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Holzheimer RG, Mannick JA, editors. Surgical Treatment: Evidence-Based and Problem-Oriented. Munich: Zuckschwerdt; 2001.

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Surgical Treatment: Evidence-Based and Problem-Oriented.

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Carcinoma of the breast

, M.D., M.B.A.

Department of surgery, Jefferson Medical College, Philadelphia, Pennsylvania; the surgical service, Thomas Jefferson University Hospital, Philadelphia; and the Breast Health Institute, Philadelphia, U.S.A.

Introduction

As we enter the new millennium, we continue to be challenged by an ever-increasing incidence of breast cancer. Between 1975 and 1996, the age-adjusted incidence of breast cancer in the USA rose from 45 to 60/100,000, roughly 1.5% per year in this interval. The incidence of breast cancer in Europe parallels the American data, with small degrees of difference in different countries, but an overall incidence that makes breast cancer the most frequently occurring malignancy in both American and European women. Despite significant incremental advances in diagnosis and treatment in the past generation, the specter of breast cancer is as haunting now as it was in the middle of the 20th century.

With respect to breast cancer mortality, according to the WHO databank, with 56 regional or national entities contributing data, several European countries surpass the USA in these unfortunate statistics, Denmark and the Netherlands being the world's leaders (1). Global differences in incidence and mortality of breast cancer, comparing, for example, the USA (high) and Japan (low), has led to hypotheses implicating environmental factors, diet, and other risk factors, such as parity, age at menarche and menopause, age at first live birth, etc., that exhibit cultural differences. Following an initial demonstration of a decrease in the age standardized death rate from breast cancer in the USA demonstrated between 1989 and 1995, similar trends were documented in Canada, the United Kingdom and several other (northern) European countries. For reasons that remain enigmatic, increasing mortality has been documented in Spain, Portugal, Greece, Hungary, Poland and Italy (2).

The etiology of breast cancer is unknown although a number of risk factors have been identified that apparently predispose to the development of breast cancer. These include female gender, increasing age, family history (first degree relative) especially if the family member's cancer occurred before menopause, early menarche, late menopause, nulliparity or late first full-term pregnancy, certain benign proliferative breast conditions, and specific genetic mutations, i.e., BRCA1 and BRCA2 genes (3, 4). However, most patients and many physicians do not appreciate the lack of any known or putative risk factors in the majority of patients who develop breast cancer (5, 6).

Diagnosis

Because breast cancer is not currently preventable, earlier detection has become the keystone of most efforts to reduce breast cancer mortality. Prior to the advent of screening mammography, despite the knowledge that cancer could exist in a pre-clinical state, “early” detection implied a small palpable tumor and depended upon a physician's examination or the patient's self-examination (BSE). Only after mammography became universally accepted for screening did the definition of early detection change to imply a non-palpable finding, apparent only on mammography. Unfortunately, mammography does not image all breast cancers, and probably 10–15% of palpable cancers are not seen on mammography. Additionally, it is in younger women (40–50) that mammography fails most often (7). Certain cancers, such as invasive lobular carcinoma, are more difficult than others to image using mammography. Ultrasound often may image palpable lesions not seen on mammograms and has the additional advantage of discriminating cystic (fluid-filled) from solid masses (8). Ultrasound, however, is not a screening technique; it is “targeted” at a palpable finding or at an area of suspicion. Magnetic resonance imaging is currently under investigation as an additional imaging technique, with intravenous gadolinium to enhance areas of suspicion (9). Thermography (the measurement of infrared emission from the breast) had been touted as a screening device for breast cancer back in the 1970's. It has not proved helpful. Computerized tomography of the breast was also previously investigated but abandoned, as well.

When screening mammography should begin has been a contentious subject and currently varies from country to country as well as from city to city. In the USA, annual mammography after age 40 is the recommendation of many cancer specialists and cancer organizations (10, 11). It has been our own practice to have women undergo a first mammogram at age 35, one more between that time and 40, and then annually after the age of 40. Modifications to this approach have been advocated for women with strong family histories of breast cancer, especially if an affected first-degree relative developed breast cancer earlier than age 40. In such families, the first mammogram should begin about 10 years earlier than the age at diagnosis of the first diagnosed relative.

The reporting of mammographic findings has become more standardized, with reproducible and precise terminology being adopted worldwide. The BI-RADS system has been developed by the American College of Radiology, with defined nomenclature to be used in each report according to this system, from 1 through 5, 1 being clearly benign and 5 being almost certainly malignant (12).

