6 Ductal Carcinoma In Situ: a Modern Approach to Patient Management

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1 6 Ductal Carcinoma In Situ: a Modern Approach to Patient Management Laura Esserman and Catherine Park 6.1 Introduction The optimal management of ductal carcinoma in situ (DCIS) is not well established [1]. DCIS, a premalignant condition that represents a spectrum of diseases, is essentially characterized by the aberrant proliferation of ductal epithelial cells that do not have the capacity to invade past the basement membrane [2, 3]. Because of this, regardless of the heterogeneity of disease among individuals, DCIS is essentially curable with mastectomy [1]. However, it is unclear how many women who are diagnosed with DCIS would ever progress to invasive cancer even without treatment. Although there are some features of DCIS, such as tumor size, histologic grade, presence of comedo necrosis, margin status, and patient age that allow some degree of risk stratification for recurrence [4 8], our inability to distinguish indolent from aggressive disease often leads to more aggressive local treatment for DCIS than for invasive cancer [9, 10]. There are several acceptable treatments for DCIS, including lumpectomy, lumpectomy plus radiation therapy (RT) with or without hormonal intervention, and mastectomy [1]. Despite this range of options, there is no proven survival benefit with any treatment option. Retrospective comparisons made of patients undergoing mastectomy indicate that there may be a 1 2% survival benefit compared to patients undergoing lumpectomy with or without RT [11 14]. This very small difference may be due to those patients who recur with invasive disease or who had occult invasive disease at diagnosis. Even with breast-conservation surgery alone, without hormone therapy or radiation, the mortality ranges from less 1 to 2% depending on tumor size and grade [15]. In the event of a recurrence, patients are equally likely to have either DCIS or invasive cancer; it is the latter, however, that is life threatening. Thus, although patients should be counseled on their full risk of recurrence including risk of recurrent DCIS, the primary treatment goal should be to prevent the development of invasive cancer. Despite the negligible differences in survival, there are significant differences in the impact of therapeutic choices for each woman. Thus, shared decision-making, including a discussion about the range of options, is the preferred way to approach the clinical decision-making for patients and clinicians. Patients may frequently become confused because of the number of options they face and the variations in physician biases and thresholds for recommending treatment. To provide perspective, we recommend stating first that treatment choice is very unlikely to affect survival, but will have a potentially significant impact on

2 126 Ductal Carcinoma In Situ: a Modern Approach to Patient Management the risk for local recurrence. In this manner, individual patients can be involved in making the decision and their personal preferences considered. The most important message for any woman is that DCIS is not life-threatening, that the risk for disease progression is not imminent, and that she has plenty of time to learn, adjust, and make an informed decision. 6.2 Treatment Options Local Treatment Options Lumpectomy or Wide Excision Alone With or Without RT The randomized trial conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP), protocol B-17, demonstrated that radiation therapy after lumpectomy reduced the risk of recurrence of DCIS by 59% (combined ipsilateral breast recurrence was 27% vs 12% at 8 years, and 13% vs 3.9% for invasive cancer recurrence). The European Organization for Research and Treatment of Cancer (EORTC) Protocol reported similar findings in their cooperative randomized trial performed in Europe. From these results, it appears that all patients undergoing lumpectomy for radiation therapy (RT) would benefit from such treatments. However, depending on the starting risk of recurrence, which can be modified further by competing risks such as age and death from serious comorbid illness, some patients may actually benefit very little from treatment while, conversely, others may derive a large benefit. Indeed, an ongoing issue is to understand how to stratify risk and select the most appropriate candidates for RT and tamoxifen treatment. Efforts to address the use of RT after lumpectomy alone for patients with favorable features (small tumor size, low-intermediate grade, negative margins) are ongoing. Single-institution prospective series have been published in which a range of outcomes after very wide excision (margins of at least 1 cm) has been reported for DCIS. One single arm study from the Joint Center for Radiation Therapy [16] enrolled 158 women with favorable DCIS (size less than 2.5 cm, grade 1 2) receiving wide excision alone with a 1-cm margin in a prospective study with close observation. The results after 3.6 years (range years) of median follow-up have been reported in abstract form only. There were 13/158 patients who experienced a recurrence, yielding an 8.2% crude risk in local recurrences, which met the stopping rules of the study. Ninety-six percent of the lesions were detected mammographically, reflecting a screened population; however, 39% had necrosis in the specimen and 6% had some high-nuclear-grade tissue. Of the 13 local recurrences, 4 were invasive. Thus, the addition of radiation would have decreased the risk of invasive breast cancer recurrence from 4/158 to 2/158, decreasing the absolute risk of invasive recurrence by approximately 1.5%. Studies from Van Nuys indicate that women with very low risk, stratified according to tumor size, margins, grade, and comedo necrosis, indicate that there is a very low risk of recurrence, in the 5% range, for patients receiving wide excision alone, suggesting that wide ductal excision may be superior to radiation [17]. However, this result applies only to cases where the extent of DCIS

