodic treatment also provided a better quality of life, suggesting that a more substantial antitumor response had a greater influence on quality of life than the negative effects of the regimen-related toxicity.950 If all published randomized trials addressing the issue of shorter versus longer duration of therapy are pooled in a meta-analysis, there is an important trend for longer duration of survival favoring longer duration of treatment.

Combination chemotherapy regimens commonly used to treat metastatic breast cancer are shown in Table 118.21. The earliest attempts at combining chemotherapeutic agents were reported by Greenspan.953 Subsequently, the five-drug combination consisting of cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone (CMFVP, or the “Cooper” regimen) initiated the modern era of combined cytotoxic therapy.954 Multiple modifications in dose, schedule, and the individual drug components were reported over the next 30 years. The most commonly used modification of the original CMFVP regimen is the three-drug (CMF) combination, without vincristine or prednisone.955 The intravenous combination prevously was shown to be inferior to the “classical” CMF.956

Doxorubicin-containing combinations are probably the most commonly used regimens today. The 5-fluorouracil, doxorubicin (Adriamycin), cyclophosphamide (FAC) regimen came into use in 1973957; shortly thereafter, other doxorubicin-containing combinations were reported.945,958 Randomized comparisons between CMF-like and FAC-like regimens have shown a higher response rate and longer time to progression for the anthracycline-containing regimens.946–959 Some individual studies and a recent meta-analysis of the contribution of doxorubicin to the “Cooper” regimen also showed a significant prolongation of survival. However, anthracycline-containing regimens produce alopecia, nausea, and vomiting with greater frequency and severity, and cardiomyopathy occurs in a dose-dependent manner.960,961 Because the added benefits gained with FAC over CMF are modest, the decision about which regimen to choose should be individualized, based on the stated objectives of treatment, understanding and acceptance of a toxicity profile, and the physician’s familiarity with a particular regimen.

Most of these drugs are myelosuppressive, resulting in substantial leukopenia and neutropenia. In addition, they are associated with nausea, vomiting, and sometimes mucositis and diarrhea. The anthracyclines produce almost universal (but transient) alopecia, and at high cumulative doses they produce cardiomyopathy. The incidence of cardiomyopathy, nausea, and vomiting decreases markedly when doxorubicin is administered as a 48- to 96-hour intravenous infusion rather than by bolus.962–964 Epirubicin is somewhat less cardiotoxic than doxorubicin965–968; the risk of cardiotoxicity can also be reduced by the co-administration of a cardiac protector, dexrazoxane.969,970 The vinca alkaloids and the platinum analogs produce peripheral neuropathy.

New Drugs

In recent years, several new, moderately effective cytotoxic agents have completed clinical trials and be3en approved for the treatment of breast cancer.971 These agents include the taxanes, paclitaxel972,973 and docetaxel,972–974 and the oral fluoropyrimidine analog capecitabine.975

The Taxanes

Paclitaxel and docetaxel are certainly among the most effective agents for the treatment of breast cancer.976–981 Administered as a single agent, paclitaxel has demonstrated activity similar or superior to other first-line chemotherapy regimens.982 The usual method to administer paclitaxel is as a 1- to 3-hour infusion every 3 weeks, at the dose of 175 mg/m2. However, over the past several years there has been increasing interest in the weekly administration of paclitaxel, usually at doses ranging between 80 and 90 mg/m2.983–985 The weekly schedule is associated with a different safety profile, with a marked reduction in myelosuppressive and infectious complications, as compared to the 3-weekly schedule of administration. There is no compelling evidence that higher doses or more prolonged durations of administration modify the drug’s efficacy in a substantial manner. Paclitaxel and docetaxel are substantially active in previously treated patients with metastatic breast cancer, including a 30 to 50% response rate in patients with anthracycline-resistant breast carcinoma.986–989 This degree of activity indicates that these two are the most effective drugs available for anthracycline-refractory breast cancer. Docetaxel and paclitaxel are not completely cross-resistant, and some patients derive clinical benefit from treatment with one taxane after developing resistance to the other.982,990,991

Paclitaxel has been evaluated in combination with various other cytotoxic agents with demonstrated efficacy against breast cancer.992,993 In combination with doxorubicin, it produces a higher response rate and duration of response than either paclitaxel alone, doxorubicin alone, or the combination of doxorubicin/cyclophosphamide.994,995 Paclitaxel administered by prolonged (24-hour) infusion combined with doxorubicin is an effective agent with limited or minimal cardiac toxicity.996–999 However, schedule-dependent pharmacokinetic interactions and increased myelosuppressive and mucosal toxicity were reported by several investigators. Combinations of bolus doxorubicin and 3-hour paclitaxel were initially reported to have very high response rates, approaching 90%, but a 20% rate of congestive heart failure after six to eight cycles of treatment.999,1000 Prolonging the administration of the two drugs by 6 to 18 hours reduces the risk of cardiac toxicity substantially. The initial very high response rates have not been replicated; in most trials with this combination, the overall response rate ranges from 50 to 70%. Other successful two-drug paclitaxel combinations included cisplatin,1001–1003 carboplatin,1004,1005 5-fluorouracil,1006,1007 or vinorelbine.992,1008,1009

Docetaxel as a single agent produces objective responses in up to 60% of patients with metastatic breast cancer previously unexposed to chemotherapy. The usual method of administering docetaxel is a 1-hour infusion every 3 weeks, at a dose of 75 to 100 mg/m2. As for paclitaxel, there is great interest in the weekly administration of docetaxel, since this schedule is associated with less myelosuppressive and musculoskeletal toxicity.1010–1012 Docetaxel as a single agent produced a higher response rate and longer time to progression than full-dose doxorubicin,1013,1014 although survival was equivalent995 for the two drugs. Docetaxel was superior to the combination of vinblastine and mitomycin1015 for all end points considered and superior to the combination of methotrexate/5-fluorouracil in terms of response rate and time to progression.1016 Docetaxel combinations with doxorubicin or epirubicin have also demonstrated substantial efficacy1017,1018 without an apparent increase in cardiac toxicity. A recent preliminary report of a randomized comparison of docetaxel/doxorubicin with cyclophosphamide/doxorubicin in first-line chemotherapy for metastatic breast cancer showed that the former combination was associated with a higher response rate and longer time to progression than the latter.1016,1018,1019 Docetaxel is also under evaluation in combination with cisplatin, carboplatin, cyclophosphamide, vinorelbine, 5-fluorouracil, and other agents.

Vinorelbine

The Vinca alkaloid vinorelbine has undergone extensive clinical evaluation that showed, in addition to excellent tolerability, objective response rates ranging from 40 to 50% in first-line and 20 to 35% in second-line therapy1020; however, it has not gained FDA approval, although it is widely used for the treatment of advanced breast cancer.

Vinorelbine is effective in patients with anthracycline-refractory tumors, although, based on indirect comparisons, it would appear to be less effective in this situation than the taxanes.1021,1022 Vinorelbine has been extensively evaluated in combination with anthracyclines,1020,1022,1023 5-fluorouracil,1024,1025 cisplatin,1026–1028 and the taxanes. The activity of these combinations appears similar to the activity of CMF or even FAC; however, only the vinorelbine/doxorubicin combination has been directly compared to a standard regimen.1029

Capecitabine

Capecitabine is a prodrug that is metabolized to 5-fluorouracil upon absorption from the gastrointestinal tract. Its oral bioavailability is excellent and it is a well-tolerated and effective palliative regimen. Capecitabine retains antitumor activity after prior therapy with an anthracycline-containing regimen and a taxane.975 Capecitabine is under evaluation in comparative trials against other effective single agents (e.g., paclitaxel) and in combination therapy. Other interventions that mimic the continuous intravenous infusion of 5-fluorouracil (uracil/Ftorafur, eniluracil/5-fu, S-1) are also under active development.

Gemcitabine

Another new drug with considerable antitumor activity in metastatic breast cancer is gemcitabine. This agent was approved for the treatment of pancreatic cancer, even though its efficacy against breast cancer is substantially higher. Gemcitabine produces responses in about 40% of patients with untreated metastatic breast cancer and in 20 to 30% of those with previous exposure to chemotherapy, including anthracycline-refractory tumors.1030–1032 The combination of gemcitabine and doxorubicin was recently reported to have substantial antitumor activity and good tolerance.1033

Between 50 and 75% of patients with metastatic breast cancer have responses to first-line chemotherapy.821 In general, patients with a good performance status, normal organ function, and limited extent of disease are more likely to respond than patients with the opposite characteristics. Only 15 to 20% of patients will achieve a complete remission, and most of those patients will develop progressive disease within the subsequent 5 years. About 10% of all complete remissions achieved with anthracycline-containing regimens last more than 10 years.810,811

Dose-intensive Chemotherapy

The correlation between dose and outcome is considered an important aspect of cancer chemotherapy.1034,1035 However, when that correlation exists, it is not necessarily linear, and for many of the agents used in the chemotherapy of breast cancer, incomplete information exists as to the shape and slope of the dose/response or dose/survival correlation. For some agents, a threshold dose may exist above which responses occur. However, this is not necessarily synonymous with a continuous dose/response effect.

The development of modern hematopoietic support techniques (autologous bone marrow or peripheral stem cell support) and the development of hematopoietic growth factors GCSF, granulocyte-macrophage colony-stimulating factor [GM-CSF], and erythropoietin) allowed the systematic testing of high-dose chemotherapy in the management of breast cancer.1036,1037 Early randomized trials within the range of doses possible without hematopoietic support provided mixed answers. Threshold doses were found for anthracyclines, platinum analogs, and perhaps other agents, below which responses were clearly inferior or nonexistent. By the mid-1970s, the technique of autologous bone marrow harvest and storage became available.1038–1040 Re-infusion of unexposed autologous marrow allowed the expansion of the range of doses at which a cytotoxic therapy could be tested. Pilot phase I/II trials using combinations of alkylators or other cytotoxic agents suggested increased overall, and especially complete response rates compared to standard-dose chemotherapy.1041–1044 Combination alkylating agent regimens used as front-line management of metastatic breast cancer (whether used as induction therapy or consolidation of responses obtained with standard-dose chemotherapy) resulted in very high response rates and clinical complete remissions ranging between 40 and 70%.1042,1044,1045 However, median response durations and median survival durations were not altered, compared to those reported with standard-dose chemotherapy alone. Some centers reported that 10 to 25% of patients treated with high-dose chemotherapy remained in an unmaintained complete remission for 5 and even 10 years after high-dose therapy.812,813,1045 Some investigators raised questions, however, regarding the comparability of data obtained from high-dose chemotherapy trials and standard-dose chemotherapy trials.1046 Several prospective randomized trials were undertaken to determine the relative therapeutic results of standard- and high-dose chemotherapy programs. Over the past 4 years, the results of some of these trials have been reported, mostly in abstract form.1047–1051

Table 118.22 describes the principal characteristics and early results of the randomized trials performed in the setting of metastatic breast cancer. All four trials are relatively small. The largest trial shows no benefit from adding a single cycle of high-dose chemotherapy to standard-dose chemotherapy.1051 Contrary to the earlier results of uncontrolled trials, there was a low conversion rate from partial to complete remissions after the administration of high-dose chemotherapy. The second largest trial showed that the early use of high-dose chemotherapy intensification resulted in prolongation of time to progression but shorter overall survival compared to high-dose chemotherapy administered upon relapse.1049,1050

Table 118.22. Randomized Trials of High-Dose Chemotherapy for Metastatic Breast Cancer.

