The Current Clinical Value of the DCIS Score

May 15, 2014

The DCIS Score provides clinically relevant information about personal risk that can guide patient discussions and facilitate shared decision making.

The management of ductal carcinoma in situ (DCIS) can be controversial. Widespread adoption of mammographic screening has made DCIS a more frequent diagnosis, and increasingly smaller, lower-grade lesions are being detected. DCIS is commonly treated with breast-conserving surgery and radiation. However, there is greater recognition that acceptable cancer control outcomes can be achieved for some patients with breast-conserving surgery alone, with radiotherapy reserved for those at higher risk of in-breast recurrence. The primary clinical dilemma is that there are currently no reliable clinicopathologic features that accurately predict which patients will have a recurrence, but risk stratification is an area of active research. Molecular profiling has the potential to assess recurrence risk based on the individual patient’s tumor biology and guide treatment decisions. The DCIS ScoreTM is a 12-gene assay intended to support personalized treatment planning for patients with DCIS following local excision. It provides information on local failure risk independent of traditional clinicopathologic features. Our group of expert breast surgeons and radiation oncologists met in December 2013 at the San Antonio Breast Cancer Symposium to discuss current controversies in DCIS management and determine the potential value of the DCIS Score in managing these situations. We concluded that the DCIS Score provides clinically relevant information about personal risk that can guide patient discussions and facilitate shared decision making.

Introduction

Ductal carcinoma in situ (DCIS) is characterized by the proliferation of neoplastic epithelial cells within the lumen of the breast ducts with an intact basement membrane. The diagnosis of DCIS was relatively uncommon before the widespread use of screening mammography, but today it represents approximately 20% of all neoplastic breast diagnoses.[1] Nearly 65,000 new cases were expected in the United States in 2013.[1] DCIS is a heterogeneous condition but has an excellent prognosis when treated. Although it is a nonobligate precursor of invasive ductal carcinoma, incompletely excised DCIS does not recur or become life-threatening in the majority of cases.[2] The risk of breast cancer mortality 10 years after the treatment of DCIS is approximately 4%.[3] In DCIS ≤ 2 cm in diameter, the risk of an ipsilateral breast event, either recurrent disease or invasive cancer, is 28.1% at 10 years and can be reduced roughly by one-half (to 12.9% at 10 years) with adjuvant radiation, although radiation has not been demonstrated to influence overall survival.[3]

The currently recommended treatment guidelines for DCIS include breast-conserving surgery plus radiation based on high-level evidence from clinical trials.[4] This approach to treatment can mean overtreatment of many women with a small DCIS (≤ 2 cm), given that wide excision alone appears to be effective for cancer control in the breast in more than 70% of cases at 10 years.[3] The National Comprehensive Cancer Network suggests that breast-conserving surgery without radiation is a reasonable option when the clinician and patient alike perceive individual risk to be low, but no recommendations are made regarding risk assessment.[4] In one recent analysis of adjuvant treatment trends, nearly one-half of 3,000 DCIS cases reviewed received breast-conserving surgery without radiation.[5] Observational studies indicate that receipt of radiation varies by demographic factors, such as age, race, and socioeconomic status, and geographic factors, such as treating institution, raising concerns that some patients at high risk of in-breast recurrence following excision are undertreated when radiation is omitted.[5-9] Risk stratification was identified as a top research priority at the National Institutes of Health’s State of the Science conference on DCIS held in 2009, yet we are still unable to accurately identify which patients are at highest risk for recurrence of DCIS or development of invasive cancer using clinicopathologic features alone.[10] Such knowledge is the foundation for individualized treatment planning, but until there is a reliable tool to predict patient outcomes, it is likely that both overtreatment and undertreatment will continue.

