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

Abstract

Background

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.

Patients and Methods

425 TNBC patients were identified from S9313. HRD score, tumor BRCA1/2 sequencing and BRCA1 PM, were performed on DNA isolated from FFPE tissue. Positive HRD status was defined as either a deleterious tumor BRCA1/2 (tBRCA) mutation and/or a pre-defined HRD score ≥ 42. Markers were tested for prognostic value on DFS and OS using Cox regression models adjusted for treatment assignment and nodal status.

Results

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 ≥42). HRD-positive status was associated with a better DFS (HR = 0.72; 95% CI 0.51– 1.00; p=0.049) and non-significant trend towards better OS (HR = 0.71; 95% CI 0.48– 1.03; p=0.073). High HRD score (≥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).

Conclusions

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.

Clinical Trials Number

Int0137 (The trial pre-dates Clinicaltrial.Gov website establishment)