Table 118.22

Randomized Trials of High-Dose Chemotherapy for Metastatic Breast Cancer.

In the third study, the control group received a standard-dose three-drug combination, whereas patients in the investigational arm received only two cycles of high-dose chemotherapy without an induction regimen.1047 There was a significant prolongation of remission duration and survival with high-dose chemotherapy in this study. The fourth trial was too small and showed no significant differences in outcome at 5 years. Several other clinical trials testing the concept of high-dose chemotherapy in metastatic breast cancer are in progress. At this point, the evidence in favor of high-dose chemotherapy is at best incomplete and does not support its use as part of standard therapy.

Combined Hormonal Therapy and Chemotherapy

Because hormonal therapy and cytotoxic therapy are thought to act by different mechanisms of action, and because the two modalities produce different patterns of toxicity, it was hypothesized that their combined use might result in enhanced therapeutic efficacy without increased toxicity. Numerous prospective randomized trials have been conducted using a combination of simultaneous chemotherapy and hormonal therapy.1052,1053 In most cases, the hormonal agent was either ovarian ablation (or LHRH analogues) or tamoxifen, although several trials used progestins or androgens. Some of these trials showed increased response rates, and a few demonstrated a slight prolongation of response duration. However, most individual trials failed to demonstrate an increase in median survival or in long-term survival in patients with metastatic breast cancer. A recent meta-analysis of randomized clinical trials in the setting of metastatic breast cancer suggested, however, a modest but significant prolongation of survival with simultaneous combination of chemotherapy and endocrine therapy.959 However, this modest advantage must be considered in the context of increased toxicity with combined therapy. Based on these results, the sequential use of hormonal therapy and chemotherapy is considered the optimal way to provide palliative therapy to patients with metastatic breast cancer.

Osseous Metastases

Osseous metastases represent the commonest type of metastatic spread in breast cancer: up to 80% of patients with metastatic breast cancer will develop bone metastases during the clinical course of the illness.1054 Bone metastases are the most frequent source of morbidity and disability related to breast cancer. Radiotherapy to painful sites of bone metastasis or impending fracture sites in weight-bearing bones is commonly used in association with other systemic treatments. Bisphosphonates are effective inhibitors of osteoclast activation and, therefore, bone resorption and the development of osteolytic bone metastases.1055,1056 Treatment with pamidronate or clodronate alone was shown to produce pain relief and radiographic evidence of healing in 20 to 25% of patients with lytic bone metastases from breast cancer in several phase II clinical trials. Two recent clinical trials demonstrated that the administration of pamidronate disodium combined with chemotherapy or hormone therapy delays the appearance and reduces the severity of bone-related complications of breast cancer.1057–1059 Similar data exist for clodronate, another second-generation bisphosphonate.1055 Bisphosphonate therapy should start at the first evidence of lytic bone metastases and be continued during the clinical course of metastatic breast cancer. Several bone-seeking radionuclides were shown to target osseous metastases and provide temporary pain relief for patients with systemic bone metastases.1060–1062 Because of protracted myelosuppression associated with these agents, they are often reserved for third-line therapy and beyond.

HER2/neu-directed Therapy

HER2/neu is a proto-oncogene that is amplified and/or overexpressed in 20 to 30% of patients with breast cancer.1064 The overexpression of HER2/neu is associated with increased tumor growth rate, enhanced metastatic rate, shorter disease-free survival and overall survival.455,1063,1064 Patients with HER2/neu over expressing tumors have a more aggressive and more malignant course than patients with non–HER2/neu-overexpressing malignancies. Because of these adverse prognostic characteristics, HER2/neu has been targeted by a variety of strategies, including monoclonal antibodies,443,1066–1069 immunoconjugates, the vaccines,662 among others.

A humanized monoclonal antibody against the extracellular domain of HER2/neu was recently developed and tested.1070,1071 As a single agent, trastuzumab (Herceptin®) produced complete and partial remissions in 13 to 20% of patients with metastatic breast cancer.444,1072 This range of activity was noted regardless of exposure to prior chemotherapy for metastatic breast cancer. In association with chemotherapy, trastuzumab improved response rate and lenthened time to progression and overall survival of the combination compared to the chemotherapy alone.448,1073 Treatment with trastuzumab was well tolerated, resulting only in low-grade fever, chills, fatigue, and constitutional symptoms primarily with the first infusion. Serious adverse events have been infrequent. However, in association with anthracycline chemotherapy, an increased incidence of subclinical and clinical cardiac toxicity has been observed. The mechanism for this interaction is under intense scrutiny, and there is much effort being expended in developing safe and noncardiotoxic combinations with chemotherapy.

Currently, patients with HER2/neu overexpressing tumors have the option of receiving therapy with trastuzumab alone or, to maximize the efficacy of treatment, trastuzumab in combination with cytotoxic therapy. The combinations of paclitaxel with trastuzumab448 or cisplatin with trastuzumab1074 have been fairly well worked out and are well tolerated and effective. Combinations of trastuzumab with other cytotoxic agents or hormonal agents are currently under development.

Symptomatic Management

Pain management, appropriate prevention of chemotherapy-related nausea, appropriate dietary intervention, and psychological support complete the multidisciplinary management of metastatic breast cancer. When used judiciously, all of these interventions contribute to the maintenance or improvement of quality of life while delaying the progression of metastatic breast cancer to the utmost.

Side Effects of Drug and Hormone Therapy

In addition to their benefits, the breast cancer treatment modalities available today have considerable side effects and toxicities. Most cytotoxic agents are myelosuppressive, resulting in short-term neutropenia, thrombocytopenia, and occasionally anemia. Many produce partial or total alopecia. Most cytotoxic agents produce some degree of nausea and vomiting, and some can produce oral and gastrointestinal mucositis, diarrhea, constipation, and peripheral neuropathy. The most serious toxicity is neutropenia, which can lead to severe infection. The correlation of neutropenia with infection appears when neutrophil count drops below 500 cells/μL, and the risk of infection rises greatly when neutrophil count drops below 100 cells/μL.1075 Sepsis associated with neutropenia is the most common cause of death during chemotherapy, whether at standard or high doses. Other important side effects of chemotherapy include ovarian ablation in premenopausal women, which brings with it the short- and long-term consequences of premature menopause, and the development of infertility.1076 Long-term side effects include a slight increase in the incidence of myelodysplastic syndromes and acute leukemias.1077,1078 Two types of chemotherapy-related myelodysplastic syndromes have been identified.1079 One, which is related to large cumulative doses of alkylating agents results in the development of acute hematologic malignancies 5 to 15 years after the initiation of therapy.1077 A second syndrome, which is attributed to topoisomerase II inhibitors, has been reported to include development of myelomonocytic leukemia (M4M5) within 2 years after the initiation of therapy.1080 The second syndrome has also been reported with to higher doses of doxorubicin, often in association with an alkylating agent and/or a hematopoietic growth factor.

Hormonal therapy is not devoid of toxic effects, either. Most types of hormonal therapy can produce hot flashes, mild nausea, fluid retention, and an increase in the incidence of thromboembolic phenomena.1081 Tamoxifen has been associated with an increased risk of endometrial hyperplasia, dysplasia, and carcinoma, as well as the development of ovarian cysts and other benign gynecologic abnormalities.1082,1083 Ocular toxicity has also been attributed to tamoxifen, especially when it is administered at high doses.1084,1085 Progestins are known to cause moderately severe fluid retention, increased appetite, and weight gain, and they can occasionally cause or contribute to glucose intolerance.823,897 The newer aromatase inhibitors and LHRH analogues appear better tolerated, although the experience with them is limited to just a few years..850,1086

Inflammatory Breast Cancer (IBC)

There is a subset of patients who have IBC, which is a locally advanced and particularly aggressive form of breast cancer.1087,1088 This disease constitutes 1 to 6% of all newly diagnosed breast cancers (probably closer to 2% in the United States). The diagnosis of IBC is based on a clinical triad of erythema, edema of the skin of the breast (peau d’orange), and ridging, a tactile sensation caused by engorged dermal lymphatics. IBC’s evolution is usually rapid, often taking less than 3 months to go from the first detectable abnormality to the establishment of a diagnosis. Because an underlying mass is frequently absent, IBC is often mistakenly treated with antibiotics on the working assumption that the patient has mastitis; a core needle biopsy usually provides a definitive diagnosis. Before the advent of systemic adjuvant therapy, the 5-year survival rate for patients with IBC after surgery, radiotherapy, or a combination of the two was reported to be less than 5% by multiple investigators.1089 Median survival seldom reached 1 year, and rapid tumor dissemination to multiple organs was the rule. Since the introduction of primary chemotherapy into the multidisciplinary management for IBC, the prognosis has improved. Most cases of IBC respond dramatically to chemotherapy; in fact, more than 90% of patients with IBC can be rendered free of locoregional disease with a combination of either chemotherapy and surgery or chemotherapy and radiotherapy, and 5-year survival rates now routinely exceed 30% and sometimes exceed 50%. Long-term follow-up of multidisciplinary protocols from several institutions has shown that 25 to 30% of IBC patients survive progression-free for at least 10 and sometimes 15 years.1090–1092 Although no randomized trials have been performed involving patients with IBC, those statistics represent such a dramatic departure from the natural history following locoregional therapy only that they provide reasonably compelling evidence of progress.1093

Despite improvements in both local and systemic control of locally advanced breast cancer and IBC achieved with modern combined-modality treatments, the majority of patients still die of the disease. Therefore, multiple attempts are underway to improve the odds of eradicating micrometastases. Among them, consolidation therapy with high-dose chemotherapy and autologous cellular support is being widely tested,1094,1095 as is the introduction of new cytotoxic drugs, specifically paclitaxel, docetaxel, and vinorelbine.1096,1099