The Oncotype DX Breast Cancer Assay for DCIS, also known as the DCIS ScoreTM, is the first multigene diagnostic assay designed to support personalized decision making for patients with DCIS following local excision. The DCIS Score was validated using patient samples from Eastern Cooperative Oncology Group trial E5194, a prospective, multicenter, single-arm clinical trial that evaluated the rate of ipsilateral breast events in patients with DCIS treated with surgical excision without radiation.[11,12] The DCIS Score became available for clinical use in December 2011, and more than 1,000 patient samples were analyzed within its first year of commercial availability.[13] Because the DCIS Score quantifies the risk of ipsilateral breast events and invasive breast cancer, this complementary clinical tool can be used to further individualize risk assessments for patients with DCIS. However, questions remain regarding how and when to order the test and how to incorporate the results into clinical decision making. Our group, comprising breast surgeons and radiation oncologists with expertise in the treatment of DCIS, convened on December 14, 2013, during the San Antonio Breast Cancer Symposium in Texas to discuss key areas of controversy in the management of DCIS and to specifically identify clinical scenarios in which the DCIS Score could add value when determining and discussing treatment options with individual women with DCIS.

Overview of the Development and Validation of the DCIS Score

A multistep strategy was used to develop and validate the DCIS Score in accordance with the rigorous, prospective-retrospective design recommended by Simon et al.[12,14] Briefly, the DCIS Score was developed as a modification of the Oncotype DX® Recurrence Score®.[15-19] Because tamoxifen use is inconsistent in patients with DCIS, a modified algorithm was developed before the clinical validation study to predict local recurrence risk, regardless of subsequent tamoxifen administration, using data from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 study and a case-control study.[15,17,20] Seven genes that were purely predictive of recurrence risk and five reference genes were ultimately chosen (Figure 1). The score calculation algorithm is scaled from 0 to 100, and the result can be used as a continuous or categorical variable. The risk categories are defined as: DCIS Score < 39, low risk; DCIS Score 39 to 54, intermediate risk; DCIS Score 55 to 100, high risk. The cut points were determined before validation based on score distributions from an independent clinical site (Marin County Medical Center in California).[21]

Primary and secondary study objectives, analytic methodology, and the statistical plan were determined before initiation of the validation study. All available specimens were analyzed with the 12-gene Oncotype DX DCIS Score. The primary objective was to determine whether the continuous DCIS Score was statistically significantly associated with ipsilateral breast event risk, with tamoxifen use included as a time-dependent variable. Univariable and multivariable Cox models were used to determine which clinical and pathologic variables were statistically significantly associated with ipsilateral breast event risk and whether the DCIS Score was significant after adjustment for these variables.[12]

E5194 was chosen as an independent study for DCIS Score validation. This nonrandomized trial was designed to determine whether a combination of clinical and pathologic features could be used to identify a subset of patients at low risk for local failure without adjuvant radiation.[11] Initiated in 1997, the trial included two cohorts of patients with nonpalpable DCIS of ≥ 3 mm who underwent breast-conserving surgery and had microscopic margin widths of ≥ 3 mm. The first cohort enrolled patients with low- or intermediate-grade DCIS of ≤ 2.5 cm. The second cohort enrolled patients with high-grade disease of ≤ 1 cm. Hormone receptor status was not routinely measured throughout the study. However, in 2000, the protocol was amended to allow adjuvant tamoxifen based on the results of NSABP B-24.[22] By design, none of the patients received adjuvant radiation. The primary endpoint was the rate of ipsilateral breast events, defined as the occurrence of invasive cancer of any histology or DCIS in the treated breast. A total of 670 eligible patients had been enrolled when the study was terminated in 2002. With a median follow-up time of 6.3 years for all patients, the 5-year risk of an ipsilateral breast event was 6.1% in the low/intermediate-grade cohort and 15.3% in the high-grade cohort (Table 1).

The DCIS Score validation study included data from 327 patients (49%) with sufficient tissue for analysis. There were no differences in baseline characteristics of patients who were included and those who were not included, except for a small difference in tumor size. More patients who were included had tumors of 6 to 10 mm (48% vs 40%) or > 10 mm (21% vs 16%) compared with those who were not included. In the validation analysis, 46 patients had an ipsilateral breast event (n = 26 for DCIS; n = 20 for invasive cancer), and 10-year event rates were 14.6% for the low/intermediate-grade group and 19.0% for the high-grade group. The continuous DCIS Score was significantly associated with ipsilateral breast events, with and without adjustment for tamoxifen use (with adjustment: hazard ratio [HR] = 2.31; 95% confidence interval [CI], 1.15–4.49; P = .02; without adjustment [see Figure 2]: HR = 2.38; 95% CI, 1.19–4.60; P = .01), as well as invasive breast cancer risk (see Figure 2: HR = 3.68; 95% CI, 1.34–9.62; P = .01). Age, menopausal status, and tumor size were also significant factors for ipsilateral breast events in univariable analysis, while DCIS Score, tumor size, and menopausal status remained significant in multivariable analysis. The HR for the DCIS Score was unchanged when adjusted for tumor size and menopausal status, indicating that it provides independent, complementary information about risk. Notably, grade and comedonecrosis were not associated with ipsilateral breast event risk.

