Introduction
Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer that comprises up to 25 % of mammographically detected breast cancers [
15]. The goals of treatment are to minimize the risk of local recurrence (LR) and invasive breast cancer while maximizing breast preservation. Most women with newly diagnosed DCIS will be treated with breast-conserving surgery (BCS) with or without radiation treatment (RT). Randomized trials have demonstrated that adding RT after surgical excision reduces the relative risk of LR by ~50 % [
7,
8,
11,
14,
16,
17,
19,
38,
42]. However, only one-half of DCIS patients treated by BCS receive RT, perhaps reflecting clinicians’ assumption that women at low risk of recurrence following treatment by BCS alone can be accurately identified [
6,
20,
22]. To date, reproducible and reliable methods using clinico-pathologic features to identify patients at low risk of LR following BCS alone have not been established and there is a need to improve individualized treatment decisions to minimize both under and over treatment [
1,
9,
21,
35,
37,
45,
46]. The 2009 National Institutes of Health State-of-the-Science Conference included the recommendation that future research on DCIS focus on the development and validation of risk stratification models to optimize treatment recommendations for each individual diagnosed with DCIS [
1].
The Onco
type DX
® DCIS Score is a multigene expression assay for DCIS patients that generates individualized estimates of 10-year risk of any LR (DCIS or invasive) and invasive LR following treatment by BCS alone [
39]. The DCIS Score is generated from an algorithm that includes 12 (seven cancer related and five reference genes) of the 21 genes in the Recurrence Score assay [
30]. The continuous DCIS Score was shown to predict an individual’s risk of LR in the Eastern Cooperative Oncology Group (ECOG) E5194 prospective cohort study of low-risk DCIS treated by BCS alone [
39]. However, participants in ECOG 5194 were highly selected for having DCIS with an expected low risk of LR. Additional data from a diverse population of women with DCIS treated by BCS alone is desired to confirm the prognostic ability of the DCIS Score. The objective of this study is to evaluate if the DCIS Score is an independent predictor of LR in a population of individuals with DCIS treated with BCS alone.
Discussion
This study validates that the DCIS Score is significantly associated with the risk of LR (DCIS or invasive) in a population of patients diagnosed with pure DCIS treated with BCS alone with negative margins. We also found the DCIS Score is associated with the risk of invasive LR and DCIS LR and provides independent information on the risk of LR in individuals selected for treatment by BCS alone.
Most women diagnosed with DCIS will be candidates for BCS. The decision to recommend additional treatment such as radiation relies on estimates of the baseline risk of LR following treatment by BCS alone. For individuals estimated to have low LR risk, guidelines include the option for treatment by BCS alone; however, the ability to identify individuals at low risk of recurrence after treatment by BCS has been inconsistent. Current clinico-pathologic criteria do not reliably identify individuals with a low risk of LR [
29]. As a result, studies report that 30–50 % of individuals with DCIS are treated by BCS alone including some individuals with higher risk DCIS who do not meet the eligibility criteria of the ECOG 5194 or RTOG 9804 clinical trials for low-risk DCIS [
6,
22,
23,
32,
43]. In E5194 the 10-year LR rate among cases with low- or intermediate-grade DCIS and tumor size ≤ 2.5 cm was 14.6 and 19.0 % for those with small (≤1 cm) high-grade DCIS [
39]. Our population-based cohort includes individuals with confirmed pure DCIS selected for treatment by BCS alone and despite having lower risk features compared to those treated with RT, the 10-year risk of LR was 19.2 % demonstrating that clinico-pathologic criteria alone are insufficient to reliably identify individuals with a low risk of recurrence [
32].
Individuals in our population cohort were not as highly selected as those in the ECOG E5194 study; for example, 32 % had high-grade DCIS, 45 % had margin width between 1 and 3 mm. Despite these differences, the risks of LR in each pre-specified DCIS risk group were remarkably similar. The 10-year rates of LR for cases with low, intermediate or high scores were 12.7, 33.0, and 27.8 % compared to 10.6, 26.7 and 25.9 % reported in the E5194 analysis, respectively. These findings validate the DCIS Score as a predictor of LR in a more diverse, population-based cohort compared to participants of the E5194 study.
The DCIS Score was not strongly correlated with age at diagnosis, or pathologic features of DCIS. On multivariable analysis, other factors associated with the development of LR include the presence of multifocality, tumor size, age <50 years at diagnosis and subtype. Nuclear grade and comedo necrosis were not independent predictors of LR on multivariable analysis after adjustment for other characteristics. The significance of nuclear grade as a predictor of LR has not been consistently identified in past studies [
10,
26,
39]. This may be related to the correlation of grade with other pathological features, variability of grading systems, inter-observer variability, or heterogeneity of grade within a DCIS lesion [
4,
18,
28,
39].