Given that any suspicious finding, whether palpable or detected only by an imaging study, requires explanation (biopsy), several techniques are available to make a diagnosis. This includes fine needle aspiration biopsy (FNA), large bore (11–14 gauge) core needle biopsy, or open surgical biopsy. It is currently considered preferable to obtain a tissue diagnosis before selection of a treatment option. When any procedure less than open surgical biopsy fails to document malignancy, adequacy of the biopsy must be questioned, and correlation between palpable or mammographic findings and the tissue diagnosis is necessary; otherwise, open surgical biopsy must be considered to document the histology precisely.

Staging

When a breast biopsy, however performed, proves the diagnosis of cancer, its clinical stage should be determined. The most commonly used staging system is that promulgated by the American Joint Committee on Cancer (AJCC) and is based upon the assessment of tumor size, local findings in breast (T) and axilla (N), and presence of overt metastatic disease (M) (table I). Staging is used to plan initial treatment, recognizing that other information, such as number of positive axillary nodes, presence or absence of steroid hormone receptors, mitotic rate (e.g. Ki-67), and certain gene products such as HER-2/neu expression, provides more accurate prognostic information than does pre-treatment clinical staging. Part of the workup of all patients with proven invasive stage I and II (A&B) breast cancer includes chest X-ray, determination of liver function studies, and bilateral mammography. Bone scan, abdominal CT scan, ultrasound or MRI is generally not recommended unless specific symptoms are present (bone scan) or if the liver function studies are abnormal (abdominal CT/US/MRI) (13).

Table I. TNM staging system for carcinoma of the breast (36).

Table I

TNM staging system for carcinoma of the breast (36).

The diagnosis of non-invasive (in situ) ductal or lobular carcinoma does not require these additional studies, since the natural history of these two entities is so different from that of invasive (ductal or lobular) carcinoma. Lobular carcinoma in situ (LCIS) is not considered malignant sui generis but is a marker for the subsequent development of a “real” cancer in either breast. The treatment of in situ ductal carcinoma (DCIS) is one of the most controversial topics in contemporary breast cancer care, treatment ranging from local excision alone to mastectomy, depending upon investigator and individual circumstances.

Treatment

For the patient with (invasive) carcinoma of the breast, treatment includes attention to the breast and the axilla, either by surgery, radiation therapy, or a combination thereof, and consideration of systemic treatment using hormonal or cytotoxic therapy. Therapeutic recommendations are made by assessment of all the available information, including clinical stage, microscopic findings, tumor biology, evidence of metastatic disease, as well as the patient's overall condition. Age alone is not a deterrent to aggressive treatment in the absence of major intercurrent disease. Based upon these data, options of treatment may be offered to each patient, based upon current guidelines using information derived from randomized clinical trials and selected retrospective analyses.

In situ lobular carcinoma (LCIS)

This disease should not be considered malignant in its own right. It is considered a risk factor or marker for the development of invasive cancer in either breast at some time in the future, approximately 25% risk within the next 30 years following the initial diagnosis (14). LCIS is usually an incidental finding at the time of a breast biopsy performed for another reason. It is often multicentric and bilateral, so that re-excision after the diagnosis has been made is not appropriate. The choice of treatment is between lifetime surveillance by semi-annual physical examinations and annual mammography versus bilateral total mastectomy (with or without reconstruction). Because both breasts are at equivalent risk for the subsequent development of invasive cancer, unilateral treatment is not a sensible choice (14).

In situ ductal carcinoma (DCIS)

Until the advent of mammography, the occurrence of DCIS as a solitary diagnosis was unusual, but the ubiquitous use of screening mammography has led to an exponential increase in its detection, usually as an area of pleomorphic calcifications without a demonstrable mass. Since the diagnosis of DCIS, by definition, excludes invasion, treatment is aimed at the prevention of invasive carcinoma or the earliest possible detection of invasive carcinoma if it were to occur. Since only a minority of patients with DCIS will progress to invasive carcinoma, the challenge has been to stratify the patients with DCIS into three groups - those who require mastectomy, those who are best treated by wide local excision and radiation therapy, and those who require only wide local excision. The classification and treatment of DCIS has been the subject for several clinical trials and consensus conferences, with vocal champions for each mode of treatment (15). The largest randomized clinical trial reported to date, from the National Adjuvant Breast Surgical Project (NSABP) protocol B-17, observed that the 5-year actuarial local recurrence for patients treated by radiation was 10%; for patients treated by “lumpectomy” alone, it was 21% (16). On this basis, the NSABP recommended radiation therapy for all women with DCIS, irrespective of tumor architecture, size or other parameters that might describe tumor behavior. Non-randomized but prospective studies have suggested that selected patients with DCIS are candidates for treatment by local excision alone, using selection criteria that include tumor size, biology, and margin status (17). These patients should generally have tumor size less than 2.5 cm diameter, absence of high nuclear grade and significant tumor necrosis, and at least 1 cm clear surgical margins following local excision (18). The goal of treatment should be breast conservation whenever possible, with a minimum likelihood of the subsequent development of an invasive carcinoma of the same breast. Attention to the axilla is not required with DCIS; if micro-invasion is documented along with the DCIS, the patient should be treated as for a T-1a, stage I cancer (vide infra). Cytotoxic chemotherapy is not indicated in patients with DCIS. The role of tamoxifen is currently being explored; current data from the NSABP randomized clinical trial B-24 suggest that tamoxifen does decrease the likelihood of ipsilateral recurrence (19).

