Impact of DNA repair deficiency signature on outcomes in triple negative breast cancer (TNBC) patients treated with AC chemotherapy (SWOG S9313).

529 Background: Biomarkers of response and resistance to adjuvant chemotherapy for TNBC are needed. Deficiency in DNA damage response (DDR) and repair pathways have been reported in TNBC and may impact response to chemotherapy. Aims: To investigate DNA damage response deficiency (DDRD) molecular signature, BRCA1mRNA expression and Tumor Infiltrating Lymphocytes (TILs) as prognostic markers in TNBC patients treated with adjuvant AC on S9313. Methods: S9313 accrued 3125 early stage BC patients to two alternative schedules of AC with no difference in outcomes between the two arms. We identified 425 (14%) patients with centrally determined TNBC with tissue availability. DDRD signature (44 gene signature, Almac Inc.) and BRCA1expression (NanoString nCounter) were performed on RNA isolated from pre-treatment FFPE tumor tissue. DDRD score was classified in quartiles. TILs evaluation was performed using previously described criteria. Markers were tested for prognostic effect on DFS and OS using Cox regression model with adjustment for randomized treatment assignment. Results: For 425 TNBC patients median age: 45 yrs, and 5 year DFS and OS = 74% and 82%, respectively. DDRD signature was successfully evaluated in 89.6% (381/425) but only 267 (62.8%) met 60% tumor content criterion for inclusion. DDRD score quartiles were associated with DFS (5 year DFS 59% & 82% in the lowest & highest quartiles respectively, p = 0.0005) and OS (5 year OS 74% and 86% in lowest and highest quartiles respectively, p = 0.008). BRCA1 expression and TILs were successfully determined in 78% and 99% samples, respectively. BRCA1expression was not associated with DFS. TILs were associated with DFS (10% increase HR = 0.88; 95% CI 0.79-0.97; p = 0.016) and OS (HR = 0.84; 95% CI 0.74-0.94; p = 0.0005). DDRD score and TILs were highly correlated (Pearson = 0.62). In multivariate model of DFS including TILs and DDRD quartiles, only DDRD remains significant (p = 0.018). Conclusions: DDRD signature was prognostic in TNBC patients treated with AC chemotherapy and has the potential to be used as a selection criterion to identify TNBC patients whose prognosis is sufficiently poor to justify evaluation of alternative treatment.