3 6.2 Treatment Options 127 is very limited and where it is possible to perform a wide excision. Two other efforts are ongoing to investigate a selected group of patients with low-risk features. One is a multi-institutional prospective randomized trial conducted by the Radiation Therapy Oncology Group (RTOG) comparing wide excision alone to wide excision with or without tamoxifen. The other is an Eastern Cooperative Oncology Group (ECOG) registry trial of low-risk women treated without radiation therapy. While randomized trials control for patient selection, surgical technique is often variable. The discrepancy in outcomes between randomized studies and the retrospective studies from the Van Nuys group indicate that there is role for standardizing surgical technique and pathologic assessment. The use of anatomical surgery for DCIS is supported by studies that demonstrate that DCIS is usually found to involve a single ductal tree, and wide excision may in fact functionally remove the ductal tissue at risk, if performed with this in mind. This hypothesis is supported by studies that demonstrate that DCIS recurrences almost always (over 90% of the time) occur in the same quadrant and are genetically identical [18]. Cancerous lesions that have loss of heterozygosity in adjacent histologically normal tissue have a higher risk of recurrence, supporting the concept of a cancerous field, or region of tissue at risk [19]. In addition, stereoarchitectural studies indicate that DCIS proliferation occurs along anatomically related branches of the mammary ductal system, further supporting this hypothesis [20, 21] Mastectomy Modified radical or total mastectomy is a very effective technique for reducing the risk of DCIS recurrence. If mastectomy is selected, RT is usually not indicated. The only exception is if there is palpable DCIS with high-grade, extensive necrosis and positive margins. There is very little data as to when these patients have a higher local recurrence rate, but these types of cases disproportionately represent the rare fatalities from DCIS. DCIS patients are ideal candidates for skin-sparing mastectomy with immediate reconstruction. Total skin-sparing mastectomy, including nipple sparing, with immediate reconstruction is also likely to be an excellent option if there is no involvement of the underlying nipple [22]. This technique removes all of the ductal tissue under the nipple, but preserves the skin, leaving the nipple and areolar skin, thus improving cosmesis by preserving the original shape of the breast and making the reconstructed breast more symmetric with the contralateral breast. Outcome studies are needed to determine whether the recurrence rates are equivalent to the non-skin-sparing approaches Treatment Options for Hormone-Responsive DCIS Tamoxifen has been shown to reduce the risk of invasive recurrences in women with cancers that express estrogen receptor (ER) [23] and to prevent the development of ER-positive disease [24]. In the NSABP B-24 trial, the use of tamoxifen was as-