Clinical stages I and II invasive carcinoma

Randomized clinical trials have documented the equal efficacy of breast conservation and modified radical mastectomy in these groups of women (2023). Breast conservation implies wide local excision of the primary lesion with microscopically clear margins, axillary dissection and radiation therapy. Modified radical mastectomy has evolved from the Patey mastectomy, including a complete axillary dissection and removal of the interpectoral fascia as well as the pectoralis minor muscle, to a lesser procedure, but still including the entire breast and a level I and II node dissection, sparing the pectoralis minor muscle. The Patey procedure is still generally performed if the nodes are clinically positive.

Within the past few years, sentinel node biopsy has emerged as a step to be considered as part of breast conservation when the axillary nodes are clinically negative (24, 25). Sentinel node biopsy with frozen section examination of the sentinel node may be performed, and the node dissection completed if the sentinel node is positive. When the sentinel node is frozen-section negative, no further axillary dissection is performed. The sentinel node is later examined using paraffin embedded fixed sections and also by immunochemical techniques. If a node is frozen-section negative but later found to harbor metastasis when the permanent sections are reviewed or by immunohistochemistry, whether it is appropriate to dissect the axilla further (levels I and II) or treat it by radiation, or to use this information only to plan systemic treatment, remains moot.

Notwithstanding the equivalent outcomes employing breast conservation and mastectomy, it is important to remember that these outcomes are equivalent for appropriately selected patients. There are women who are still best served by mastectomy because of their increased risk of local recurrence. Local (breast) recurrence after breast conservation is not as ominous as is local recurrence in the incision or on the chest wall after mastectomy. Such recurrence following mastectomy almost always implies systemic failure, i.e., metastatic disease. Local recurrence following breast conservation does not. So-called salvage mastectomy can be performed following local recurrence with a reasonably high expectation of the patient remaining free from systemic disease. Relative contraindications to breast conservation are summarized in table III.

Table III. Relative contraindications to breast conservation.

Table III

Relative contraindications to breast conservation.

With respect to these contraindications, patient participation is vitally important when considering the tumor-to-breast size ratio, since for some women, a smaller breast is an acceptable alternative to mastectomy so long as they know what to expect. Likewise, the number of attempts to secure clear surgical margins requires the patient's input. For some women, more than one attempt is too much; for others two, even three, tries may be acceptable. In addition, there are some women for whom the possibility of local recurrence, however small, is too great for them to consider, and mastectomy is their appropriate choice.

When mastectomy is performed, breast reconstruction should be discussed and offered. Whether reconstruction is performed at the same time as mastectomy or at a later date reflects patient choice. Whether autologous tissue or a saline filled expander/implant is chosen is also between patient and reconstructive surgeon, not the surgical oncologist. There are no data to indicate that reconstruction increases the incidence of or affects the ability to detect recurrent cancer.

Adjuvant therapy

In many patients with (clinical) stage I and II carcinoma of the breast, adjuvant therapy should be considered following local treatment, whether by breast conservation or mastectomy. For women with tumors less than 0.5 cm in diameter, (T-1-a) and negative axillary nodes, systemic treatment using either tamoxifen or cytotoxic chemotherapy is not indicated. When the tumor is between 0.6 cm and 1.0 cm in diameter (T-1-b), despite the absence of axillary metastasis, adjuvant therapy is often a consideration. If the tumor is estrogen receptor positive, tamoxifen alone is the choice. If receptors are absent, and/or if the tumor exhibits what are considered “unfavorable” characteristics, including lymphatic/vascular invasion at tumor site, elevated S-phase fraction, elevated Ki-67, high levels of mutated p53 or HER2/neu overexpression, cytotoxic chemotherapy is given, followed by tamoxifen for receptor positive cancers. Chemotherapy alone is considered for women with receptor negative cancers.. With tumors greater than 1.0 cm in diameter, even when axillary nodes are negative, chemotherapy followed by tamoxifen is a usual recommendation for estrogen receptor positive lesions, chemotherapy alone for those that are receptor negative.