In the categorical analysis, the majority of patients scored in the low-risk category (n = 230); however, nearly 30% of patients, all of whom were enrolled in E5194 on the basis of low-risk clinicopathologic features, fell into the intermediate- or high-risk categories (n = 53 and n = 44, respectively). The DCIS Score risk category significantly quantified the 10-year risks of both ipsilateral breast events and invasive cancer (see Figure 2). The 10-year rates of ipsilateral events in the low-, intermediate-, and high-risk groups were 10.6%, 26.7%, and 25.9%, respectively (P = .006), and the 10-year rates of invasive breast cancer were 3.7%, 12.3%, and 19.2%, respectively (P = .003).

The validation study of the DCIS Score supported its commercial use in the United States for women with DCIS treated by local excision, with or without tamoxifen. A second validation study is currently under way to confirm the association of the DCIS Score with the risk of ipsilateral breast events. Secondary objectives include evaluation of the score in patients with narrower margins and in those with larger tumor size. An exploratory analysis of the ability of the DCIS Score to predict benefit from radiation will also be conducted. Additional data will come from several ongoing clinical utility and registry studies. One of these is a registry study of patients in the American Society of Breast Surgeons Mastery Program for whom DCIS Score results as well as clinicopathologic variables will be collected. The Athena network is currently conducting a large screening study in California that will track patients for decades. A DCIS Score will be obtained for all patients found to have DCIS. This registry study will provide important information about the natural history of DCIS for those who opt for watchful waiting as well as insights into chemoprevention for those who choose drug therapy over excision.[23] Additional implementation studies are under way to determine the impact of the DCIS Score on both provider recommendations and patient satisfaction with radiation treatment decisions.

Using the DCIS Score for Clinical Decision Making

The role of radiation therapy in the management of DCIS

Numerous studies and the overview analysis conducted by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) have shown that the use of radiation after breast-conserving surgery for DCIS reduces the risk of an ipsilateral breast event by 50% or more relative to breast-conserving surgery alone.[3,24-33] In the EBCTCG analysis for DCIS of ≤ 2 cm diameter, the risk of any ipsilateral breast event was decreased from 18.1% to 7.6% at 5 years, a 10.5% absolute risk reduction, and from 28.1% to 12.9% at 10 years, a 15.2% absolute benefit. There is no known subset of patients that does not obtain risk reduction with adjuvant radiation, regardless of age, margin status, tumor size, or grade.[3] Despite the large effect of radiotherapy in reducing in-breast recurrence after breast-conserving surgery for DCIS, and the fact that approximately one-half of all ipsilateral breast events are invasive cancers, overall survival and breast cancer–specific survival are the same with excision alone and excision followed by radiotherapy, which emphasizes the noninvasive nature of DCIS. The overall high survival rates for DCIS in general complicate decision making when it comes to adjuvant radiation. Radiation therapy delivery is expensive, burdensome, and associated with acute and long-term side effects in some patients. Many physicians, as well as patients, are interested in omitting radiation, as evidenced by recent data revealing that nearly one-half of all patients do not receive radiation after breast-conserving surgery for DCIS.[5] These findings raise an important question: Are the right patients receiving radiation?

To date, conversations with patients about risk reduction have been based on population data obtained from clinical trials. The DCIS Score is the first tool that individualizes risk assessment based on the unique biology of the patient’s DCIS. An economic analysis derived from the validation study also indicates that its use for identifying candidates for radiotherapy may be cost-effective relative to current practice.[34] Our group therefore discussed the role of the DCIS Score in this situation from two angles: (1) Can the DCIS Score currently be used to identify patients at high risk who would therefore be candidates for radiation? and (2) Alternatively, can it be used to identify patients who are at very low risk of recurrence if treated with breast-conserving surgery alone? If we consider a hypothetical cohort of 100 clinically low-risk patients treated universally with radiation vs treated with radiation based on intermediate or high DCIS Score, we see that using the DCIS Score has the potential to spare approximately 55 women from radiation that is likely to have little benefit (Table 2). On the other hand, radiotherapy administration is not universal following excision of DCIS. As a result, some women in whom radiotherapy is omitted are undertreated and thereby placed at unnecessary risk for invasive breast cancer. It is therefore equally desirable to find tools that allow us to safely omit radiation and to ensure that patients receive radiation when appropriate.