Prevention of Invasive Breast Cancer in Women with Intraductal Carcinoma in Situ (DCIS)

The concept of intraductal carcinoma in situ (DCIS) was first introduced by Broders in 1932.1106 From that time until mammography became widely available, less than 3% of newly diagnosed breast cancers were classified as DCIS. Because such lesions were most often detected as palpable masses that contained areas of microinvasion, there was little or no debate regarding their management: mastectomy with axillary dissection was the treatment of choice. Information that was obtained during that era with regard to the biology and natural history of the disease has been of little relevance to the nonclinically detectable DCIS free of any invasive component that is being diagnosed with increasing frequency as the result of mammography. At present, at least 20 to 30% of mammographically detected cancers are DCIS.1107

During the last decade, a concerted effort has been made to obtain information about the natural history of this version of the disease and how it should be treated. Since 1985, the NSABP has been at the forefront of these efforts. During that year, a paradoxical situation arose. As a result of the first report of findings from an NSABP randomized clinical trial (B-06) demonstrating that lumpectomy followed by radiation therapy was as effective for women with invasive breast cancer as was modified radical mastectomy,1108 breast preservation began to be advocated for the management of invasive disease, whereas mastectomy was recommended for the management of noninvasive breast cancer. That circumstance, which resulted in uncertainty about the clinical management of women with small, localized DCIS that had been detected by mammography, prompted the NSABP to conduct a controlled randomized trial (B-17) to investigate whether removal of localized DCIS with tumor-free margins of excised tissue (a procedure referred to as a lumpectomy, although most women had no palpable mass) followed by radiation therapy was more effective than lumpectomy alone in the prevention of a second ipsilateral breast tumor (IBT), particularly one that was invasive. Regardless of whether DCIS is a precursor of invasive cancer or a marker for that disease, the primary purpose of any treatment for DCIS is to prevent the subsequent occurrence of an invasive cancer. The findings from the B-17 study, which were first reported in 1993, demonstrated that, after 5 years of follow-up, lumpectomy and postoperative radiation therapy were more effective than lumpectomy alone for the prevention of both invasive and noninvasive IBTs.1109 A subsequent analysis after 8 years of follow-up confirmed the worth of lumpectomy and radiation therapy for the treatment of localized, mammographically detected DCIS.1110 Additional findings demonstrated that there were no pathologic, clinical, mammographic, or biologic discriminants that could identify those patients who would not benefit from radiation therapy after lumpectomy.1111,1112

During the conduct of the B-17 trial, several circumstances arose that led the NSABP to implement the B-24 study, a second randomized clinical trial involving women with DCIS. One such situation related to the observation that many women with DCIS were ineligible for the B-17 trial because their mammograms showed scattered calcifications that were thought to be either benign or associated with unremoved DCIS or because the margins of their resected breast tissue, despite several excisions, continued to be involved with DCIS. These women were treated with mastectomy because of the concerns that unremoved DCIS would progress to invasive cancer or that a small, unidentified focus of invasive tumor associated with DCIS would remain unremoved.

Another circumstance that gave rise to the conduct of the B-24 trial related to information that demonstrated the importance of the drug tamoxifen for the treatment of invasive breast cancer. Findings from animal studies had shown that tamoxifen had both anti-initiator and antipromoter properties.1113–1115 In addition, findings from NSABP trials, as well as results of studies conducted by other investigators had shown that tamoxifen prevented tumor recurrences in the ipsilateral breasts1116 and second primary tumors in the contralateral breasts1117–1121 of men who had undergone lumpectomy and radiation therapy for primary invasive breast cancer. For these reasons, it was considered appropriate to conduct B-24 to test the hypothesis that, in patients with DCIS, particularly in those with tumor-positive specimen margins or with mammographic evidence of scattered calcifications unlikely to be associated with invasive cancer, lumpectomy, postoperative radiation therapy, and tamoxifen would be more effective than lumpectomy and radiation alone in preventing invasive and noninvasive cancers in the ipsilateral breast. Recently reported findings from B-24 have shown that tamoxifen administered in conjunction with radiation therapy after lumpectomy was more effective than radiation alone for the prevention of invasive cancers in both the ipsilateral and contralateral breast and at metastatic sites.1122

The findings from the B-17 and B-24 studies were found to be associated with the recently reported results from the NSABP BCPT (P-1), which demonstrated that tamoxifen reduced by 50% the risk of invasive and noninvasive breast cancer in women at increased risk for such tumors.1123 Of particular relevance to the finding in B-24 that tamoxifen reduced the incidence of invasive breast cancer in women with a history of DCIS was the observation in P-1 that tamoxifen dramatically reduced the rate of invasive breast cancer in women who had a history of either atypical hyperplasia or LCIS, conditions also considered to be pathologic markers for or precursors of invasive breast cancer.

B-17, The First Randomized Clinical Trials for DCIS

Study Design, Patient Eligibility, Radiation Therapy, and Analyses

A detailed description of the study design, which includes patient eligibility requirements, a description of the type of surgery and radiation therapy used, follow-up, study end points, and statistical analyses, appears in both the 5-1109 and 8-year1110 reports of the B-17 trial. Women who had small, localized DCIS detected by either physical examination or mammography were eligible for the study. All patients underwent a lumpectomy with removal of the tumor and a sufficient amount of normal breast tissue so that specimen margins were histologically tumor-free. Women with a histologic diagnosis of DCIS whose mammograms showed evidence of scattered calcifications were eligible if no tumor was present on histologic examination of the tissue that contained the calcifications.

After women had undergone lumpectomy and given written consent, they were randomly assigned between October 1, 1985 and December 31, 1990 to receive either ipsilateral breast irradiation or no radiation therapy. To avoid an imbalance in characteristics according to treatment assignment, randomization was performed according to a stratification scheme using age (≤ 49 or > 49 years), tumor type (DCIS or DCIS plus LCIS), method of detection (mammography, clinical examination, or both), and axillary dissection (performed or not performed). Axillary dissection was obligatory at the onset of the study but subsequently became optional on the basis of evidence to indicate that it was not necessary in the treatment of DCIS.

The protocol stipulated that radiation therapy (50 Gy) be started no later than 8 weeks after surgery. The technique used was similar to that described in previous NSABP studies.1124 Patients underwent semiannual follow-up examinations, and mammography was performed annually. A tumor detected at a local or regional site after the initial operation was considered an event only when a tissue biopsy of the lesion was positive. A tumor detected at a distant site was considered an event when clinical, radiographic, or pathologic findings indicated that tumor was present. The presence of an IBT or CBT, regional or distant metastasis, second primary tumors other than a breast tumor that occurred as a first event after the operation, or a patient’s death in the absence of evidence of recurrent breast cancer was used to determine event-free survival.

Findings in the two treatment groups were compared for all randomized patients with follow-up data. A total of 818 women were entered in the trial (Table 118.23): 405 women were treated by lumpectomy alone and 413 by lumpectomy followed by radiation therapy. All women for whom follow-up information was available, including those who failed to meet the entry criteria, were included in the analyses. The mean follow-up time was 90 months (range, 67 to 130 months). No differences were observed between treatment groups in the distribution of selected patient and tumor characteristics (Table 118.24).

Table 118.23. B-17 Study Information.

Table 118.23

B-17 Study Information.

Table 118.24. Patient and Tumor Characteristics in the B-17 and B-24 Trials.

Table 118.24

Patient and Tumor Characteristics in the B-17 and B-24 Trials.

The percentage of women who remained event-free was determined by the Kaplan-Meier life-table estimate1125 and the two treatment groups were compared by the use of a two-sided log-rank test.1126 The Cox proportional hazards model was used to compute comparisons adjusted for stratification variables1127; findings did not differ from those obtained by use of the unstratified analysis. The Cox model was also used to evaluate interactions among treatment and covariates. Average annual rates of occurrence for specific events were computed and compared by exact binomial tests. RRs and 95% CIs were derived from the Cox model for the event-specific end points.1117 The cumulative probability of specific events comprising disease-free survival was determined using cumulative incidence functions.1118

Assessment of Tumor Size

The tumor sizes listed in the report of B-17 were those submitted to the NSABP Biostatistical Center by the investigators who had enrolled the patients. In some instances, tumor size had been obtained from a mammogram; in others, gross pathologic tumor size had been obtained from the surgically resected tissue. In still other cases, tumor size had been obtained from clinical examination. Because there has been increased emphasis on the use of tumor size for therapeutic decision making with regard to DCIS, an extensive review of the tumor sizes that had been submitted was conducted by NSABP Headquarters personnel. Tumor sizes determined from clinical, pathologic, and mammographic examinations were reviewed separately, and many of the patients contributed to each of the three assessments. The mammograms were reviewed by one NSABP Headquarters radiologist, who was unaware of either clinical or pathologic tumor size or of any other patient or tumor characteristics. Size of tumor mass was recorded in all mammograms in which such a mass was demonstrated. All measurements were taken using routine views. Where no mass was evident, size of the cluster of calcifications was noted. Radiology reports submitted to the NSABP Biostatistical Center were used to obtain such information for patients whose films were unavailable for central review.

Clinical Assessment

Headquarters review of the clinical information submitted during the study was performed for 809 of 814 patients. No tumor was palpable in 83% of the women; 17% of the women had tumors that were clinically palpable. Thirty-eight percent of the palpable tumors were recorded as being ≤ 1 cm in size, 35% were 1.1 to 2.0 cm, and 27% were ≥ 2.0 cm. Thus, 89% of the 809 tumors clinically assessed were 0 to 1 cm in size.

Pathologic Assessment

No gross tumor was found in 431 (54%) of 797 resected specimens, all of which contained DCIS. Forty-six percent of the 797 specimens that were pathologically assessed were found to have gross tumor. Of these, 71% were recorded as being ≤ 1.0 cm in size, 23% were 1.1 to 2.0 cm, and 5% were ≥ 2.0 cm. Thus, on pathologic examination, 692 of the 797 resected specimens (87%) either had no gross tumor or gross tumors that were reported as being ≤1.0 cm in size. Only 2% of all specimens examined had gross tumors of ≥2.0 cm.

Mammographic Assessment

A total of 730 mammograms (90% of all patients included in the analyses) were centrally reviewed. A tumor mass was identified in 16% of these. Fewer than one-third (31%) of the masses had associated calcifications, and 44% of the masses (7% of the 730 mammograms evaluated) were ≤ 1.0 cm in size. A tumor mass greater than 2.0 cm was identified in only 2% of mammograms. Nearly 80% of the mammograms demonstrated either scattered (7%) or clustered (70%) microcalcifications, but no mass. In 73% of mammograms that demonstrated clustered calcifications, the size of the cluster was ≤ 1.0 cm. An additional 3% of mammograms demonstrated architectural distortion with no mass or calcifications. There were no mammographic abnormalities in 4% of cases. The mammographic characteristics were distributed uniformly among the two treatment groups. Reports from mammograms that were unavailable for central review showed similar characteristics; approximately 20% indicated the presence of a tumor mass and 80% showed microcalcifications. The majority of the masses and microcalcifications were small.