4 128 Ductal Carcinoma In Situ: a Modern Approach to Patient Management sociated with a 30% reduction in risk of recurrence in all patients with DCIS after lumpectomy and radiation compared to placebo. A reanalysis of a subset of patients enrolled in this trial with available pathology specimens calculated the benefits of tamoxifen based on ER and progesterone receptor expression [25]. Consistent with its role in invasive cancers, tamoxifen was found to benefit only those patients who, on central pathology review, had ER-positive disease. There is very little data on the impact of tamoxifen in the treatment of DCIS after lumpectomy in the absence of RT. An international randomized trial from the UK designed to address this question found that tamoxifen alone after lumpectomy was not effective in reducing the risk of recurrences [26]. However, the results are difficult to interpret because when lack of accrual threatened to close the trial, patients were allowed to choose to receive RT or not or tamoxifen or not and then were randomized. There are other lines of indirect evidence, however, that lend credence to the efficacy of tamoxifen as a primary treatment [24], primarily in the prevention setting where tamoxifen decreases the risk of contralateral breast cancers, including DCIS. While tamoxifen is an approved part of the treatment for DCIS, it is associated with several side effects that may discourage women from taking it. The more serious side effects include the 1% additional risk of endometrial cancer in postmenopausal women, the very rare incidence of uterine sarcoma, and an increased risk of thromboembolic events primarily in women over the age of 60 years [24]. In addition, the most commonly reported reversible side effects include hot flashes and vaginal discharge. However, it is incumbent on physicians to remind patients that the majority will not experience any side effects. In the future, postmenopausal women may have other hormone treatment options that are associated with fewer side effects. Aromatase inhibitors have been approved as first-line hormonal therapy for invasive cancer. Two aromatase inhibitors, anastrozole and letrozole, are now approved for adjuvant therapy in postmenopausal women with hormone-receptorpositive disease [27, 28]. A randomized trial is currently ongoing (NSABP protocol B-35) to compare tamoxifen to anastrozole after RT. However, there is increasing interest in the use of aromatase inhibitors because of their reduction in ipsilateral and contralateral breast cancer and because of their favorable side-effect profile. Hence, while these are nonstandard treatments outside of a trial for women with DCIS, either could be considered if there was a contraindication for or side effects from tamoxifen. 6.3 Biomarkers of Disease and Outcome In randomized trials, although the overall decrease in relative risk with RT was substantial, subset analysis after pathologic review of the NSABP B-17 protocol demonstrated that a specific pathologic feature, comedo necrosis, modified the absolute benefit from RT, based on the risk of recurrence of disease [7]. In Table 6.1, we take the data from the NSABP B-17 trial to demonstrate the benefits of RT based on the presence of marked or moderate comedo necrosis (Fig. 6.1A) versus slight or absent

5 6.3 Biomarkers of Disease and Outcome 129 comedo necrosis (Fig. 6.1B). When we translate the underlying risk and the relative benefit into absolute benefit, we see that the absolute benefit is quite a bit more substantial (25 vs 7% at 5 years) or 27 versus 8% at 8 years for women with marked or moderate comedo versus absent or slight. In other words, the relative benefit of radiation is more than doubled for the patients with comedo (Table 6.1). The Kerlikowski, population-based study of 1,036 women who received lumpectomy alone for DCIS found that the presence of a palpable mass and high-grade histology were the only factors that were significantly associated with a higher risk of recurrence [15]. In this study, which followed patients for a median of over 80 months, high-grade histology was clearly a marker of increased risk of recurrence, especially invasive recurrence. Among women with high-grade lesions, at 5 years, there was a 28.9% risk of recurrence (11.8% invasive recurrence and 17.1% DCIS recurrence), compared to a 9.6% risk of recurrence among individuals with low-grade lesions (4.8% invasive, 4.8% DCIS). The Van Nuys index also supports Fig. 6.1 Two examples of ductal carcinoma in situ (DCIS) are shown at X power. a, on the left, shows a high-grade lesion with central necrosis and b, on the right, shows an intermediategrade solid lesion without evidence of necrosis Table 6.1 Ipsilateral breast recurrence rate at 5 and 10 years follow-up. Modified from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-17 and NSABP B-24 trials. Outcomes from NSABP B-17 are stratified by comedo necrosis. Rates of combined invasive and ductal carcinoma in situ (DCIS) recurrence 8 10 years after the initial diagnosis of DCIS are shown. Note that while there is some benefit from radiotherapy in both groups, the vast majority of patients without comedo necrosis derive relatively little benefit, either because 80% of the patients would not have developed a DCIS or invasive recurrence (lumpectomy alone), or because they progress despite radiotherapy (12%) Years of follow-up Comedo Lumpectomy Lumpectomy + radiotherapy 5 years Marked/Moderate 35% 10% 25% Slight/Absent 17% 10% 7% 8years Marked/Moderate 40% 13% 27% Slight/Absent 20% 12% 8% Absolute benefit of radiotherapy