One practical way to use the DCIS Score at the current time is to help patients understand their individual risk of ipsilateral breast recurrence events and the likelihood that the recurrence is invasive breast cancer. This information could affect or reassure their decision making about adjuvant radiation. Patients with a lower risk of recurrence may be candidates for, and feel comfortable receiving, more conservative treatment approaches, while those with a higher risk of recurrence may be candidates for, and may be comfortable receiving, more aggressive treatment. Several in our group currently discuss risk with their patients relative to an average woman’s risk of developing breast cancer to provide context. As shown in Table 3, we can create visual aids using population data and reasonable data extrapolations for DCIS along with tools such as the Gail model for estimating risk in an unaffected woman with similar demographics. The Gail model uses the following clinical variables to generate individual invasive breast cancer risk within the next 5 years and up to age 90: current age, age at menarche, age at first live birth, number of first-degree relatives with breast cancer, number of previous breast biopsies, whether any breast biopsy has shown atypical hyperplasia, and race.[35] It has been validated in several racial groups, although it may underestimate risk in African-American women who have undergone several biopsies, and it needs to be validated in Hispanic women.[35] Nonetheless, when applicable, the Gail model results provide a context for the interpretation of risk in an individual and how the diagnosis of DCIS alters that risk.

For example, consider a hypothetical case: our patient is a 55-year-old white woman who was 11 years old at menarche. She had her first child at age 32 years, and her mother received a diagnosis of breast cancer 10 years ago. She had one previous breast biopsy, which showed atypical ductal hyperplasia (ADH), but she has not received a diagnosis of DCIS or lobular carcinoma in situ. Compared with the “average” woman who has a 5-year breast cancer risk of 1.5%, this patient has a risk of 6% according to the Gail model. How would these estimates change if she had DCIS instead of ADH? Let us imagine this patient has an estrogen receptor (ER)–positive, 1-cm, grade 3 DCIS treated with breast-conserving surgery with surgical margins cleared by several millimeters. We could estimate her risk using data from clinical trials and the EBCTCG overview and see a range of estimates for the next 5 and 10 years (Table 3). Now let us determine her individualized risks for both an ipsilateral breast event and invasive breast cancer based on a DCIS Score of 19, which places her into the low-risk stratum. As shown in Figure 3, our patient with DCIS has a 12% risk of any ipsilateral breast event and a 5% risk of invasive breast cancer during the next 10 years based on her DCIS Score. Comparing 5-year with 10-year risk data (Table 3), we see that her risk of invasive disease is not much greater than that of the “average” woman without DCIS, and it is similar to that of the woman with ADH, neither of whom would be radiation candidates. Notice, too, that her risk is substantially lower than the 10-year population estimate from the EBCTCG overview, shown in Table 3. In this case, the clinician and patient alike may opt to omit radiation or feel reassured when making this choice based on the relatively low risk of an ipsilateral event or invasive breast cancer. Conversely, had the DCIS Score indicated a relatively high risk, a different decision may have been reached based on the physician’s and patient’s levels of risk tolerance.

Determining adequate margin size

Another area of controversy is defining “adequate” margin width. Surgical margin width is an important determinant of local failure in DCIS. A positive margin is associated with higher risk; however, the definition of a negative and/or adequate surgical margin remains under debate.[4,10] There is general concern that a margin of < 1 mm is inadequate and may be associated with a higher likelihood of recurrence, while a goal of consistently obtaining margins of > 10 mm will lead to an increase in surgical site deformities but will not reduce recurrence risk.[4] A margin width of at least 2 mm may be required for patients who undergo breast-conserving surgery plus radiation; however, the optimal margin width for breast-conserving surgery without radiation remains to be determined.[10,36] The issue regarding margins is especially problematic for patients with DCIS because DCIS margins are more difficult to assess pathologically as a result of skip lesions and morphologic overlap with ADH. Because this issue remains controversial, the decision to perform a re-excision in patients with “inadequate” margins varies significantly in clinical practice.