Location of Primary Tumor and of IBT

The location of primary tumors and postoperative IBTs was determined from mammographic, operative, and pathologic reports submitted to the NSABP Biostatistical Center. Tumors were classified as being either in a specific quadrant,1106 on the border between two quadrants,1107 central (i.e., in a subareolar position or at the border of a quadrant and the areola1108, or diffuse (i.e., in more than one of the preceding locations).1109 There was concordance in the location within the breast of both primary DCIS and IBT in 84% of women in whom the site of these tumors was known. When the frequency with which the primary DCIS and IBT were reported to have occurred in the same quadrant was determined in these women according to whether their IBT was invasive or DCIS, the concordance was greater in the latter group (52 vs. 80%). This discordance in location between an invasive IBT and its primary tumor was observed in both treatment groups.

Benefit From Radiation Therapy After Lumpectomy

Sites, rates, and relative risks of first events according to treatment group.One hundred four of 143 first events (73%) that occurred in the group treated with lumpectomy alone were IBTs, as compared with 47 of 91 first events (52%) in the group treated with lumpectomy and radiation therapy. The average incidence rate per thousand women per year of all first events was reduced by 43% as a result of radiation therapy (64.0 in the group that received lumpectomy alone versus 36.8 in the group that received radiation therapy; RR 0.57, 95% CI .44–.75; p .00004). The average annual incidence rate of IBT was reduced by 59% as a consequence of radiation therapy (46.5 in the group treated with lumpectomy alone and 19.0 in the group treated with lumpectomy and radiation therapy; p < .000005). The rate of noninvasive cancer was reduced by 47% (22.8 and 12.1 in the two treatment groups, respectively; p = .007) and the rate of invasive cancer by 71% (23.7 and 6.9, respectively; p < .000005). At 8 years of follow-up, the cumulative incidence of an IBT of any type occurring in women whose primary tumor was treated with lumpectomy alone was 26.8%; in women treated with lumpectomy followed by radiation therapy, it was 12.1%. The cumulative incidence of a noninvasive IBT was 13.4% in women treated with lumpectomy alone and 8.2% in women treated with lumpectomy and radiation therapy; the cumulative incidence of an invasive IBT was 13.4% in the former group and 3.9% in the latter group. The cumulative incidence of all first events other than an IBT was not significantly different in the two treatment groups: 11.0% in the group treated with lumpectomy alone and 12.5% in the group treated with lumpectomy and radiation therapy (p = .96).

Of particular interest were the findings regarding the cumulative incidence of CBTs that occurred through 8 years of follow-up. In the 814 patients comprising both groups, 5.7% demonstrated a CBT that occurred as a first event or at any other time; 4.2% of these were invasive and 1.5% were noninvasive. The average annual incidence rates in each of the two treatment groups in B-17 were 0.58 and 0.77 (p = .55). The cumulative incidence of invasive and noninvasive CBTs in both treatment groups, although small, was always slightly greater for the invasive than for the noninvasive tumor type. There was no significant difference between the two treatment groups in the rate of second primary cancers, with the exception of those that occurred in the contralateral breast (p = .72). The overall survival rate through 8 years of follow-up was 94% for women treated with lumpectomy alone and 95% for those who received lumpectomy followed by radiation therapy (p = .84).

IBT according to selected mammographic and clinical characteristics at diagnosis of primary DCIS (Table 3)

The size of a mammographically detected tumor mass was not a significant predictor of an IBT. The rate of IBT in either treatment group was not significantly different, regardless of whether the detected tumor was ≤1 cm or greater than 1 cm in size. There was, however, a reduction in the rate of IBT following radiation therapy in both tumor-size categories.

Among women in both treatment groups whose mammograms showed calcifications and no tumor mass, those whose mammograms demonstrated either clustered calcifications greater than 1.0 cm in their maximum diameter or scattered calcifications had a significantly greater rate of IBT than did those whose mammograms showed clustered calcifications of ≤1.0 cm in size. The RR of a noninvasive IBT was greater in women whose mammograms demonstrated clustered calcifications greater than 1.0 cm in size or scattered calcifications than in women whose mammograms showed calcifications ≤1.0 cm. There was no evidence of such a trend in women with invasive IBT. As was the case with tumor size, there was a reduction in the rate of IBT after radiation therapy in women whose mammograms showed evidence of calcifications. This decrease occurred regardless of whether the IBTs were invasive or noninvasive.

The rate of IBT was less after radiation therapy in women whose mammograms demonstrated only architectural distortion but no mass or calcifications. There was also a slight reduction in the rate of IBT after radiation therapy in women whose mammograms were normal or demonstrated other findings.

No significant correlation was noted between method of detection of the primary DCIS (i.e., by mammography only or by mammography and clinical examination) and rate of IBT. No difference in rates of IBT was noted in women whose DCIS was detected by mammography only and in those whose tumors were detected by both mammography and clinical examination. As with the other characteristics, there was a reduction in IBT in women in both groups who received radiation therapy.

Age at diagnosis was not a significant predictor for IBT. Rates of IBT and RRs did not differ across age groups. A reduction in the rate of IBT among patients who received radiation therapy was evident in all age groups.

IBT according to selected pathologic characteristics

The outcome of patients with DCIS was examined relative to each of nine pathologic characteristics.1128 In each of the nine, the average annual hazard rate of IBT was lower in the group that received radiation therapy than in the group treated by lumpectomy alone (Table 118.24). When the two treatment groups were compared relative to the rate of IBT in each subcategory of each tumor characteristic (e.g., good or poor nuclear grade, comedo necrosis moderate/marked or absent/slight) an overall benefit from the use of radiation therapy was observed. Univariate proportional hazard modeling showed that, of the nine pathologic features evaluated individually, only nuclear grade, comedo necrosis, specimen margin status, and histologic tumor type were significant prognostic variables for IBT. However, when these variables were examined by multivariate analysis, only moderate/marked comedo necrosis and uncertain/involved tumor margin status were independent predictors of IBT. Most important, the findings indicated that, when comedo necrosis and tumor margin status were examined together, patients with tumor-free specimen margins and those with slight comedo necrosis had less chance of developing an IBT than did patients whose margins were involved with tumor and demonstrated moderate to marked comedo necrosis (Table 118.25). However, not only did both good- and poor-risk patients benefit from radiation therapy but their outcomes also became similar subsequent to such treatment.

Table 118.25. Average Annual Hazard Rate of Second Ipsilateral Breast Tumor Related to Margins of Resection and Comedonecrosis in B-17.

Table 118.25

Average Annual Hazard Rate of Second Ipsilateral Breast Tumor Related to Margins of Resection and Comedonecrosis in B-17.

B-24, The Second Randomized Clinical Trial for DCIS

Study Design, Patient Eligibility, Radiation Therapy, Tamoxifen, and Analyses

A detailed description of the study design, which includes patient eligibility requirements, a description of the type of surgery, radiation, and tamoxifen therapy used, follow-up, study end points and statistical analyses, appears in the 5-year report of the B-24 trial.1122 Women admitted to the B-24 study were similar in all aspects to those enrolled in B-17, except that women who had positive specimen margins or mammographic findings unlikely to be related to invasive cancer were eligible. This similarity is indicated by the concordant distribution of patient age, method of detection, and tumor type among the two studies (see Table 118.24). The size of tumors in B-17 patients was slightly greater than those in women enrolled in B-24, and the incidence of specimen margins containing tumor in women in B-24 was, as anticipated, greater than that in women in B-17, where eligibility criteria required that margins be tumor-free. After women had undergone lumpectomy and given written consent, they were randomly assigned between May 9, 1991 and April 13, 1994 to receive either radiation therapy to the ipsilateral breast and placebo (n = 902), or radiation therapy and tamoxifen (n = 902). To avoid an imbalance in characteristics according to treatment assignment, randomization was performed according to a stratification scheme using age (≤49 years or >49 years), tumor type (DCIS or DCIS plus LCIS), and method of detection (mammography, clinical examination, or both).

Radiation therapy (50 Gy) was administered as in B-17 and other NSABP trials. Placebo or tamoxifen 10 mg twice daily, administered within 56 days of lumpectomy, was given continuously for 5 years. No dose modifications were made for either agent. Patients underwent semiannual follow-up examinations, and mammography was performed annually. Primary end points were the occurrence of invasive or noninvasive tumors in either the ipsilateral or contralateral breast. Tumors detected at local or regional sites were accepted as events only if tissue biopsy of the lesion was positive. Tumors detected at distant sites (i.e., before local or regional invasive cancer was noted) were considered to be events if clinical, radiographic, or pathologic findings showed that a tumor was present. Tumors in either the ipsilateral or contralateral breast, regional or distant metastases, second primary tumors other than a breast tumor that occurred as a first event, or death in the absence of evidence of recurrent breast cancer were used to determine event-free survival.

Cause-specific hazards of failure and hazard rate ratios for the various end points were calculated with exact binomial methods used to test for differences in rates by treatment group. The Cox proportional hazards model was used to calculate RRs of failure according to prognostic covariates and treatment simultaneously and to determine whether there was a differential response to therapy according to characteristics (e.g., treatment-covariate interactions).1129 Cumulative probability of events was calculated by means of cumulative incidence curves, which correctly accounted for competing risks.1128 Event-free and total survival curves were calculated by Kaplan-Meier analysis. Pointwise asymptotic 95% CI are presented for cumulative incidence and survival curves.

The aim was to achieve 85% power to detect a 50% lower occurrence of invasive cancer in women who received tamoxifen, with a one-sided 0.05 significance criterion. It was anticipated that women who received tamoxifen would have outcomes at least as favorable as those of women who received placebo; therefore, the original study design characterized the tests as one-sided. However, all p values reported are two-sided.

The Benefit From Tamoxifen in Addition to Lumpectomy and Radiation Therapy

Sites, Rates, Relative Risks, Cumulative Incidence of First Events, and Survival According to Treatment Group

DCIS patients in B-24 who were treated with lumpectomy and radiation therapy showed an additional benefit from tamoxifen. The advantage was mainly due to a decrease in the rate of invasive cancer, especially in the ipsilateral breast (Table 118.26).