6 130 Ductal Carcinoma In Situ: a Modern Approach to Patient Management the presence of comedo necrosis and high-grade lesions as significant factors associated with increase risk. Their index, based on size, margins, and grade/comedo necrosis indicates that if a patient has DCIS that has either high-grade lesions or extensive comedo necrosis (unless they have a very tiny lesion with greater than 1 cm margins), they are no longer low risk and therefore have a higher recurrence rate as well as benefiting from RT. The relative benefit of tamoxifen of 30% reduction in risk holds regardless of comedo necrosis. In the NSABP B-24 trial, where women who underwent lumpectomy and RT for DCIS were randomized to receive 5 years of tamoxifen or placebo, we see again that the presence of comedo accelerates the chance of recurrence: 2.7% per year (27/1,000 per year) versus 1.3% per year (13/1,000 per year). However, given that the benefits of tamoxifen are limited to the ER-positive subset and that many cases with significant comedo necrosis are ER negative, it is possible that the benefit of tamoxifen in the comedo group is underestimated because this group is likely to be enriched for ER-negative DCIS. Specific biomarkers, in this case comedo necrosis and ER, can provide real guidance for patients facing important decisions regarding the pros and cons of treatment and whose morbidity may outweigh the benefits in a significant proportion. This is by no means a complete assessment of the existing literature that evaluates the utility of other factors that have been used to stratify risk such as age, size of DCIS, and margin status. Each of these has been shown to be an independent predictor of risk in various studies [5 7], and may also be important in further identifying subsets of patients with very favorable biology or, conversely, those in whom RT and hormonal therapy are warranted. 6.4 Preventing Contralateral Breast Cancer Focusing on contralateral disease, a meta-analysis of nine breast cancer adjuvant trials conducted by the NSABP reported a cumulative risk of invasive breast cancer of 5.1% after 5 years, which was reduced to 1.9% with tamoxifen use [29]. In the NSABP B-24 trial, tamoxifen reduced the cumulative 5-year incidence of invasive contralateral breast cancer from 2.3% to 1.8%, and that of invasive ipsilateral breast cancer from 4.2% to 2.1%. The risk of developing contralateral breast cancer in the nonirradiated breast was nearly as high as the risk of developing ipsilateral breast cancer in the irradiated breast. Tamoxifen reduced the cumulative 5-year risk of DCIS by 80% in the contralateral breast (1.1% in the placebo group vs 0.2% in the tamoxifen group) compared to a reduction of 17% in the ipsilateral breast (5.1% in the placebo group vs 3.9% in the tamoxifen group) [30]. Thus, with the use of tamoxifen, the magnitude of the reduction in risk for DCIS was greatest in the contralateral breast, probably due to the beneficial effects of radiation in the ipsilateral breast. To date, no study has demonstrated a difference in mortality between lumpectomy and RT and lumpectomy alone. Although invasive cancer occurrences after treatment of lumpectomy can lead to metastatic disease and death [31], the low