Our group discussed the potential role of the DCIS Score in assisting with re-excision decisions. We acknowledge that the DCIS Score has not been specifically studied for this clinical application. Nevertheless, we identified a few scenarios in which it could be informative. For example, in the case of a patient with narrow margins, the DCIS Score could be helpful for the clinical choice between radiation and re-excision. If the margin is < 3 mm, knowledge of the DCIS Score could influence treatment decisions. For example, a patient with low- or intermediate-grade disease who wishes to avoid radiotherapy would generally be recommended for re-excision to achieve a margin width of at least 3 mm based on the E5194 data for observation after excision. A high DCIS Score in this situation, however, would mean that the patient avoids unnecessary re-excision because radiotherapy is indicated and surgical margins of 1 to 2 mm can be sufficient when radiation therapy is intended.

Surgical decision making: mastectomy vs breast-conserving surgery plus radiation

Historically, mastectomy was the initial treatment method for DCIS in the pre-mammography era, when it was typically diagnosed as a large, palpable mass. Mastectomy reduces the risk of local failure to < 1% at 5 years.[37] However, large clinical trials such as NSABP B-17 and European Organisation for Research and Treatment of Cancer (EORTC) 10853 demonstrated that breast-conserving surgery plus radiation is an acceptable treatment option for many patients with DCIS. Indeed, the goals of DCIS treatment today typically include allowing the patient to keep her breast, decreasing the risk of an invasive breast cancer recurrence, and achieving good cosmesis and a good quality of life. Approximately 70% of patients today undergo breast-conserving surgery, with the remaining 30% undergoing mastectomy because of medical necessity or patient choice.[38] Mastectomy rates vary by geographic region and have increased slightly in recent years, including rates of prophylactic contralateral mastectomy for DCIS, which were found to have risen 150% from 1998 through 2005 in a recent Surveillance, Epidemiology, and End Results (SEER) analysis.[39] Increasing mastectomy rates may be due to improved reconstructive outcomes available today and the widespread use of magnetic resonance imaging; however, some patients may be choosing aggressive surgery because of inaccurate risk perception and anxiety.[40]

Our group discussed whether the risk estimates provided by the DCIS Score can be used to influence surgical treatment choice. We acknowledge that the DCIS Score has not been studied for this specific clinical application, but some in the group could envision clinical scenarios in which a DCIS Score might influence a surgeon’s decision making. The turnaround time for the DCIS Score is generally 10 to 14 days. The DCIS Score can be determined from a core biopsy specimen, and if a surgeon orders the test on a biopsy sample, the results are available to inform the discussion of subsequent surgical options. It is conceivable that a low DCIS Score could reassure a low-risk patient who initially opted for mastectomy to avoid radiation that breast-conserving surgery without radiation is a reasonable alternative likely to result in a low risk of invasive breast cancer. On the other hand, a high DCIS Score could be informative in a patient’s decision to choose mastectomy, particularly if the score indicates a high likelihood of invasive recurrence and she is disinclined to receive radiation. This case raised concerns for several in the group that the DCIS Score used in this fashion would contribute to overtreatment with mastectomy, particularly because it has not been fully studied for its ability to predict radiotherapy benefit.

Radiation Therapy Oncology Group (RTOG) study 9804 randomized a group of patients with DCIS, who were similar to the low-risk cohort enrolled in E5194, to observation vs breast radiotherapy after breast-conserving surgery. At 7 years’ median follow-up, the in-breast recurrence rate was 6.7% with observation alone vs 0.9% with radiotherapy.[24] The very low event rate in the radiotherapy arm of RTOG 9804 supports the finding that radiotherapy is effective in those with a high risk of DCIS recurrence, as we would anticipate a similar spread of DCIS Scores in the RTOG population as was seen in the E5194 group. Therefore, some in our group asserted that a high DCIS Score in a patient who is otherwise a good candidate for breast conservation should indicate the need for adjuvant radiotherapy, not mastectomy. Furthermore, patients who are adamantly opposed to or fearful of radiation at diagnosis often accept treatment after consultation with a radiation oncologist who discusses the risks and benefits of radiation. If the DCIS Score were used to determine surgical choice before consultation with the radiation oncologist, some women may opt for mastectomy before receiving thorough education about their options. Moreover, it can be confusing to patients to hear different messages from different disciplines about the need for and side effects from radiation. A major theme that emerged from this discussion was the need for multidisciplinary collaboration and balanced discussion about the potential morbidity and risks of both local failure and radiation. Ideally, a multidisciplinary team would determine when to order a DCIS Score and work together to present a consistent discussion of the results with the patient.

