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Virnig BA, Shamliyan T, Tuttle TM, et al. Diagnosis and Management of Ductal Carcinoma in Situ (DCIS). Rockville (MD): Agency for Healthcare Research and Quality (US); 2009 Sep. (Evidence Reports/Technology Assessments, No. 185.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

4Discussion

Summary and Discussion

Question 1

In the United States the incidence of DCIS has risen from 5.8 per 100,000 women in 1975 to 32 per 100,000 in 2005. The incidence of DCIS increased in all age categories with the greatest rise among those older than 50 years of age. Age adjusted DCIS incidence rates increased 7.2-fold from 1980 to 2001. While other countries, including Sweden and the Netherlands, have also observed increases in DCIS in recent years, no country has experienced as steep an increase in DCIS as the United States. Yet, examining DCIS incidence alone takes the condition out of context. Over this same period, incidence of invasive breast cancer has also increased dramatically from 105.1 per 100,000 women in 1975 to 123.7 per 100,000 in 2005. The incidence of invasive breast cancer has also increased in all age categories, and the greatest increase has been in women over the age of 50. Thus, separating increases in the incidence of DCIS from increases in breast cancer incidence is not easily achieved.

Incidence of DCIS peaks around age 65–69 and declines after that. Prior to age 40 DCIS is a rare condition that accounts for less than 10 percent of all breast cancers.

The increase in DCIS has not been uniform across histologic types. Comedo histology is associated with a particularly high risk of recurrence but has been more stable over recent years than noncomedo histology. Low-grade DCIS, generally considered to be less likely to recur or develop into invasive breast cancer, accounts for the majority of the recent increase in the United States. Similar trends for invasive breast cancer have also been reported; the greatest increases in incidence of invasive breast cancer have been observed for ‘low risk’ versus ‘high risk’ cancers. This pattern has been interpreted by some as an indication that breast cancer is over diagnosed, but it is possible that it reflects the natural history of the transition from DCIS to invasive cancer and the varying amount of time that transition takes.

While not well studied, several demographic risk factors are associated with DCIS incidence; with few exceptions, they are also risk factors for invasive breast cancer. Older age, less education, white (versus African American) race, and urban residence were demographic factors associated with DCIS incidence.

Breast density was one of the strongest risk factors for both DCIS and invasive breast cancer with a 364 percent increase in incident DCIS among those with the highest breast density according to pooled analyses of 11 studies.403 Physically active women had a 34–47 percent reduction in adjusted odds of DCIS.

HRT is an example of a risk factor that differs importantly between invasive breast cancer and DCIS. Randomized trials of HRT (such as the Women’s Health Initiative) have not commented on whether they observed any differences in DCIS between treated and untreated groups. The exact effect, however, is difficult to evaluate since they have not explicitly reported that there were no differences. Other studies have found no effect of HRT use on DCIS incidence or have found inconsistent effects of HRT use, depending on years of use.

Few risk factors for invasive breast cancer (including tobacco, dietary factors, and BMI) have been carefully examined for DCIS. As these are somewhat weaker risk factors for breast cancer, the value of fully evaluating their role for DCIS is not clear.

Many investigators point to increased use of mammography as the likely explanation for the increased incidence in DCIS, but the increased incidence cannot be entirely explained by an increase in screening. Randomized studies of mammography point to small increases in DCIS and greater increases in invasive cancer detection. These increases are offset by important declines in breast cancer mortality. Supporting the conclusion that the increases in DCIS and invasive breast cancer are not due to screening alone are observations related to changes in incidence rates. Cumulative incidence of DCIS per 1,000 mammograms increased from 0.9 in January 1997 to 1.7 in December 2003, whereas the incidence of DCIS per 100,000 women increased seven-fold.

A number of factors may protect against DCIS incidence, typically due to their association with decreased invasive breast cancer incidence. For example, higher intake of green tea was associated with a small inconsistently lower risk of breast cancer across the studies404 and recurrence in early stage (I and II) cancers.405 Higher intake of soy foods was associated with a modest, inconsistent decrease in breast cancer across studies.406,407 Understanding whether these measures also prevent DCIS could improve understanding of the biology of DCIS and aid efforts to prevent invasive and noninvasive breast cancer.

Pharmacological prevention of DCIS with tamoxifen and raloxifene shows significant promise for the prevention of DCIS408 and is the subject of ongoing investigation. Particular attention should be paid to the differential effects of the two drugs on preventing DCIS and invasive breast cancer.

