Identification of patients with DCIS with low-risk clinicopathology who benefit from radiation therapy with and without endocrine therapy after breast-conserving surgery assessed with the 7-gene biosignature.

528 Background: Ductal carcinoma in situ (DCIS) accounts for 20% of breast cancers. For most patients with DCIS, the standard treatment involves breast-conserving surgery (BCS) followed by radiotherapy (RT). Adjuvant endocrine therapy (ET) is typically recommended for hormone receptor-positive disease. However, prospective trials have failed to identify a low-risk CP group not benefitting from RT with respect to ipsilateral breast recurrence (IBR), with no modern trials evaluating ET. We utilized the 7-gene predictive DCIS biosignature to assess the effects of RT and/or ET on 10yr IBR in women with low-risk CP DCIS. Methods: Women (n=926) from four DCIS cohorts treated with BCS had tissue samples analyzed at a CLIA lab (Laguna Hills, CA). Low-risk CP was defined with RTOG 9804-like criteria (margin negative by no-ink on tumor) or MSKCC-like criteria using nomogram-weighted factors (low-risk score<220, excluding number of re-excisions, using negative margin, and RT treatment). Women with either low-risk CP criteria were classified as molecular Low Risk (DS≤2.8, no Residual Risk subtype, RRt) or High Risk (DS>2.8 +/- RRt) using the 7-gene DCIS biosignature. Ten-year IBR Kaplan-Meier rates and Cox proportional hazard ratios (HR) were calculated for ET and RT. Results: Overall, 66% of 926 women were classified as low risk by one of the CP criteria. Patients with low-risk CP treated without ET (n=315) had 10yr IBR rates of 13% after BCS without RT and 7% with RT (HR=0.51, p=.10), while those treated with ET (n=291) had 10yr IBR rates of 9% after BCS without RT and 4% with RT (HR=0.39, p=.09). Overall, 37% of women were classified as low risk (n=338) by the biosignature and had a 10yr IBR rate of 5.6% after BCS with no significant ET (HR=0.66, p=.41) or RT benefit (HR=0.88, p=.78) in multivariable analysis. Of patients with low-risk CP, 48% of those treated without ET were classified as High Risk by the biosignature and had elevated 10yr IBR rates without RT (21%) and a substantial RT benefit (HR=0.31, p=.03, n=151), while 59% of those treated with ET after BCS were classified by the biosignature as High Risk and had elevated 10yr IBR rates without RT (14%) and a 9% absolute reduction from RT (HR=0.22, p=.02, n=173). Patients with concordant low-risk CP and biosignature Low Risk (n=269) had a 5.5% 10yr IBR rate after BCS and no significant RT (HR=1.10 95% CI 0.33 to 3.7, p=.87) or ET benefit (HR=0.44, 95%CI 0.1 to 1.6, p=.22) in multivariable analysis. Conclusions: The 7-gene biosignature provided better identification of patients with low 10yr IBR rates and no significant RT benefit compared to using CP low-risk criteria. Importantly, the biosignature classified over half of women with low-risk CP treated with ET as High Risk. This group received a substantial benefit from RT, while those with biosignature Low Risk did not.