Table 118.26. Sites, Rates, and Relative Risks (RRs) of First Events in B-24.

Table 118.26

Sites, Rates, and Relative Risks (RRs) of First Events in B-24.

The rate of all breast cancer events (i.e., both invasive and noninvasive in the ipsilateral and contralateral breasts and at regional or distant sites) decreased from 29.3 per 1,000 patients per year in the placebo group to 18.3 in the tamoxifen group (RR 0.6, 95% CI 0.5–0.8; p = .0009). The rate of invasive and of noninvasive tumors decreased by 43% and 31%, respectively. The lower rate of ipsilateral breast tumors in the group that received tamoxifen occurred for invasive tumors only (44% reduction; p = .03). Of significance was the observation that the estimated RR of contralateral breast cancer was 0.5 (0.3–0.9), a 52% reduction in contralateral breast tumors for those who received tamoxifen. Survival was 97% for the two groups of patients (p = .74) at 5 years from study entry. Six women in the placebo group and four in the tamoxifen group who subsequently died had invasive cancer. Two of the former and three of the latter had invasive ipsilateral breast tumors.

Relation of Characteristics to Outcome

Age at diagnosis was significantly associated with occurrence of tumor in the ipsilateral breast. Younger patients in the two treatment groups were at higher risk than older patients for such an event (Table 118.27). The annual rate of ipsilateral breast tumor per 1,000 women aged 49 years or younger who received placebo was 33.3; it was 13.0 for women aged 50 years or older. Tamoxifen administration resulted in a 38% reduction in ipsilateral breast tumors in women younger than 50 years and a 22% reduction in women older than 50 years.

Table 118.27. Relation Between Selected Characteristics of Patients and Tumors and Rates and Relative Risks of Ipsilateral Breast Tumors in B-24.

Table 118.27

Relation Between Selected Characteristics of Patients and Tumors and Rates and Relative Risks of Ipsilateral Breast Tumors in B-24.

The presence of positive tumor margins after surgery was also associated with an increased rate and RR of invasive or noninvasive tumors in the ipsilateral breast. Similar findings occurred in patients whose DCIS was palpable, as compared with those whose disease had been diagnosed by mammography alone. The risk was lower for cancer in the ipsilateral breast among women who received tamoxifen, irrespective of margin status (22% lower in women in the tamoxifen group whose sample margins were negative and 44% in women whose margins were either positive or unknown). For the few women whose DCIS was clinically apparent at the time of study entry, failure rates were substantially higher in the two groups than for women whose DCIS was evident only on mammography (see Table 118.27).

Women whose initial DCIS showed comedonecrosis, as reported by institutional pathologists, were about twice as likely to develop an ipsilateral breast tumor as women whose DCIS showed no comedonecrosis. This observation was more strongly associated with the occurrence of a noninvasive than with an invasive tumor. The rate of ipsilateral breast tumor occurrence was, however, lower by a similar degree in the tamoxifen group in women who had no comedonecrosis (23%) and in those who showed evidence of comedonecrosis at entry (31%). None of the patient or initial tumor characteristics were associated with a significantly increased risk of contralateral breast cancer.

Adverse Events

Information about toxic events was available for 1,781 (98.7%) of the randomized patients. The side effects from tamoxifen are listed in Table 118.28. When related to the degree of occurrence of similar events in the placebo group, the side effects from tamoxifen were minimal. The rate of endometrial cancer in the tamoxifen-treated group of patients was 1.53 per 1,000 patients per year versus 0.45 per 1,000 per year in the placebo group (i.e., a net increase of 1.08 or 0.1% per year). No deaths from endometrial cancer were observed in the tamoxifen group. The increase in the rate of deep-vein thrombosis and pulmonary embolism were minimal (<1%).

Table 118.28. Adverse Events in B-24 by Treatment Group.

Table 118.28

Adverse Events in B-24 by Treatment Group.

Relation of the B-17 and B-24 Trials to Each Other and to the NSABP Prevention Trial (P-1)

Because the B-17 and B-24 studies were similar, except for the inclusion in B-24 of women with more extensive DCIS, the findings from the B-24 trial may be considered within the context of those from B-17. Because the reduction in the rate of invasive breast cancers and the cumulative incidence of all breast cancer events at 5 years in women who received placebo and underwent lumpectomy and radiation therapy in B-24 was almost identical to that in women who were treated by lumpectomy and radiation therapy in B-17, there is justification for interrelating the two studies. The spectrum of results from the two studies clearly depicts the advantage from radiation therapy, as well as the added benefit of tamoxifen. In the B-17 study, the cumulative incidence of all breast cancer-related events in women with DCIS treated by lumpectomy alone was about 25% at 5 years. The cumulative incidence was 13% after radiation therapy in the two trials and 8% when tamoxifen was given in B-24. This benefit was due partly to the lower rates of contralateral breast cancer and of invasive cancer at regional and distant sites in tamoxifen-treated women. Thus, tamoxifen and radiation therapy led to a 68% lower cumulative incidence of all breast cancer events (77% reduction in all invasive breast cancer events and about a 64% reduction for all noninvasive events) at 5 years of follow-up than was observed in women who were treated with lumpectomy alone in B-17.

The findings from the B-17 and B-24 studies may be related to those of the NSABP P-1 prevention trial, which showed that tamoxifen administered to women at increased risk for breast cancer led to 50% fewer noninvasive tumors (both DCIS and LCIS) and 49% fewer invasive tumors than occurred in the group that received placebo. Findings from B-17 showed that lumpectomy-treated women with a history of DCIS were at greater risk for invasive breast cancer than were women in P-1 who had a history of either LCIS or atypical hyperplasia. In B-17, the rate of an invasive breast cancer event was 158 per 1,000 women per 5 years, whereas in P-1 it was found that the rates of LCIS or atypical hyperplasia were 65 and 51 per 1,000 women per 5 years, respectively. The results from both the B-17 and B-24 studies showed that invasive cancer rates in DCIS patients who received radiation therapy alone were higher (i.e., about 80 per 1,000 women per 5 years) than those in patients with a history of either LCIS (65 per 1,000 women per 5 years) or atypical hyperplasia (51 per 1,000 women per 5 years) who had received tamoxifen alone.

Conclusion

The findings from NSABP B-17 and B-24, two large prospective randomized clinical trials, clearly demonstrate the need for revised thinking about the nature of DCIS and its treatment. DCIS should no longer be viewed as a distinctly independent pathologic entity that should be completely removed by either a lumpectomy or a mastectomy. Lumpectomy is currently considered by some to be limited to the situation when it can be ensured that not only has an expansive amount (e.g., ≥1 cm) of breast tissue that is entirely tumor-free been removed around the excised tumor, but that there also exists no mammographic evidence of any aberration. When those stipulations cannot be fulfilled, mastectomy has been advocated. The more diligent the microscopic pathologic examination of tissue and the better the mammographic and associated diagnostic techniques that are employed, the more likely that some residual abnormality will be detected and, under their reasoning, that a mastectomy would be performed. That circumstance would, indeed, be a regressive approach to the management of DCIS. Fortunately, the results of the B-17 study have clearly shown that, in women with localized DCIS detected by mammography, there is justification for the use of radiation therapy after lumpectomy to decrease the rate of occurrence of both invasive and noninvasive IBTs. Indeed, the B-17 findings failed to show any cohort of DCIS patients who did not benefit from receiving postoperative radiation therapy. Regardless of the size of a mammographically detected tumor mass or identified cluster of microcalcifications, of the method of detection, or patient age, radiation therapy resulted in a benefit. When tumors were measured histologically, the same conclusion was reached for tumors of less than 1 cm or ≥1 cm in size. The pathologic findings from the study also failed to provide evidence of a discriminant for DCIS patients who should not receive postoperative radiation therapy.

The results from the B-24 trial have demonstrated that women with DCIS treated by lumpectomy and radiation therapy received additional benefit from tamoxifen. There was a reduction in the rate of invasive and noninvasive tumors in the contralateral breast and at regional or distant sites in these women. When all breast cancer-related events were combined, there was a significantly lower rate and cumulative incidence in the tamoxifen-treated group. As a result of these findings, it becomes apparent that, when treatment strategies for DCIS are being considered, merely focusing on the frequency with which ipsilateral breast tumors occur after lumpectomy for DCIS is a limited view.

Finally, the B-24 findings contribute to the decision-making process about the treatment of patients with mammographically detected DCIS when there is radiologic or pathologic evidence that all of the cancer was not removed after lumpectomy. The implication from the B-24 results is that mastectomy could be avoided more frequently than at present, particularly when scattered calcifications are seen radiographically, when margins of an excised lumpectomy specimen contain DCIS or when a tumor is at or close to a margin. The value of tamoxifen, when used in combination with radiation therapy to lower the occurrence of invasive cancer, justifies the suggestion that combined therapy should replace mastectomy for the treatment of DCIS patients in whom radiologic findings are unlikely to be related to invasive tumor.

Prevention of Invasive Breast Cancer in Women at Increased Risk

Little consideration was given to the prevention of breast cancer1130,1131 before the mid-1980s. At that time, the theory was promulgated that dietary fat might be associated with the occurrence of the disease and that restricting fat intake could perhaps reduce its incidence.1130 However, a trial to test that hypothesis has only recently been implemented. The use of retinoids for the prevention of breast cancer was proposed in 1987, when a study was initiated to evaluate the effectiveness of fenretinide (4-HPR),1131,1132 but, to date, no information about the outcome of that study has been reported.

In November 1984, the NSABP expressed interest in conducting a study to evaluate the worth of tamoxifen as a breast cancer preventive agent. It was hypothesized that there might be a link between the finding of a decrease in cancer of the contralateral breast after administration of the antiestrogen tamoxifen to women with invasive cancer and the potential of that drug to prevent breast cancer in healthy women. The use of tamoxifen to treat patients with clinically detectable breast cancer had been among the most successful therapeutic efforts of the 1980s. Studies had demonstrated that, when used alone or in combination with chemotherapy for the treatment of advanced breast cancer1133–1137 or as postoperative adjuvant therapy in stages I and II disease,1118,1138–1141 tamoxifen reduced tumor recurrence and prolonged survival. Of particular importance was the observation that women who received the drug had a significantly lower incidence of contralateral breast cancer than women who received placebo1118,1120,1121,1141,1142 and experienced only minimal side effects. Tamoxifen had also been shown to interfere with the initiation and promotion of tumors in experimental systems and to inhibit the growth of malignant cells by a variety of putative mechanisms. Moreover, the extensive literature available with regard to the pharmacokinetics, metabolism, and antitumor effects of tamoxifen in experimental animals as well as in humans1143–1146 further supported the propriety of evaluating the worth of the drug as a preventive agent.