Irrespective of tumor size, if axillary nodes contain metastasis, adjuvant chemotherapy is the current standard of care, unless intercurrent disease precludes its use. In patients whose tumors are also hormone receptor positive, tamoxifen is employed once chemotherapy has been completed. Tamoxifen, when prescribed, is used for five years, from time of treatment or from the time adjuvant chemotherapy has been completed, depending upon when the tamoxifen is begun. Several trials have thus far confirmed five years as an appropriate duration of treatment (26, 27). The risk of tamoxifen-related endometrial proliferation, even cancer, mandates annual pelvic examinations. Routine endometrial biopsy and/or pelvic ultrasound have not proved valuable for screening asymptomatic women.

Induction or neo-adjuvant chemotherapy as described below for stage III cancers is often now a consideration in patients with clinical N-1 axillae, irrespective of tumor size (T-1, N-1, or T-2, N-1) or for women with large T2 (> 3 cm) or T-3 cancers even if the axilla is clinically negative. Trials of induction chemotherapy in these groups of patients are not mature enough to be able to state unequivocally that survival is enhanced. However, breast conservation as an alternative to mastectomy has been possible in a majority of these patients, even those with initially large cancers.

Clinical stage III (A and B) invasive carcinoma

This group of patients with more locally advanced disease should undergo a more extensive pre-treatment evaluation than patients with stage I or II cancers. Bone scan should be performed, and abdominal ultrasound, CT, or MRI should be considered. Even in the absence of overt findings of systemic disease (M-0), most of these patients do have microscopic metastasis beyond the axilla. Traditionally, many of these patients were considered “inoperable,” and mastectomy was forsaken in favor of what was considered palliative radiation therapy, often without even removing the lesion. Over the course of the past generation, however, neo-adjuvant or induction chemotherapy, currently using an anthracycline-based regimen, has produced significant “down-staging” in up to 80–90% of these patients. Complete clinical remission is uncommon (< 10%), but significant enough regression may occur using induction chemotherapy to permit wide local excision of previously large (> 5 cm) lesions. In these situations, breast conservation may be employed instead of mastectomy, including wide local excision, levels I and II axillary dissection and radiation therapy. Sentinel node biopsy in this group of patients must be considered investigational.

If mastectomy is still required based upon the clinical findings after several cycles of induction chemotherapy, a full axillary dissection is usually part of the procedure. Following local therapy, most of these women are treated with further chemotherapy, with tamoxifen added for tumors that are hormone receptor positive. However, these patients do not fit comfortably into published practice guidelines, and their care must be individualized.

Post-mastectomy radiation therapy

Within the past several years, new attention has been focused on the use of post-mastectomy radiation therapy to chest wall and supraclavicular areas. Although a standard treatment following radical mastectomy in the 1950's, failure to prove a survival benefit led to its abandonment. Two clinical trials published in 1997 reported increased diseasefree and overall survival benefit from chest wall and regional node irradiation following mastectomy (28, 29). On the basis of these trials, despite considerable controversy and other trials that refute these conclusions, current recommendations often include such treatment in women with four or more positive axillary lymph nodes. Whether the internal mammary chain of lymph nodes should be included in the radiation field is even more controversial.

Clinical stage IV carcinoma

In this group of patients, metastatic systemic disease is detected as part of the pre-treatment evaluation. Therefore, the actual findings may be quite variable, from patients with clinically occult breast lesions but positive findings in lungs, liver, bones, or elsewhere at the time of diagnosis, to patients with locally advanced disease and these other systemic findings as well. Whenever possible, the histological diagnosis of metastasis should be established, but often, this diagnosis is based upon a combination of clinical findings and imaging studies. Recognizing that the treatment of systemic disease is palliative, a plan based upon symptoms and findings is appropriately established to both prolong life and enhance its quality. For those women with advanced local findings in breast and axilla, or elsewhere, radiation may effect significant local improvement. For women with painful bone metastasis, local radiation therapy achieves rapid relief of symptoms.