There was consensus among the expert breast pathologists involved in this study to a priori define the presence of multifocal DCIS as the presence of at least two foci of DCIS separated by at least 5 mm [
36]. In a previous analysis based on an institutional cohort, we found that the presence of multifocal DCIS was an independent predictor of LR [
34]. We used the same definition in order to evaluate the impact of multifocality on the risk of LR in the population cohort. Using the predefined definition, 20 % of patients in the population cohort had multifocal DCIS. The 10-year risk of LR was 33.6 % for those with multifocality compared to 15.5 % for those without multifocal disease (adjusted HR 1.97; 95 % CI 1.27, 3.02;
P = 0.003). The reasons why individuals with multifocal DCIS experienced a higher risk of LR are unclear. It is possible that the presence of multifocality is associated with a greater burden of residual disease or it may be a marker of molecular heterogeneity [
3]. Among individuals without multifocality, the 10-year risk of LR among individuals with a low DCIS score was 9.7 % compared to 27.1 and 27.0 % for those with intermediate and high risk scores, respectively.
There are noteworthy clinical implications regarding our findings. Currently, the eligibility criteria for the E5194 and RTOG 9804 studies is used by clinicians to identify individuals with an expected low risk of LR following BCS (age > 50 years, nuclear grade 1 or 2, margins > 3 mm). For these women the role of routine radiation continues to be debated. Our results suggest that the DCIS Score can be of clinical utility particularly for individuals with low-risk features of DCIS to identify those at higher risk of recurrence who may benefit from further treatment. In addition, the DCIS Score provides individualized estimates of recurrence risk. This can help clinicians and patients better weigh recurrence risks against the potential benefits and toxicities of treatment.
The present study has several notable strengths. The study cohort is population-based and includes a more diverse population of individuals with DCIS selected for treatment by BCS alone. We performed an extensive, systematic pathologic review by expert breast pathologists using contemporary classifications to confirm the diagnosis of pure DCIS and a rigorous, predefined statistical analytical plan, including pre-specified cut-points for the DCIS Score and study objectives. We applied the same pre-specified cut-points for the DCIS Score used in the E5194 analysis and found that the DCIS Score is valid in a population of women with DCIS. The low-risk group appears to have a lower risk of LR than those in the intermediate or high-risk group (HR 0.53, 95 % CI 0.34, 0.80) (the study was not powered to evaluate difference between the intermediate and high-risk group). In addition, for the low-risk group, we did not observe a lower risk of LR with lower cut-points. We did observe a significant decrease in the rate of LR over time. However, for each time period, individuals in the low-risk DCIS Score group had a significantly lower risk of LR than those in the intermediate or high-risk groups. There was no interaction between the DCIS Score and year of diagnosis and the DCIS Score remained significantly associated with the risk of LR on multivariable analysis adjusting for year of diagnosis. The 10-year risk LR among individuals treated in year 2000–2003, with median follow-up interval was 7.9 years, was 12.1 %; for those in the low-risk DCIS Score group treated during this time period without multifocality, the 10-year risk of LR was 5.8 % (2.9–11.3 %) compared to 20.7 and 22.4 %, (P = 0.03) for the intermediate and high-risk DCIS Score groups.
The study has several potential limitations. Patients were not randomized and were selected for treatment by BCS alone based on clinico-pathologic features and patient preference. During the time interval of this study, many pathology reports lacked tumor size and resection margin width information [
31,
40]. Therefore, margin width and tumor size data were incomplete. In addition, data on clinical presentation or family history of breast cancer which may predict for LR were not available [
24]. Tamoxifen utilization during the time period of this study was limited. Complete data on tamoxifen usage (in younger women) was not available. Among women older than 65 years, only 17 % received tamoxifen and compliance was not available. However, 95 % of cases treated with BCS alone had ER-positive DCIS and therefore slightly lower event rates might be expected with tamoxifen administration [
2,
5,
25].
In summary, we confirm that the DCIS Score independently predicts the risk of LR in a population of individuals with DCIS who were treated with BCS. The DCIS Score quantifies individualized risk of LR which can help guide treatment recommendations and help reduce over treatment for women at low risk and under treatment for those with a significant risk of recurrence who may benefit from further treatment.
Acknowledgments
This work was supported in part by funding from the Canadian Cancer Society Research Institute and by the Institute for Clinical Evaluative Sciences (ICES), which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). The opinions, results and conclusions reported in this paper are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred. Genomic Health, Inc. provided funding to the Sunnybrook Research Institution in support of this work. Dr. Rakovitch is the LC Campbell Chair for Breast Cancer Research.