7 6.5 Decision-Making Tools for Treatment of Ipsilateral DCIS 131 likelihood of this event suggests that the maximum difference in mortality between an aggressive (mastectomy or lumpectomy and RT) or less aggressive approach (lumpectomy) would be a difference of 1 2%, if any, even with a 20-year followup. A similarly small difference would be anticipated as a result of treatment with tamoxifen. 6.5 Decision-Making Tools for Treatment of Ipsilateral DCIS There are numerous of sources of data that inform us about the outcomes after various treatments for DCIS (Table. 6.2). However, what may be the most valuable for patients in guiding their individual decision-making is to provide a range of outcomes that would fit their particular situation, and which synthesizes the available data. Using the findings discussed in this chapter, we believe that the data support the use of decision guides based on comedo necrosis/grade and ER status. The first stratification in risk should be on the basis of the presence of either comedo or highgrade DCIS and secondarily on ER status (Tables 6.3 and 6.4). The other would include noncomedo or low-grade DCIS (Tables 6.5 and 6.6). Note that the absolute magnitude of benefit from RT in terms of invasive breast cancer occurrence is much higher in patients with comedo or high-grade lesions. There is still a range of possible outcomes even within this biologic separation. Other factors that are also known to modify risk include tumor size, surgical margins, and age, which may help to further stratify a patients risk. Larger lesions and younger age (< 40 years) would shift the expected outcomes toward the higher recurrence rates, and older age and smaller tumor size would shift the predictions to Table 6.2 University of California San Fransisco Carol Franc Buck Breast Care Center decision guide for women with DCIS showing estimated risks of recurrence over a follow-up of 8 10 years (no discrimination). The entire range of outcomes described in the literature, including the randomized trials and population-based and large cohort studies are represented here. ER Estrogen receptor, N/A not applicable Affected breast Opposite breast Overall survival Any recurrence cancer DCIS + Lumpectomy alone 5 40% 3 20% 5% % Lumpectomy and radiation 4 15% 2 10% 5% % Lumpectomy, radiation, and tamoxifen (if ER positive) 2 8% 1 15% 2.5% % Tamoxifen alone (if ER positive) N/A N/A 2.5% % Mastectomy < 1 2% < 1 1% 5% %

8 132 Ductal Carcinoma In Situ: a Modern Approach to Patient Management Table 6.3 Estimated risks of recurrence for DCIS over a follow-up of 8 10 years: moderate to marked comedo or high grade; estrogen receptor (ER) positive. The range of possible outcomes according to treatment options for patients with either moderate or marked comedo necrosis or high-grade DCIS stratified by ER-positive disease are represented here. These patients derive a significant reduction in invasive cancer recurrence from radiation than those with noncomedo, low- to intermediate-grade lesions (see Table 6.4) Affected breast Opposite breast Overall survival Any recurrence cancer DCIS + invasive Lumpectomy alone 28 40% 14 24% 5% % Lumpectomy and radiation 13 15% 7 9% 5% % Lumpectomy, radiation, and tamoxifen (if ER positive) 7 10% 4 6% 2.5% % Tamoxifen alone N/A N/A 2.5% % Mastectomy 1 2% 1% 5% % Table 6.4 Estimated risks of recurrence for DCIS over a follow-up of 8 10 years: moderate to marked comedo or high grade; ER negative. The range of possible outcomes according to treatment options for patients with either moderate or marked comedo necrosis or high-grade DCIS stratified by ER-negative disease are represented here. These patients derive a significant reduction in invasive cancer recurrence from radiation than those with noncomedo, low- to intermediategrade lesions (see Tables 6.5 and 6.6) Affected breast Opposite breast Overall survival Any recurrence cancer DCIS + invasive Lumpectomy alone 28 40% 14 24% 5% % Lumpectomy and radiation 13 15% 7 9% 5% % Mastectomy 1 2% 1% 5% % the lower limits for recurrence. As patients move to a range that provides the best estimate of risk, they can then put the risk of treatment into context, and hopefully determine with more accuracy, what their potential absolute benefit is. A goal for the future is to develop individually tailored decision aids, similar to those available for invasive breast cancer decision-making ( It is important for clinicians to emphasize that DCIS is not a cancer with metastatic potential. It is incumbent upon physicians to recognize the potential impact of therapy on patients who have indolent disease that will never progress. We believe that these decision guides can help put the impact of therapy into perspective [32].