Whether metastasis is recognized at the time of initial diagnosis or at some interval after treatment, recommendations for treatment are similar. The likelihood of response to any hormonal or cytotoxic chemotherapeutic regimen is not predictable, but does relate to the length of time between initial diagnosis and diagnosis of metastasis; the longer this socalled “free interval”, the better the response to treatment.

These women with documented metastatic disease should not undergo mastectomy since it will not prolong their lives. Rarely will local surgery produce significant palliation that cannot be achieved by irradiation alone.

Management of local recurrence following breast conservation

Because radiation to the same anatomic area is not appropriate, women who develop a local recurrence following breast conservation are best served by mastectomy. Because the axilla was dissected at the time of the initial breast conservation procedure, total mastectomy rather than a more radical procedure is indicated. In patients who had undergone sentinel node biopsy as the only axillary procedure at the time of the initial diagnosis, then develop local recurrence, there are not yet any firm guidelines. If the recurrence is invasive in character, then dissection of residual nodal tissue at levels I and II would be prudent.

Whether adjuvant therapy should be used following mastectomy for local recurrence in patients who had undergone breast conservation is uncertain. Although several studies have not documented a major risk of subsequent systemic failure following local recurrence alone, other retrospective analyses suggest that women who have local recurrence within two years after initial treatment are at high-risk for systemic disease, as are young women with local recurrence (3033). These women are certainly candidates for systemic treatment following mastectomy.

Patients who have recurrence on chest wall or in the incision following mastectomy are not quite similar to those who have local recurrence in the breast following breast conservation. When local recurrence follows mastectomy, it is more often a manifestation of systemic disease. The surgical excision of local recurrence after mastectomy, even if easily performed, should be balanced against the ability to follow the progression or regression of the recurrence following systemic treatment. Advanced local recurrence often responds well to radiation therapy. Prognosis seems to relate to the disease-free interval between initial diagnosis and recurrence. If the “free interval” is greater than two years, treatment is more likely to be effective and for a longer period of time. Conversely, it is especially ominous if recurrence takes place while the patient is undergoing adjuvant chemotherapy.

Male breast cancer

Too little concern has been voiced about carcinoma of the male breast, because of its relative rarity. Traditional teaching had suggested that male breast cancer represented about 1% of all breast cancer, but the changing incidence of the disease, increasing more rapidly among women than men, has decreased this proportion despite its actual increased incidence as well. Although the literature prior to the 1990's indicated a poorer prognosis for male breast cancer, when comparably staged, the outcomes are equivalent (34).

Treatment of male breast cancer parallels that of carcinoma of the female breast. Mastectomy has been the mainstay of treatment. Because the tumors more easily become fixed to the chest wall, there is still a role for radical mastectomy, although modified mastectomy has become the usual procedure of choice. Clinical trials of breast conserving surgery have not been reported, although the choice of breast conservation is appropriate if the (same) criteria of wide local excision and clear margins can be fulfilled. The same principles also guide adjuvant therapy, including tamoxifen, since most male breast cancers express high levels of hormone receptors (35). Prior to tamoxifen, orchiectomy had been the “standard” technique of hormonal manipulation, but currently this is reserved for patients with metastatic carcinoma who recur following an initial response to tamoxifen and/or other hormonal therapies.

Follow-up of the breast cancer patient

Whenever possible, a member of the treatment team, i.e., surgeon, radiation oncologist or medical oncologist, should follow each patient with breast cancer. Often there are geographical constraints that interfere with this recommendation, and commonly, as managed care has gained greater penetration within the medical community in the USA, the primary physician now discharges this follow-up function. For patients who have undergone breast conservation, the treated breast should be imaged about six months following completion of radiation therapy and at six-month intervals for two years, then annually. The contralateral breast should be imaged annually. Clinical examination is performed quarterly for the first two years following treatment, then every six months thereafter until five years have passed, then at least annually. Additional studies, such as chest X-ray, liver function studies, “tumor markers” (CEA, CA27.29), and bone scans play little role in follow-up in the absence of specific symptoms, since the “earlier” diagnosis of recurrence has not been found to affect survival.

The diagnosis and treatment of breast cancer do not lend themselves to straightforward standardization. Alternatives of therapy are often available, with differing and conflicting perceptions of risks and benefits. Dogma must not replace reason as each patient's clinical and personal situation is addressed. Patient and physician must explore these options together to select the most appropriate choices to achieve the desired result - the eradication of this dread disease.

Table II. Stage grouping using TNM system (36).

Table II

Stage grouping using TNM system (36).

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Copyright © 2001, W. Zuckschwerdt Verlag GmbH.
Bookshelf ID: NBK6879

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