Question 2

There is generally strong evidence that post-diagnostic MRI can alter with treatment planning. Compared with mammography, MRI is more sensitive for detecting multifocal and contralateral cancer and for estimating tumor size. Given the growth pattern of DCIS, accurate histological determination of size and extent can be difficult. Moreover, limitations inherent in tissue processing make tumor measurement difficult. Finally, determining DCIS size is typically limited by the difficulty in reconstructing the 3-diminsional extent using 2-dimensional pathology slides. As a result, pathological examination can overestimate and underestimate tumor sizes depending on the plane of section. Some authors have argued that MRI measurements may be more accurate than those in the pathology laboratory. However, others have argued that breast MRI leads to more unnecessary biopsies and potentially more mastectomies.

Since about 15 percent of patients with DCIS identified on core needle biopsy are diagnosed with invasive breast cancer after BCS or mastectomy, the feasibility and accuracy of SLNB after excision is relevant to decisions regarding surgical management of women with biopsy-diagnosed DCIS. Given the current use of needle biopsy, rather than excisional biopsy, it seems reasonable to treat DCIS as possible invasive cancer and follow the rules for SLNB. Results from studies evaluating the accuracy of SLNB after excision are not consistent. An analysis from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32, Krag et al. reported that the SLN biopsy false negative rate was significantly increased after excisional biopsy compared with core needle biopsy or fine needle aspiration (needle biopsy, 8.1 percent; excisional biopsy, 15.3 percent).1 Other studies have not demonstrated differences in the accuracy of SLN after excision.

The overall incidence of SLN metastases among women with initially diagnosed with DCIS is unknown, but one study reported the overall incidence of SLN metastases to be as high as 9 percent. The incidence of SLN metastases was highest for women whose final diagnosis was invasive breast cancer, followed by patients with final diagnoses of DCISM and very slight for women whose final diagnosis was DCIS.

Question 3

The risk factors for poorer DCIS outcomes are different from risk factors for DCIS incidence but closely match risk factors for poorer invasive cancer outcomes. Estimates of the impact of these characteristics on survival shows a surprising lack of depth and, with few exceptions, is limited to studies of recurrence. This is likely due to the low incidence of outcomes other than invasive recurrence, even after 10 years. Younger age at diagnosis is a consistent adverse prognostic factor for DCIS outcomes. Women over age 40 or 50 consistently have reduced risk of DCIS or invasive recurrence than younger women. Surprisingly few studies report racial differences in DCIS outcomes.

SEER-based studies report higher all-cause mortality among African American women than white women diagnosed with DCIS and higher breast cancer mortality for African American women than white women. Studies of racial differences in DCIS recurrence point to a somewhat complex story. When adjusting for demographic factors alone, African American women are more likely than white women to experience a recurrence. However, the studies that adjust for a more detailed set of tumor factors find no difference between racial groups. This suggests that there may be differences in the tumors between African American and white women. This finding needs to be further explored. Studies of Asian and Hispanic women with DCIS point to their experience being similar to those of white women. In some cases, these women have superior outcomes relative to white and African American women. There is only one study reporting outcomes after DCIS diagnosis for Native American women and that study included only 82 subjects. Further work is needed to examine the outcomes of DCIS in this population.

Positive surgical margins are consistently associated with increased DCIS and invasive breast cancer recurrence. In general, larger tumors were associated with higher rates of local DCIS and invasive recurrence than smaller tumors. While labeled somewhat inconsistently, tumors assigned a higher pathological or nuclear grade (3) have consistently higher probability of local DCIS or invasive recurrence than those at intermediate or low grade (2 or 1). Comedo necrosis, a factor unique to DCIS, is strongly and consistently associated with poorer outcomes and increased risk of DCIS or invasive recurrence. In multiple reports from the same institution using a moderate sized cohort, the lack of calcification was strongly associated with DCIS or invasive carcinoma recurrence.

Few of the important markers of tumor aggressiveness in invasive breast cancer are well studied in DCIS. ER positivity has been reported to be linked with a decreased risk of recurrence in several small studies. The rate of ER testing, however, is quite low (20 percent). Ongoing trials of tamoxifen and aromatase inhibitors may contribute to more routine testing of ER status in the future.

DCIS is rarely tested for Her2 positivity, but, nonetheless has been linked to increased risk of recurrence in several small studies. The promise of treating Her2 positive tumors with trastuzumab is being studied in ongoing trials and points to the possibility that Her2 evaluation in women with DCIS might become more common.

