Validated biomarkers are needed to improve risk assessment and treatment decision-making for women with ductal carcinoma in situ (DCIS) of the breast. The Oncotype DX^® DCIS Score (DS) was shown to predict the risk of local recurrence (LR) in individuals with low-risk DCIS treated by breast-conserving surgery (BCS) alone. Our objective was to confirm these results in a larger population-based cohort of individuals. We used an established population-based cohort of individuals diagnosed with DCIS treated with BCS alone from 1994 to 2003 with validation of treatment and outcomes. Central pathology assessment excluded cases with invasive cancer, DCIS < 2 mm or positive margins. Cox model was used to determine the relationship between independent covariates, the DS (hazard ratio (HR)/50 C_p units (U)) and LR. Tumor blocks were collected for 828 patients. Final evaluable population includes 718 cases, of whom 571 had negative margins. Median follow-up was 9.6 years. 100 cases developed LR following BCS alone (DCIS, N = 44; invasive, N = 57). In the primary pre-specified analysis, the DS was associated with any LR (DCIS or invasive) in ER+ patients (HR 2.26; P < 0.001) and in all patients regardless of ER status (HR 2.15; P < 0.001). DCIS Score provided independent information on LR risk beyond clinical and pathologic variables including size, age, grade, necrosis, multifocality, and subtype (adjusted HR 1.68; P = 0.02). DCIS was associated with invasive LR (HR 1.78; P = 0.04) and DCIS LR (HR 2.43; P = 0.005). The DCIS Score independently predicts and quantifies individualized recurrence risk in a population of patients with pure DCIS treated by BCS alone.

Background: Methods: Results: Conclusion:

Background: Most women with ductal carcinoma in situ (DCIS) will receive breast-conserving surgery (BCS) and radiation (RT). RT can be omitted for women at low risk of local recurrence (LR). The Oncotype DX DCIS score (DS) predicts LR risk after BCS alone. This study assesses the impact of RT and DS on LR risk. Methods: Population-based cohort analysis of individuals with DCIS treated by BCS ± RT from 1994–2003. Treatment and outcomes were determined by linkage and chart review. We used a propensity score–adjusted multivariable model to examine associations between DS and LR and evaluate the impact of RT. All statistical tests were two-sided. Results: The cohort includes 571 individuals treated by BCS alone, 689 cases treated with BCS + RT. Median follow-up was 9.4 years. On multivariable analysis, factors associated with LR include RT, age at diagnosis, tumor size, and multifocality. Adjusting for these factors, the DS risk group was statistically significantly associated with LR risk (hazard ratio high/intermediate = 1.75, 95% confidence interval = 1.28 to 2.41, P < .001). Women with a low-risk DS treated by BCS alone had an LR risk of 10.6% at 10 years and a small benefit from RT, while those with a high DS had a higher risk of LR (25.4%) after BCS alone and greater benefit from RT. A subgroup of patients with favorable clinicopathological features had a high-risk DS; these patients had a higher than expected risk of LR after BCS alone and a greater benefit with RT. Conclusions: The DS molecular assay improves risk stratification and estimates of RT benefit in individuals with DCIS treated with breast-conserving therapy.

Purpose: There is concern that women with multifocal ductal carcinoma in situ (DCIS; confined to one quadrant) who are treated with breast-conserving surgery face a high risk of local recurrence; therefore, many are treated with mastectomy. The objective of this study is to evaluate the significance of multifocality and the outcomes of women with multifocal DCIS treated with breast-conserving therapy. Methods: The records of patients treated with breast-conserving surgery for DCIS between 1982 and 2000 were reviewed. Multivariate analyses were performed to evaluate the effects of multifocality and other prognostic factors on the rate of local recurrence. Results: Of 615 cases of DCIS reviewed, 310 (41%) received breast-conserving surgery and 305 (40%) received breast-conserving surgery plus radiation (n = 260 with multifocality, n = 314 without multifocality, and n = 31 focality unreported). On multivariate analysis, multifocality (hazard ratio [HR] = 1.80; 95% CI, 1.15 to 2.80; P = .01), radiation treatment (HR = 0.46; 95% CI, 0.29 to 0.74; P = .001), margin width 4 mm or smaller (HR = 1.74; 95% CI, 1.03 to 2.92; P = .04), and high nuclear grade (HR = 1.65; 95% CI, 1.02 to 2.65; P = .04) were associated with risk of local recurrence. The detrimental effect of multifocality was limited to women who did not receive radiotherapy; the local recurrence–free survival rate at 10 years was 59% for women with multifocal disease and 80% for women without multifocality (P = .02). Among women treated with breast-conserving surgery plus radiation, there was no difference in 10-year local recurrence–free survival (80% v 87%; P = .35). There was no association between multifocality and the development of invasive recurrence. Conclusion: Multifocality is a significant predictor of local recurrence in women who receive breast-conserving surgery for DCIS without radiotherapy; however, low recurrence rates can be achieved if adjuvant radiation is administered.

Purpose Better tools are needed to estimate local recurrence (LR) risk after breast-conserving surgery (BCS) for DCIS. The DCIS score (DS) was validated as a predictor of LR in E5194 and Ontario DCIS cohort (ODC) after BCS. We combined data from E5194 and ODC adjusting for clinicopathological factors to provide refined estimates of the 10-year risk of LR after treatment by BCS alone. Methods Data from E5194 and ODC were combined. Patients with positive margins or multifocality were excluded. Identical Cox regression models were fit for each study. Patient-specific meta-analysis was used to calculate precision-weighted estimates of 10-year LR risk by DS, age, tumor size and year of diagnosis. Results The combined cohort includes 773 patients. The DS and age at diagnosis, tumor size and year of diagnosis provided independent prognostic information on the 10-year LR risk (p ≤ 0.009). Hazard ratios from E5194 and ODC cohorts were similar for the DS (2.48, 1.95 per 50 units), tumor size ≤ 1 versus > 1–2.5 cm (1.45, 1.47), age ≥ 50 versus < 50 year (0.61, 0.84) and year ≥ 2000 (0.67, 0.49). Utilization of DS combined with tumor size and age at diagnosis predicted more women with very low (≤ 8%) or higher (> 15%) 10-year LR risk after BCS alone compared to utilization of DS alone or clinicopathological factors alone. Conclusions The combined analysis provides refined estimates of 10-year LR risk after BCS for DCIS. Adding information on tumor size and age at diagnosis to the DS adjusting for year of diagnosis provides improved LR risk estimates to guide treatment decision making.