The role of adjuvant tamoxifen

Tamoxifen has been shown to reduce local recurrence as well as contralateral disease and is recommended for patients with ER-positive tumors.[4] NSABP B-24 demonstrated that this approach significantly reduces the risk of subsequent ipsilateral and contralateral breast cancers in patients with ER-positive DCIS.[22,41] Most cases of DCIS are ER-positive, yet the use of adjuvant tamoxifen is variable in clinical practice, and many patients do not complete treatment.[42-44] Up to one-third of patients who start endocrine therapy for breast cancer discontinue it within 3 years, and fewer than 40% of older women with ER-positive DCIS complete the fifth year of prescribed tamoxifen.[43,45] Many women are therefore not receiving or completing a treatment with proven benefit.

Our group discussed whether the DCIS Score could be used to influence discussions about adjuvant tamoxifen for DCIS. According to the validation study, the association of the DCIS Score with ipsilateral breast event risk was seen with or without tamoxifen treatment. However, the study did not evaluate whether the DCIS Score predicts benefit from tamoxifen. At the current time, because the DCIS Score provides individualized risk information, the results could be used to encourage compliance with adjuvant tamoxifen when risk is high or to reassure a low-risk patient with intolerable side effects that early discontinuation is not unreasonable. These conversations would not necessarily warrant ordering the DCIS Score on their own, but if the score is available, it may provide additional context when discussing risk reduction and the risks and benefits of adjuvant tamoxifen.

Conclusions

The DCIS Score is the first clinically validated genomic assay for DCIS that provides a patient with an individualized prediction of her 10-year risk of local failure after breast-conserving surgery, based on the unique biology of her individual disease. It offers biological information that can be used in addition to patient age, extent of DCIS, and margin of excision to aid in clinical decisions. It is a bidirectional tool, meaning that when placed into clinical context, it has the potential to inform decisions about when certain treatments are needed as well as when they might be safely omitted. A major caveat, however, is that at the current time, the DCIS Score is best used for patients who have a similar profile to those included in the E5194 validation study. Ongoing research will delineate its ability to predict radiation benefit as well as local failure risk in patients with clinical features that were underrepresented in or excluded from E5194. Such results may extend the future applicability of its use, even in patients who may choose watchful waiting for low-risk DCIS.

The use of the DCIS Score does not replace the need for careful consideration and thoughtful discussions with our patients. Instead, it can be used by clinicians from multiple disciplines, including surgeons, radiation oncologists, and medical oncologists, to augment and inform those conversations and empower women to make treatment choices that reflect their personal level of risk tolerance (Table 4). Personal thresholds of health risk tolerance differ widely among patients according to other health factors, and it is essential that each patient has the opportunity to determine her own level of risk tolerance when making treatment decisions, particularly when there is little impact on mortality. The DCIS Score assists both patients and clinicians in achieving this goal by providing a personalized risk estimate that is more meaningful to the individual patient than population estimates derived from clinical trials.

Acknowledgments:Medical writing support was provided by Lori K. Pender, PharmD, MPH, and WC Communications, LLC, Wyckoff, New Jersey, and funded by Genomic Health, Inc.

References:

1. DeSantis C, Ma J, Bryan L, Jemal A. Breast cancer statistics, 2013. CA Cancer J Clin. 2014;64:52-62.

2. Sanders ME, Schuyler PA, Dupont WD, Page DL. The natural history of low-grade ductal carcinoma in situ of the breast in women treated by biopsy only revealed over 30 years of long-term follow-up. Cancer. 2005;103:2481-4.

3. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast. J Natl Cancer Inst Monogr. 2010;2010:162-77.

