Impact of homologous recombination deficiency biomarkers on outcomes in patients with triple-negative breast cancer treated with adjuvant doxorubicin and cyclophosphamide (SWOG S9313)

Homologous recombination deficiency (HRD)-causing alterations have been reported in triple-negative breast cancer (TNBC). We hypothesized that TNBCs with HRD alterations might be more sensitive to anthracycline plus cyclophosphamide-based chemotherapy and report on HRD status and BRCA1 promoter methylation (PM) as prognostic markers in TNBC patients treated with adjuvant doxorubicin (A) and cyclophosphamide (C) in SWOG9313. In total, 425 TNBC patients were identified from S9313. HRD score, tumor BRCA1/2 sequencing, and BRCA1 PM were carried out on DNA isolated from formalin-fixed paraffin-embedded tissue. Positive HRD status was defined as either a deleterious tumor BRCA1/2 (tBRCA) mutation or a pre-defined HRD score a parts per thousand 42. Markers were tested for prognostic value on disease-free survival (DFS) and overall survival (OS) using Cox regression models adjusted for treatment assignment and nodal status. HRD status was determined in 89% (379/425) of cases. Of these, 67% were HRD positive (27% with tBRCA mutation, 40% tBRCA-negative but HRD score a parts per thousand 42). HRD-positive status was associated with a better DFS [hazard ratio (HR) 0.72; 95% confidence interval (CI) 0.51-1.00; P = 0.049] and non-significant trend toward better OS (HR = 0.71; 95% CI 0.48-1.03; P = 0.073). High HRD score (a parts per thousand 42) in tBRCA-negative patients (n = 274) was also associated with better DFS (HR = 0.64; 95% CI 0.43-0.94; P = 0.023) and OS (HR = 0.65; 95% CI 0.42-1.00; P = 0.049). BRCA1 PM was evaluated successfully in 82% (348/425) and detected in 32% of cases. The DFS HR for BRCA1 PM was similar to that for HRD but did not reach statistical significance (HR = 0.79; 95% CI 0.54-1.17; P = 0.25). HRD positivity was observed in two-thirds of TNBC patients receiving adjuvant AC and was associated with better DFS. HRD status may identify TNBC patients who receive greater benefit from AC-based chemotherapy and should be evaluated further in prospective studies. Int0137 (The trial pre-dates Clinicaltrial.Gov website establishment).