Question 4

Whole breast radiation therapy following BCS is associated with a reduction of local DCIS or invasive carcinoma recurrence but has no impact on breast cancer mortality or total mortality. Both randomized and observational studies consistently reported a statistically significant decrease in local DCIS or invasive carcinoma associated with receiving whole breast RT after BCS. For example, the investigators from NSABP-17 reported that whole breast radiation therapy following breast conserving surgery was associated with a reduction of local DCIS or invasive carcinoma recurrence but no impact on breast cancer mortality or total mortality. While statistically significant, the actual population impact of the additional treatment is small—approximately 114 recurrences per 1,000 women treated would be avoided over 10 years through use of radiation. No trial has found a reduction in breast cancer or all cause mortality associated with the use of RT following BCS. RT did not eliminate the impact of adverse prognostic factors such as involved margins and tumor size.

While not studied in a randomized fashion, several observational studies comparing outcomes between mastectomy and BCS or BCS+RT found women undergoing mastectomy were less likely than women undergoing lumpectomy plus radiation to experience local DCIS or invasive recurrence. Women undergoing BCS alone were also more likely to experience a local recurrence than women treated with mastectomy. We found no study showing a mortality reduction associated with mastectomy over BCS with or without radiation. This lack of benefit is particularly striking since clinically larger, multicentric and more problematic tumors will be more likely to be treated with mastectomy than BCS with or without radiation.

Investigators from the NSABP-24 trial assessed the value of tamoxifen following BCS + RT for patients with DCIS and found that it reduces risk of recurrent DCIS or invasive carcinoma. The trial found that tamoxifen was associated with a 50 percent reduction in invasive ipsilateral and contralateral disease but had no impact on all-cause mortality. Adverse events were consistent with tamoxifen’s usual profile.

Clinical issues that are the subject of ongoing investigations are the value of aromatase inhibitors for preventing local DCIS or invasive recurrence or contralateral disease. Finally, trials are examining whether trastuzumab (herceptin) is effective in treating DCIS that is Her2 positive. These trials would assess the potential benefit for the 26 percent of women whose tumors are positive for this adverse prognostic indicator.

Ongoing trials are examining whether APBI is equivalent to whole breast irradiation for treating DCIS. There are three accelerated radiation protocols, all of which reduce the time needed to complete therapy from 6½ weeks for whole breast radiation therapy to between 1 and 5 days. The treatment is focused on the area immediately around the lumpectomy site, the area where recurrences are most likely to occur. Three approaches to APBI are currently being investigated: Intraoperative Radiotherapy (IORT)—1 day of treatment, Intracavitary Brachytherapy (MammoSite®)—5 days of treatment, and 3-D Conformal/External Beam Radiotherapy—5 days of treatment.

Other Issues

The relationship between DCIS and invasive breast cancer remains unclear. Ethical factors make it impossible to do any sort of natural experiment to assess the rate at which untreated DCIS devolves in invasive cancer. In some instances, one suspects that some DCIS may be underdiagnosed invasive cancer where the pathology sections simply missed the invasive area, but that cannot be the whole story. The arguments for a close relationship can be found in the similarity of risk factors for both the incidence of the diseases and their response to treatment.

From a clinical perspective it seems prudent to approach the conditions as one. Certainly screening makes no effort to distinguish them, nor should it. Given the rate of error in needle biopsies, presumptive DCIS should be treated as potential invasive cancer until a more definitive pathological sample is available. This strategy would re-enforce the enthusiasm for SLNB for DCIS cases.

The difference comes with treatment. The aggressiveness of treatment would presumably differ between DCIS and invasive breast cancer just as it presently does for invasive breast cancer by stage of diagnosis.

Ongoing Studies

Table 36 summarizes the ongoing studies as of May 2009. A number of clinical trials are underway that should shed important light on the diagnosis, evaluation, and treatment of DCIS.

Table 36. Ongoing studies related to DCIS registered in www.clinicaltrials.gov.

Table 36

Ongoing studies related to DCIS registered in www.clinicaltrials.gov.

Cover of Diagnosis and Management of Ductal Carcinoma in Situ (DCIS)
Diagnosis and Management of Ductal Carcinoma in Situ (DCIS).
Evidence Reports/Technology Assessments, No. 185.
Virnig BA, Shamliyan T, Tuttle TM, et al.

AHRQ (US Agency for Healthcare Research and Quality)

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