4. National Comprehensive Cancer Network (US). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Breast Cancer version 3.2013 [Internet]. Fort Washington, Pa: National Comprehensive Cancer Network; 2013. [Updated 2013 May 3; cited 2013 October 17.] Available at: http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf.

5. Haque R, Achacoso NS, Fletcher SW, et al. Treatment of ductal carcinoma in situ among patients cared for in large integrated health plans. Am J Manag Care. 2010;16:351-60.

6. Baxter NN, Virnig BA, Durham SB, Tuttle TM. Trends in the treatment of ductal carcinoma in situ of the breast. J Natl Cancer Inst. 2004;96:443-8.

7. Joslyn SA. Ductal carcinoma in situ: trends in geographic, temporal, and demographic patterns of care and survival. Breast J. 2006;12:20-7.

8. Buchholz TA, Theriault RL, Niland JC, et al. The use of radiation as a component of breast conservation therapy in National Comprehensive Cancer Network Centers. J Clin Oncol. 2006;24:361-9.

9. Zujewski JA, Harlan LC, Morrell DM, Stevens JL. Ductal carcinoma in situ: trends in treatment over time in the US. Breast Cancer Res Treat. 2011;127:251-7.

10. Allegra CJ, Aberle DR, Ganschow P, et al. National Institutes of Health State-of-the-Science Conference Statement: Diagnosis and Management of Ductal Carcinoma In Situ, September 22–24, 2009. J Natl Cancer Inst. 2010;102:161-9.

11. Hughes LL, Wang M, Page DL, et al. Local excision alone without irradiation for ductal carcinoma in situ of the breast: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009;27:5319-24.

12. Solin LJ, Gray R, Baehner FL, et al. A multigene expression assay to predict local recurrence risk for ductal carcinoma in situ of the breast. J Natl Cancer Inst. 2013;105:701-10.

13. Tan V, Bailey H, Tsiatis A, et al. The Oncotype DX DCIS Score and quantitative gene expression for ER, PR, and HER2: 1,071 patients. St. Gallen Conference 2013; Abstract P147.

14. Simon RM, Paik S, Hayes DF. Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst. 2009;101:1446-52.

15. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351:2817-26.

16. Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24:3726-34.

17. Habel LA, Shak S, Jacobs MK, et al. A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients. Breast Cancer Res. 2006;8:R25.

18. Dowsett M, Cuzick J, Wale C, et al. Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen: a TransATAC study. J Clin Oncol. 2010;28:1829-34.

19. Albain K, Barlow WE, Shak S, et al; Breast Cancer Intergroup of North America. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol. 2010;11:55-65.

20. Mamounas E, Tang G, Fisher B, et al. Association between the 21-gene recurrence score assay and risk of locoregional recurrence in node-negative, estrogen receptor-positive breast cancer: results from NSABP B-14 and NSABP B-20. J Clin Oncol. 2010;28:1677-83.

21. Baehner FL, Yoshizawa CN, Butler SM, et al. The development of the DCIS Score: scaling and normalization in the Marin Medical Laboratories cohort. Poster presented at the American Society of Clinical Oncology Breast Cancer Symposium; September 2012; San Francisco, Calif. Abstract 190.

22. Fisher B, Dignam J, Wolmark N, et al. Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet. 1999;353:1993-2000.

23. Peres J. DCIS test helps filter at-risk patients. J Natl Cancer Inst. 2012;104:1853-5.

24. McCormick B. RTOG 9804: a prospective randomized trial for “good risk” ductal carcinoma in situ (DCIS), comparing radiation (radiation) to observation (OBS). J Clin Oncol. 2012;30(suppl):Abstract 1004.

25. Fisher B, Costantino J, Redmond C, et al. Lumpectomy compared with lumpectomy and radiation therapy for the treatment of intraductal breast cancer. N Engl J Med. 1993;328:1581-6.

26. Fisher B, Dignam J, Wolmark N, et al. Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B 17. J Clin Oncol. 1998;16:441-52.

27. Fisher B, Land S, Mamounas E, et al. Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the National Surgical Adjuvant Breast and Bowel Project experience. Semin Oncol. 2001;28:400-18.

28. Houghton J, George WD, Cuzick J, et al; UK Coordinating Committee on Cancer Research; Ductal Carcinoma in situ Working Party; DCIS trialists in the UK, Australia, and New Zealand. Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia, and New Zealand: randomised controlled trial. Lancet. 2003;362:95-102.