As a result of all of these considerations, on June 1, 1992, the NSABP initiated the BCPT, subsequently known as the NSABP P-1 trial, the first study of its kind to be conducted in the United States. The primary aim of that study was to determine whether tamoxifen reduced the incidence of breast cancer in women at increased risk for the disease. In addition, because tamoxifen had been shown to perturb lipid and lipoprotein metabolism and because those changes could, in turn, influence a patient’s risk of coronary artery disease, it seemed appropriate that the effects of the drug on serum cholesterol, on both high- and low-density lipoprotein, and on the incidence of mortality from coronary disease should be assessed simultaneously. Because there was also evidence to indicate that tamoxifen might have a beneficial effect on women with osteoporosis due to its estrogen agonist activity, it was deemed appropriate that the effect of tamoxifen on osteoporosis also be evaluated in the study. The P-1 trial also provided an opportunity to obtain genetic information about breast cancer from a high-risk population. It was believed that the genetic studies planned for the trial could provide information about the incidence of BRCA-1 and BRCA-2 mutations in the study population and answers to the question of whether tamoxifen was effective in women with such abnormalities.

P-1 Study Design, Participant Eligibility, Risk Assessment, and Analysis

Women at increased risk for breast cancer were randomly assigned to receive either placebo or tamoxifen (20 mg/day) for 5 years. Women were considered to be at increased risk if they were 60 years of age or older, were between 35 and 59 years of age with a 5-year predicted risk for breast cancer of at least 1.66%, or had a history of LCIS. Women with a history of DCIS were not included in the trial because the worth of tamoxifen and of radiation therapy for the treatment of DCIS was already being evaluated in two other clinical trials, B-171109,1110,1111,1147 and B-24,1122 which had been initiated by the NSABP in 1985.

By September 30, 1997, after 13,388 women aged 35 years and older had been randomly assigned in the trial, participant entry was terminated. On March 24, 1998, an independent data-monitoring committee, which had provided oversight for the study since its inception, determined that, in accordance with prespecified rules for stopping the study, the findings that demonstrated a reduction in breast cancer risk were sufficiently strong to justify disclosure of the results. Although a description of the conduct of the study had appeared earlier,1148 the first report of the P-1 findings was published on September 16, 1998.1123 A subsequent commentary addressing many of the issues that had been generated by the initial report appeared in May 1999.1149 Those articles provide more detailed information about the study design, conditions for participant eligibility, biostatistical analyses, findings, and other aspects of the trial.

An algorithm based on a multivariate logistic regression model employing combinations of risk factors was used in the P-1 trial to estimate the probability (risk) of the occurrence of breast cancer over time.1150 The variables included in the model were a woman’s age, race, number of first-degree relatives with breast cancer, nulliparity or age at first live birth, number of breast biopsies, pathologic diagnosis of atypical hyperplasia, and age at menarche. The 1984–1988 SEER rates of invasive breast cancer were used as the rates that were expected to occur. The total U.S. mortality rates for the year 1988 were used to adjust for the age-specific competing risk of death from causes other than breast cancer.

Breast cancer risk assessments were used to determine the eligibility of women for the study. From April 22, 1992, through May 20, 1997, risk assessments were performed for 98,018 women; 57,641 (58.8%) of these were deemed eligible, on the basis of their risk, for participation in the trial. Of this group, 14,453 women agreed to be medically evaluated for complete eligibility. A total of 13,954 women met all eligibility requirements.

All analyses were based on assigned treatment at time of randomization, regardless of treatment status at the time of analysis. All randomly assigned participants with follow-up were included in the analyses. Average annual event rates for the study end points were calculated for each treatment group by means of a procedure in which the number of observed events was divided by the number of observed event-specific person-years of follow-up. Two-sided p values for tests of differences between the treatment groups for the rates of invasive breast cancer, noninvasive breast cancer, and invasive endometrial cancer were determined by use of the exact method, assuming that the events came from a Poisson distribution and conditioning on the total number of events and the person-years at risk.1151 The mean time on the study for the 13,175 participants who were included in the analysis was 47.7 months; 73.9% had a follow-up exceeding 36 months, 67.0% were followed for more than 48 months, and 36.8% had follow-up exceeding 60 months. The median follow-up time was 54.6 months.

Participant Characteristics

Of the 13,175 participants included in the analysis, 39% were 35 to 49 years old at randomization, 31% were aged 50 to 59 years, and 30% were 60 years of age or older (Table 118.29). Only 3% of the participants were 35 to 39 years of age and 6% were 70 years of age or older. Almost all participants were white (96%), more than one-third (37%) had had a hysterectomy, 6% had a history of LCIS, and 9% had a history of atypical hyperplasia. The distribution of participants among the placebo and tamoxifen groups relative to these characteristics was similar.

Table 118.29. Characteristics at Time of Randomization for P-1 Participants Included in the Analyses.

Table 118.29

Characteristics at Time of Randomization for P-1 Participants Included in the Analyses.

Almost one-quarter (24%) of the participants had no first-degree relatives with breast cancer, more than one half (57%) had one first-degree relative with the disease, 16% had two, and 3% had three or more. About one-quarter of the women had a 5-year predicted breast cancer risk of 2.00% or less. Almost three-fifths (58%) had a 5-year risk of between 2.01% and 5.00% and 17% had a risk of more than 5.00%.

The Benefit from Tamoxifen

Reduction in Breast Cancer Risk

There was a highly significant reduction in the incidence of invasive and noninvasive breast cancer as a result of tamoxifen administration. There was a 49% reduction in the cumulative incidence of invasive breast cancer through 69 months of follow-up—43 versus 22 per 1,000 women in the placebo and tamoxifen groups, respectively (p < .00001). The reduction in risk was 50% (p < .002) for noninvasive breast cancer related to a decrease in the incidence of both DCIS and LCIS. No survival differences were observed. Nine deaths were attributed to breast cancer (i.e., six in the group that received placebo and three in the tamoxifen group).

To assess the consistency of tamoxifen across the population, rates of invasive cancer were calculated for various subgroups of women (Table 118.30). When the rate of invasive breast cancer was examined according to age, a decrease was observed in all age groups after tamoxifen administration. The rate decreased by 44% in women 49 years of age or younger, 53% in women who were ≥50 years of age, 51% in women between the ages of 50 to 59 years, and 55% in women 60 years of age or older. In women with a history of either atypical hyperplasia or LCIS, the risk of invasive cancer was reduced by 86% and 56%, respectively. A reduction in risk was also observed in women with any category of predicted 5-year risk. There was a 63% reduction in women with a 5-year predicted risk of ≤2.00% and a 66% reduction in those with a risk of ≥5.01. Of particular interest was the observation of a similar reduction in the rate of breast cancer among women who received tamoxifen, regardless of whether they had no, one, two, or three or more first-degree relatives with breast cancer. There was a 54% reduction in women with no first-degree relatives with the disease; in women with three or more, the reduction was 49%.

Table 118.30. Rates for Invasive Breast Cancer by Age, 5-Year Predicted Breast Cancer Risk, Number of First-Degree Relatives with Breast Cancer, History of Lobular Carcinoma in Situ (LCIS), or History of Atypical Hyperplasia.

Table 118.30

Rates for Invasive Breast Cancer by Age, 5-Year Predicted Breast Cancer Risk, Number of First-Degree Relatives with Breast Cancer, History of Lobular Carcinoma in Situ (LCIS), or History of Atypical Hyperplasia.

Additional evidence of the effectiveness of the drug was provided by the observation that, during each of the first 6 years of follow-up, tamoxifen administration resulted in a significant reduction in the risk of invasive cancer. The rates of decrease in years 1 through 6 were 35%, 55%, 39%, 49%, 69%, and 55%, respectively.

When invasive breast cancers that occurred were related to selected tumor characteristics, particularly important was the finding that a 69% reduction was noted in the rate of ER-positive tumors in the group that received tamoxifen. No such reduction was observed, however, in the rate of breast cancers that were ER negative. Similarly, the rate of invasive breast cancer among women in the tamoxifen group was less than that among women in the placebo group in all categories independent of tumor size. The greatest difference was noted in the occurrence of tumors that were 2.0 cm or less in size at the time of diagnosis. The rate of occurrence of tumors 1.0 cm or smaller was reduced by 42% as a result of tamoxifen administration; the rate of tumors 1.1 to 2.0 cm was reduced by 62%. A similar reduction (i.e., 50% and 57%, respectively) was observed in the rates of breast cancer in women who had either no nodal involvement or one to three nodes involved with tumor.

Breast Cancer Risk Reduction from a Global Perspective

At this juncture, it seems reasonable to attempt to determine, on the basis of the P-1 data, whether tamoxifen should be administered to a large population of eligible women, even though the vast majority of them would never develop breast cancer and even though not all tumors would be prevented in the women who would have had a tumor. Because it is not possible to identify a priori those women who either would or would not benefit from taking the drug, that issue is difficult to address.

According to NCI estimates, approximately 29 million women in the United States would have been potentially eligible for the P-1 trial and would, thus, have been expected to respond to tamoxifen in a manner similar to that of P-1 participants. The number of women in that population who have the potential to benefit from receiving tamoxifen might be estimated by using the data reported in our recent publication of the P-1 findings. Because the average annual rate of the occurrence of invasive breast cancer in each 1,000 participants in the placebo group of P-1 was 6.76, it might be estimated that, in the population of 29 million women, almost 1 million would, during a 5-year period, have the potential for being diagnosed with such a tumor. In the tamoxifen group of P-1, where the rate of such tumors was 3.43 per 1,000 women per year, approximately 500,000 invasive breast cancers might be detected during that time. Thus, almost one half of 1 million invasive breast cancers would be prevented in the expanded population. A similar estimate indicates that almost 200,000 noninvasive tumors (either DCIS or LCIS) would be prevented. In view of these estimates, the benefits that might be achievable by more widespread use of tamoxifen cannot be viewed as trivial.

It must be emphasized that the magnitude of benefits observed in the P-1 study relates to the level of breast cancer risk in the women being evaluated. The higher that risk in women who comprise a population, the greater the number of breast cancers that will occur and, thus, the greater the benefit from tamoxifen. A broad spectrum of risks existed among women who participated in the P-1 study. In some, the risk of developing invasive breast cancer was just high enough to make them eligible for the trial, whereas, in others, the risk was much higher. If, for example, the 5-year predicted risk in all of the women comprising the population of 29 million were ≥5.01%, it would be estimated that almost 2 million invasive cancers would have occurred in the placebo group and 650,000 in the tamoxifen group during a 5-year period. Thus, approximately 1.2 million invasive breast cancers might have been prevented.