9 6.6 Novel Therapies for Prevention 133 Table 6.5 Estimated risks of recurrence for DCIS over a follow-up of 8 10 years: noncomedo or low grade; ER positive. The range of outcomes for the available treatment options for patients with minimal or noncomedo necrosis or low- to intermediate-grade DCIS lesions are represented here. Note that radiation therapy has a relatively small impact on reducing the risk of invasive recurrence (1 4%) Affected breast Opposite breast Overall survival Any recurrence cancer DCIS + invasive Lumpectomy alone 5 20% 3 10% 5% % Lumpectomy and radiation 3 12% 2 6% 5% % Lumpectomy, radiation, and tamoxifen 2 5% 1 3% 2.5% % Tamoxifen alone (no data) 2 5% 2 3% 2.5% % Mastectomy < 1% < 1% 5% % Table 6.6 Estimated risks of recurrence for DCIS over a follow-up of 8 10 years: noncomedo or low grade; ER negative. The range of outcomes for the available treatment options for patients with minimal or noncomedo necrosis or low- to intermediate-grade DCIS lesions are represented here. Note that radiation therapy has a relatively small impact on reducing the risk of invasive recurrence (1 4%) Affected breast Opposite breast Overall survival Any recurrence cancer DCIS + invasive Lumpectomy alone 5 20% 3 10% 5% % Lumpectomy and radiation 3 12% 2 6% 5% % Mastectomy < 1% < 1% 5% % 6.6 Novel Therapies for Prevention Cyclooxygenase type 2 inhibitors, statins and tyrosine kinase inhibitors are being evaluated primarily for their roles in breast cancer prevention, but are also being considered as therapeutic interventions for trials for patients with DCIS. It is important that we identify agents that are useful in reducing the progression of ER-negative lesions and work to reduce the risk of progression of ER-positive lesions where tamoxifen and aromatase inhibitors are not sufficient. It is critical that new agents are developed with the idea that women with DCIS are, for the most part, healthy

10 134 Ductal Carcinoma In Situ: a Modern Approach to Patient Management and are at minimal risk of dying from breast cancer. Thus, novel agents introduced must be very safe and preferably have secondary health benefits. 6.7 Conclusions Treatment strategies and clinical trials that may elucidate the biology of disease and new therapies to prevent the progression of DCIS to invasive cancer are needed. Patients with DCIS have an excellent overall prognosis, and so it is critical not to introduce interventions with potentially adverse long-term consequences. Treatment for DCIS should balance two key goals: (1) maximal reduction of the risk of progression to invasive cancer, and (2) minimal risk to this group of healthy women who do not yet face the risks of metastasis and death associated with invasive cancer. RT appears to have the greatest impact on patients destined to develop early invasive recurrence (within 5 years). Our goal should be to better understand the biology of DCIS and develop early predictors of invasive recurrence, targeting predominantly those patients for therapeutic interventions such as RT. Early development of invasive cancer may be primarily in the comedo subset, as discussed in this chapter. In addition, patients with DCIS are at risk of developing contralateral breast cancer, and DCIS biology may provide important clues for cancer prevention [33]. References 1. Morrow, M. et al. Standard for the management of ductal carcinoma in situ of the breast (DCIS). CA Cancer J Clin 52, (2002). 2. Schnitt, S. J. & Connolly, J. L. Classification of ductal carcinoma in situ: striving for clinical relevance in the era of breast conserving therapy. Hum Pathol 28, (1997). 3. Allred, D. C., O Connell, P., Fuqua, S. A. & Osborne, C. K. Immunohistochemical studies of early breast cancer evolution. Breast Cancer Res Treat 32, 13 8 (1994). 4. Vicini, F. A. et al. Relationship between excision volume, margin status, and tumor size with the development of local recurrence in patients with ductal carcinoma-in-situ treated with breast-conserving therapy. J Surg Oncol 76, (2001). 5. Silverstein, M. J. et al. The influence of margin width on local control of ductal carcinoma in situ of the breast. N Engl J Med 340, (1999). 6. Hetelekidis, S. et al. Predictors of local recurrence following excision alone for ductal carcinoma in situ. Cancer 85, (1999). 7. Fisher, E. R. et al. Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) eight-year update of Protocol B-17: intraductal carcinoma. Cancer 86, (1999). 8. Jensen, R. A. & Page, D. L. Ductal carcinoma in situ of the breast: impact of pathology on therapeutic decisions. Am J Surg Pathol 27, (2003). 9. Ernster, V. L. Prophylactic mastectomy in women with a high risk of breast cancer. N Engl J Med 340, 1838; discussion 1839 (1999). 10. Ernster, V. L., Barclay, J., Kerlikowske, K., Grady, D. & Henderson, C. Incidence of and treatment for ductal carcinoma in situ of the breast. JAMA 275, (1996). 11. Harris, J. R. e. in Breast Dis (2000).

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