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. Nearly 65,000 new cases were expected in the United States in 2013. 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. The risk of breast cancer mortality 10 years after the treatment of DCIS is approximately 4%. 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.
The currently recommended treatment guidelines for DCIS include breast-conserving surgery plus radiation based on high-level evidence from clinical trials. 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. 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. In one recent analysis of adjuvant treatment trends, nearly one-half of 3,000 DCIS cases reviewed received breast-conserving surgery without radiation. 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. 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. 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).
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.
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. 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. 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. 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.
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