On the other hand, if the 5-year predicted risk in all 29 million women were ≤2.0%, then approximately 300,000 tumors might have been prevented. Consequently, expanding the findings from the P-1 trial to a larger population of putatively similar women vividly demonstrates the potential impact that the wider use of tamoxifen, or of a similar drug of proven efficacy, could have in diminishing the extent of the breast cancer problem. The P-1 findings support the axiom that small benefits attained in a disease that occurs frequently can result in an advance of major proportions. (These statements do not imply, however, that tamoxifen should be administered to all 29 million women.)

Adverse Effects from Tamoxifen

There was considerable concern, both before and during the conduct of the P-1 study, about the dangers of liver damage, hepatoma, colon cancer, and retinal toxicity that might be associated with tamoxifen. However, no liver cancers have been observed in either the placebo or tamoxifen groups of P-1, and, although posterior subcapular opacities were more frequently observed in women who received tamoxifen,1152 there has been no evidence of either macular degeneration or vision-threatening toxicity in that group. There have been too few ophthalmic toxicities from tamoxifen administration in the P-1 trial to warrant making a recommendation that the drug be withheld from women such as those who participated in that study.

Even greater concern was expressed about the risks of endometrial cancer and vascular-related toxic events, predominantly in postmenopausal women who participated in the P-1 trial. The issue has been raised, primarily in the lay press, about whether the benefit that was achieved by a reduction in the incidence of breast cancer was sufficiently great to justify the use of tamoxifen as a chemopreventive agent despite the risk of those events.1153 Each dot represents a single individual among 1,000 P-1 participants who developed an endometrial cancer, a pulmonary embolus, a stroke, or a deep-vein thrombosis over a 5-year period (i.e., the rate per 1,000 women per 5 years). About 7 per 1,000 women, or less than 1 woman per 100 (0.7%), in the tamoxifen group developed endometrial cancer over a 5-year period. The findings that all invasive endometrial cancers were stage 1 and that no deaths from endometrial cancer were reported were of clinical significance. Although no data are currently available to indicate that women who take tamoxifen should have regular endometrial biopsies or undergo vaginal ultrasound examination, all those who take the drug should be advised to undergo an annual gynecologic evaluation and to report any abnormalities that might be evident.

When the undesirable vascular events attributable to tamoxifen were evaluated, the findings showed that, over a 5-year period, 0.2 to 0.3% of women experienced a stroke, about 0.2% had a pulmonary embolism, and between 0.2 and 0.3% exhibited a deep-vein thrombosis. Those events occurred less frequently in women ≤49 years of age but were somewhat more frequent in women aged ≥50 years. In the latter group, the rate of endometrial cancer was about 1% over 5 years; for each of the vascular-related events, it was less than 1%. Because women who had had a hysterectomy were not at risk for endometrial cancer, the major undesirable side effects in that population consisted only of vascular-related events. The rate of these was similar to the rate of such events in women who had not had a hysterectomy.

When P-1 participants were evaluated with regard to undesirable events from tamoxifen that could have an effect on their quality of life (Table 118.31), 12% more women in the tamoxifen than in the placebo group experienced some degree of hot flashes and 20% more reported vaginal discharge. Of those women who had hot flashes, only about 8% more women in the tamoxifen group than in the placebo group reported that their hot flashes were extremely bothersome; about 2% more described their vaginal discharge in the same manner.

Table 118.31. Distribution of P-1 Participants in the Placebo and Tamoxifen Groups by Highest Percentage of Hot Flashes, Vaginal Discharge, and Depression Reported.

Table 118.31

Distribution of P-1 Participants in the Placebo and Tamoxifen Groups by Highest Percentage of Hot Flashes, Vaginal Discharge, and Depression Reported.

A recently published report on the health-related quality-of-life component of the P-1 trial provided information to indicate that weight gain and depression (see Table 118.31), two clinical problems anecdotally associated with tamoxifen treatment, did not increase in frequency in the women who participated in the study.1153 Moreover, overall rates of sexual activity remained similar for women in both the placebo and tamoxifen groups.

Relationship Between the Beneficial and Harmful Effects of Tamoxifen

Given the impressive benefits from tamoxifen and the low rates of adverse events experienced as a result of administration of the drug, the issue arises as to how best to convey to a woman what her net benefit from taking tamoxifen is likely to be. The issue is a complex one. The higher a woman’s risk for breast cancer, the more likely it is that tamoxifen will confer a substantial benefit; however, determining the benefit for women who have a lower increased risk may be more difficult. How the side effects of tamoxifen administration are related to its benefits is important in deciding whether the intervention is worthwhile. This relationship may be examined in several ways. Assessing the extent of a benefit when primary or secondary prevention strategies are employed is relatively straightforward. In such a circumstance, the number of events expected minus the number of events prevented indicates the net benefit. In chemoprevention, the net benefit is confounded by the side effects that result from the agent employed, in this case, tamoxifen. To consider an endometrial cancer or a vascular event, as observed in the P-1 study, to be “equivalent” to a breast cancer and to conclude that the prevention study merely “exchanged one event for another” is an unjustifiable assumption. To subtract an undesirable event from a beneficial one is inappropriate because the two are not of equal value. For example, to subtract an unfavorable event such as endometrial cancer, which has a morbidity and mortality rate that is less than that from a breast cancer, is not appropriate because the morbidity and mortality rates from a hysterectomy for endometrial cancer are likely to be less than those resulting from surgery, radiation therapy, and chemotherapy for a breast cancer that would have occurred in the absence of tamoxifen administration.

Candidates for Tamoxifen

Who should take tamoxifen to decrease the risk of developing breast cancer? Women younger than 50 years of age who meet the eligibility requirements of the P-1 trial are likely to be considered highly eligible for tamoxifen because their risk of an adverse event is practically nil and because the reduction in the incidence of breast cancer for the group overall is reduced by almost one half. Moreover, the greater the risk, the greater the benefit.

Postmenopausal women who have had a hysterectomy are also favorable candidates for tamoxifen because they cannot develop endometrial cancer. Because women with a history of LCIS or atypical hyperplasia are at particularly high risk for breast cancer and because tamoxifen reduces that risk, the level of benefit achieved markedly outweighs the adverse effects that might result from tamoxifen administration. In addition, because the risk of invasive breast cancer in women with localized DCIS is at least as high if not higher than that for women with a history of LCIS or atypical hyperplasia, the benefit the former group would receive from tamoxifen, insofar as reducing their rate of invasive breast cancer is concerned, is likely to eclipse the consequences of any adverse effects from the drug.

Although, to date, no information is available to indicate whether women who are at increased risk for breast cancer because they carry BRCA1 or BRCA2 mutations should be considered candidates for tamoxifen, these women should be afforded that option, particularly if they are contemplating having bilateral mastectomy to prevent the disease.

The decision to prescribe tamoxifen for women 50 years of age or older who have stopped menstruating, have not had a hysterectomy, and have no history of LCIS, DCIS, or atypical hyperplasia, is less clear. Because the incidence of adverse events remains constant regardless of the cancer risk in these women, it is evident that the greater the risk, the less controversial the issue. The greater the mortality and morbidity associated with breast cancers that have been prevented by tamoxifen, the greater the benefit from the drug when the benefit is balanced against potential adverse events. A precise level of risk above and below which a woman should or should not be considered a candidate for tamoxifen has not yet been determined and is likely to be difficult to agree upon. The probability that an adverse event from tamoxifen will occur in women 50 years of age or older should not prevent the use of tamoxifen in this age group. This recommendation is supported by the following two major considerations: (1) the P-1 study was unblinded by an independent group of investigators from a variety of disciplines so that study participants who took placebo (including women aged 50 years or older) could either choose to receive tamoxifen or participate in the NSABP P-2 trial, a new study in which women 50 years of age and older who take tamoxifen will serve as the standard group against which the benefits and adverse effects from the SERM raloxifene will be measured, and (2) British investigators did not alter their prevention trial because of the adverse endometrial cancer and vascular events reported in P-1. These circumstances clearly indicate that, in the general population, there must be a substantial number of women 50 years of age and older for whom tamoxifen administration is considered appropriate.

It must be emphasized, however, that, before a woman is advised to begin taking tamoxifen, her overall clinical status must be evaluated. Her physical well-being must be assessed to ensure that she does not have co-morbid conditions that make the administration of tamoxifen not only undesirable but inappropriate. Moreover, the task of recommending tamoxifen for women at increased risk for breast cancer should be undertaken by only those individuals who are free of personal bias, possess complete and accurate information about breast disease, know how to determine a woman’s risk for breast cancer, and are adept at counseling her about her individual course of action.

Comments Relative to the P-1 Findings

The P-1 findings clearly demonstrate that tamoxifen reduces the risk of breast cancer in a substantial number of women at increased risk. As is evident, however, after each demonstration of a therapeutic advance, uncertainty arises with regard to the clinical application of the findings. Failure to resolve all of the issues and to answer all of the questions that have arisen as a result of the P-1 study does not necessarily detract from either the credibility or the importance of the results, which have opened doors to new pathways for scientific investigation. The following comments address some of the concerns that have arisen subsequent to the publication of the P-1 findings.

Timing and Duration of Tamoxifen Administration

Some have expressed concern about the duration of tamoxifen administration. It has been speculated that, if the drug is given for only 5 years, tumor growth might merely be delayed for a short time and that tumors will subsequently appear when the drug is discontinued. Findings from NSABP B-14, a trial that was conducted to evaluate the worth of tamoxifen for the treatment of patients with node-negative, ER-positive tumors, have not supported that concern.1116 In that study, the benefit from 5 years of tamoxifen administration persisted through 10 years of follow-up. Giving the drug for more than 5 years, however, failed to enhance its effect. Most important, the reduction in the incidence of contralateral breast cancer observed with 5 years of tamoxifen therapy continued through 10 years of follow-up; a 37% decrease was observed at that time. Because the findings from both the B-14 and P-1 trials demonstrated that the breast tumors prevented were ER positive, it is likely that the benefit noted in the P-1 trial will persist after study participants discontinue taking tamoxifen. Although additional studies are necessary before this issue can be resolved, the value of 5 years of tamoxifen therapy cannot be disputed at this time.

Another important question concerns the optimal time at which to begin tamoxifen administration. It is likely that alterations were already present in the breast cells of women who developed tumors while they were enrolled in the P-1 study. Because these tumors were diagnosed early in the follow-up period, there would seem to be no merit in delaying administration of the drug to women for whom it has been deemed appropriate.