29. Julien JP, Bijker N, Fentiman IS, et al. Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: first results of the EORTC randomised phase III trial 10853. EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. Lancet. 2000;355:528-33.

30. Bijker N, Meijnen P, Peterse JL, et al. Breast-conserving treatment with or without radiotherapy in ductal carcinoma-in-situ: ten-year results of European Organisation for Research and Treatment of Cancer randomized phase III trial 10853-a study by the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. J Clin Oncol. 2006;24:3381-7.

31. Emdin SO, Granstrand B, Ringberg A, et al; Swedish Breast Cancer Group. SweDCIS: radiotherapy after sector resection for ductal carcinoma in situ of the breast. Results of a randomised trial in a population offered mammography screening. Acta Oncol. 2006;45:536-43.

32. Ringberg A, Nordgren H, Thorstensson S, et al. Histopathological risk factors for ipsilateral breast events after breast conserving treatment for ductal carcinoma in situ of the breast-results from the Swedish randomised trial. Eur J Cancer. 2007;43:291-8.

33. Holmberg L, Garmo H, Granstrand B, et al. Absolute risk reductions for local recurrence after postoperative radiotherapy after sector resection for ductal carcinoma in situ of the breast. J Clin Oncol. 2008;26:1247-52.

34. Alvarado MD, Harrison BL, Solin LJ, Ozanne EM. Cost-effectiveness of gene expression profiling for ductal carcinoma-in-situ (Oncotype DCIS Score). Presented at CTRC-AACR San Antonio Breast Cancer Symposium; December 2012; San Antonio, Tex. Abstract P-5-15-01.

35. National Cancer Institute (US). Breast cancer risk assessment tool [Internet]. Bethesda, Md: US Dept of Health and Human Services, National Institutes of Health. [Updated 2011 May 6; cited 2014 January 5.] Available at: http://www.cancer.gov/bcrisktool/about-tool.aspx#gail.

36. Dunne C, Burke JP, Morrow M, Kell MR. Effect of margin status on local recurrence after breast conservation and radiation therapy for ductal carcinoma in situ. J Clin Oncol. 2009;27:1615-20.

37. Owen D, Tyldesley S, Alexander C, et al. Outcomes in patients treated with mastectomy for ductal carcinoma in situ. Int J Radiat Oncol Biol Phys. 2013;85:e129-34.

38. Hwang ES. The impact of surgery on ductal carcinoma in situ outcomes: the use of mastectomy. J Natl Cancer Inst Monogr. 2010;2010:197-9.

39. Tuttle TM, Jarosek S, Habermann EB, et al. Increasing rates of contralateral prophylactic mastectomy among patients with ductal carcinoma in situ. J Clin Oncol. 2009;27:1362-7.

40. Partridge A, Adloff K, Blood E, et al. Risk perceptions and psychosocial outcomes of women with ductal carcinoma in situ: longitudinal results from a cohort study. J Natl Cancer Inst. 2008;100:243-51.

41. Allred DC, Anderson SJ, Paik S, et al. Adjuvant tamoxifen reduces subsequent breast cancer in women with estrogen receptor-positive ductal carcinoma in situ: a study based on NSABP protocol B-24. J Clin Oncol. 2012;30:1268-73.

42. Bailes AA, Kuerer HM, Lari SA, et al. Impact of race and ethnicity on features and outcome of ductal carcinoma in situ of the breast. Cancer. 2013;119:150-7.

43. Virnig BA, Torchia M, Jarosek SL, et al. Use of endocrine therapy following diagnosis of ductal carcinoma in situ or early invasive breast cancer. Data Points # 14 (prepared by the University of Minnesota DEcIDE Center, under Contract No. HHSA29020100013I). Rockville, Md: Agency for Healthcare Research and Quality; August 2012. AHRQ Publication No. 12-EHC093-EF.

44. Nassar H, Sharafaldeen B, Visvanathan K, Visscher D. Ductal carcinoma in situ in African American versus Caucasian American women: analysis of clinicopathologic features and outcome. Cancer. 2009;115:3181-8.

45. Burstein HJ, Prestrud AA, Seidenfeld J, et al; American Society of Clinical Oncology. American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol. 2010;28:3784-96.