Findings From Two European Prevention Trials

Another issue that has resulted in criticism of the P-1 study arose as a consequence of findings reported from two European prevention trials1154,1155 that failed to verify the results obtained from P-1. The simultaneous reports from a British study and an Italian study resulted in a misunderstanding among the public, the media, and physicians, who failed to realize that the three studies were too dissimilar in design, population enrolled, and other aspects to permit extrapolating teh European results to the P-1 study. Although an effort has been made to attempt to explain the reasons for the differences, any conclusions reached in that regard must be viewed as speculative.1156,1157 The disparate findings from each of the three trials relate to differences in boundaries that were defined a priori in each study. To view the results of the two European studies as being “apparently contradictory”1158 to those of P-1 and to contend that the findings from one study either confirmed or rejected the findings of the others is inappropriate. Because (1) many fewer breast cancer events occurred in the British and Italian studies than in P-1, (2) the criteria for selecting participants were different in the three trials, (3) study participants had different risks for breast cancer, (4) there were some differences in protocol compliance among the trials, (5) hormone replacement therapy was used in the two European studies but not in P-1, and because of other differences as well, the studies are not comparable. Consequently, the value judgment that the two European studies failed to confirm the P-1 study is unwarranted because there was, in actuality, “no contest” between them.

The Meaning of Prevention

The use of the term prevention to describe the P-1 findings has prompted a great deal of debate. When the study was designed, that term was used to indicate a reduction in the incidence (risk) of invasive breast cancer that occurred over the period of the trial. Whether the benefit achieved from tamoxifen in the P-1 study was due to the drug’s interference with the initiation (genetic changes in normal cells resulting from carcinogenic agents), promotion (clonal expression and genetic changes resulting in the progression of preneoplastic lesions to noninvasive and malignant tumors), or to hindrance in the growth of (phenotypically expressed) occult tumors is unknown. Because it is likely that a broad spectrum of molecular-biologic and pathologic changes in breast tissue existed among participants at the time of their entry into the trial, it might be assumed that all of the mechanisms may have been responsible for the finding.

Our study, as well as other prevention trials that are currently being conducted or that are in the planning stages, is likely to be incapable of providing information to resolve the conundrum about precisely where tamoxifen exerts its effect. Nonetheless, the absence of specific information to resolve the issue does not detract from the evidence indicating that, in the P-1 trial, tamoxifen did, in fact, prevent the clinical expression of tumors, an action that is the goal of disease prevention. Moreover, we have never indicated that our use of the term prevention in the P-1 study implied that the initiation of breast cancers had been prevented or even that all tumors that were prevented from becoming detectable during the course of the trial had been permanently eradicated. Nonetheless, we consider the term to be appropriate as we have defined it. Despite that fact, the FDA replaced prevention with the term risk reduction. In the final analysis, it matters little which term is used; the P-1 data continue to stand on their own merit. Considered at face value, they provide the first evidence that the administration of a systemic agent can change the natural history of seemingly healthy women who are at increased risk for developing invasive or noninvasive breast cancer. And, in that regard, they have a historic relationship to the findings of another study that we reported in 1975, which demonstrated for the first time that postoperative adjuvant chemotherapy could alter the outcome of women with invasive breast cancer.1159

Conclusion

Almost half of the invasive and noninvasive breast cancers in the P-1 trial were prevented, in all age groups, by the administration of tamoxifen. Thus, the findings from that study support the hypothesis that breast cancer can be prevented in women at increased risk for the disease. Because thousands of women with invasive breast cancer die each year despite what is viewed to be today’s effective treatment, we cannot afford to deny those who do qualify for tamoxifen preventive treatment the opportunity to receive it.

Although more studies are needed to address the issues that have arisen as a result of the P-1 findings, on the basis of the data from that trial, we consider it highly appropriate to offer tamoxifen to women similar to those who participated in that study. To that end, the new NSABP P-2 chemoprevention trial will evaluate postmenopausal women at increased risk for breast cancer who are similar to P-1 participants. In P-2, the toxicity, risks, and benefits of the SERM raloxifene will be compared with those of tamoxifen. Although raloxifene has been shown to prevent osteoporosis, its value in reducing the rate of breast cancer without increasing the risk of endometrial cancer has yet to be established. Although science is too complex to permit one to make predictions with regard to future directions for breast cancer research, the findings from P-1 clearly indicate that much of such research must be related to prevention. Agents that have the ability to prevent the occurrence of ER-negative tumors must be discovered and evaluated, and new, more effective SERMs with different mechanisms of action must be developed. Despite the fact that scientists have failed to eradicate breast cancer in the second millennium, the twentieth century can be viewed, in retrospect, as a period during which progress was made in the understanding, treatment, and prevention of the disease.

Perspectives

With the rapid rate of change in basic and clinical cancer research, it is sometimes difficult to see things in perspective. Some ideas that are new seem to have been around a long time, whereas other concepts seem to gain acceptance very slowly. In fact, the situation has been far from static. Table 118.32 lists in very general terms some of the features of breast cancer progress in recent decades. For the first half of this century, breast cancer thinking was stuck in an anatomic mode leading to radical surgical concepts, and clinical research amounted to little more than counting cases and outcomes in tumor registries. With the advent of chemotherapy and the realization that breast cancer was more likely to be a systemic disease and that it was a disorder of growth regulation, new ideas quickly took hold.

Table 118.32. Trends in Breast Cancer Research and Treatment.

Table 118.32

Trends in Breast Cancer Research and Treatment.

One avenue of research was to determine the optimal amount of surgery necessary, whereas the other was to combine surgery with adjuvant chemotherapy treatments to improve cure rates. When attention then focused on metastasis and issues of drug resistance, there began a happy convergence of basic and clinical researchers into what is now called translational research. From today’s perspective, it is easy to see that we have made the transition from anatomic to biologic thinking and have many new and exciting avenues for further progress. In this chapter, some of the new biologic approaches can be seen in the recent adjuvant chemotherapy programs, in the combined-modality programs (notably the use of herceptin and other antibodies), in the exploration of preoperative chemotherapy as a drug sensitivity test, in the use of modulators with adjuvant chemotherapy, and, perhaps most important for the immediate future, in the use of tamoxifen as a preventative. In this sense, tamoxifen is presented not as a simple antiestrogen but as a biologic growth factor inhibitor. Another investigative strategy would evaluate other interventions that might interfere with the initiation and/or promotion breast cancers. Although there are several candidates for evaluation (e.g., low-fat diets or retinoids), one that is particularly interesting is somatostatin, an antagonist of IGF-1.

Tamoxifen and related agents are newly classified as SERM. Although tamoxifen has traditionally been regarded as an estrogen, research has shown1160 that it is a significant inhibitor of serum IGF-1 levels. Other studies have shown that young women with high serum IGF-1 levels have a significantly higher risk for developing breast cancer.1161 IGF-1 inhibitors such as the stomatostatin analog, octreotide, have been shown in laboratory systems to interact with tamoxifen to inhibit tumor growth more than either drug alone.1162 A current NSABP trial (B-29) will test the combination of octreotide and tamoxifen compared to tamoxifen alone as adjuvant treatment for women with ER-positive tumors.

Recent trials evaluating dose intensification have provided conflicting and somewhat disappointing results, indicating that we should put more effort into a better understanding of cancer cell biology and less on trying to overwhelm tumors with massive force. However, it is clear that systemic therapies have become more effective and the relative importance of surgery and radiation therapy have shifted. It is easier to obtain local control than it is to control metastases, even the micrometastases at which adjuvant therapies are aimed. Therefore, efforts must be directed at these systemic therapies. New ways of introducing cytotoxic agents, such as liposomal doxorubicin, have already been tested and show promise. Other efforts to devise progressively better regimens for systemic treatment, both for adjuvant and advanced disease, should certainly persist.

New therapeutic modalities, such as immunomodulators, may one day require evaluation. Targeted immune cells may be used to introduce cytotoxic agents, such as tumor necrosis factor, directly to tumor cells, or to alter tumor cells genetically in order to suppress their growth. Such approaches may be tested alone or in conjunction with chemo- and hormonal therapeutic agents of proven value. Evaluation of methodologies for overcoming drug resistance and for modulating the action of chemotherapeutic agents based on pharmacologic principles should also continue, as should testing of currently available modalities in novel ways.

Another research strategy that has had moderate success is mammography screening. Using the best methodology, there is a meaningful reduction in mortality. The exact dimension of the benefits of screening are still controversial, but there is little dispute that mortality is reduced, at least in women aged 50 to 74. But even with the best figures, only a 30 to 40% decrease in mortality is seen, still a minority of the cases discovered. Although improvements in mammographic equipment, techniques, and scheduling may improve this outcome, it is clear that the physical diagnosis of cancers, even subclinical ones, will not find enough cancers before they have successfully metastasized. Therefore, we must continue to make progress in the areas of breast cancer prevention and of early treatment of systemic metastases as described above. One happy but still troubling aspect of successful mammographic screening is the continued increase in the proportion of small tumors. Sorting out how much treatment is appropriate in these cases will continue to occupy our attention. Another concern is that even patients with small cancers diagnosed by mammography remain at high risk for the development of a second breast cancer unless they undergo bilateral mastectomy, which is not a desirable means of cancer prevention. The value of tamoxifen as a prevention agent in these cases needs careful consideration.

It is likely that any discussion of breast cancer will have as its major component information regarding the mechanisms and feasibility of chemoprevention. The results of the NSABP BCPT are of fundamental importance in taking us in new directions. These findings are arguably one of the most important public health advances in breast cancer, mainly because they demonstrate that it is feasible to intervene and reduce breast cancer incidence with a pharmacologic agent, which opens new avenues for research. Breast cancer results from DNA damage, and, although it is possible that lifestyle changes can diminish this, it will take intervention with active agents, with their risk of side effects, to control or reverse this fundamental cause.

Last, but probably most important, because it brings us to the core of the problem, are all of the new advances in molecular biology and genetics. Along with the discovery of the BRCA genetic mutations are other important insights into how genes work. Among these are P53, telomerase, the whole family of targets for SERMS and mechanisms of angiogenesis and its control. The BRCA story has moved from clinical studies and pattern searching to investigations of mechanisms, now known to be in the realm of DNA repair. This also raises interest in these genes in sporadic breast cancer. Understanding the BRCA mutations and their relationship to causation and progression of breast cancer might expose targets of opportunity for research. New evidence of involvement of viral factors in human breast cancer has recently emerged. Better fundamental understanding of the etiology and pathogenesis of breast cancer should provide new approaches that are likely to have a major impact on therapy, diagnosis, and prevention. As it has for decades, the rate of progress continues to increase. New knowledge continues to offer us new possibilities and new challenges.

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