Determining homologous recombination deficiency scores with whole exome sequencing and their association with responses to neoadjuvant chemotherapy in breast cancer

Abstract Recent studies demonstrated that homologous repair deficiency (HRD) score is a useful marker for response to poly (ADP-ribose) polymerase inhibitors or platinum-based chemotherapy. We determined HRD scores and elucidated the clinicopathologic characteristics of HRD-high tumors and their response to non-platinum-based chemotherapy. Primary breast cancer patients (n = 120) were pre-operatively treated with paclitaxel followed by 5-fluorouracil/epirubicin/cyclophosphamide (P-FEC). Germline and somatic homologous recombination related gene mutations (gHRRm and sHRRm, respectively) and HRD scores were analyzed using whole exome sequencing (WES) in tumor tissues obtained before chemotherapy. Of 120 tumors, 30 were determined to be HRD-high tumors, significantly associated with high Ki-67 (P = 0.014), ER negativity (P = 0.007), and PR negativity (P = 0.021). Triple-negative cancers showed significantly higher HRD scores than the luminal, luminal-HER2, and HER2 subtypes (P = 0.023, 0.016, and 0.033, respectively). HRD scores were significantly higher in tumors with gHRRm than in those with sHRRm (P = 0.002) or wild-type HRR genes (P = 1.44e-4), but no significant difference was found in HRD scores between tumors with sHRRm and wild-type HRR genes (P = 0.206). HRD-high tumors had significantly (P = 0.003) higher pCR rates and higher near-pCR rates (P = 0.049) compared with those of the HRD-low tumors in all tumors and the luminal subtype, respectively. HRD-high tumors were associated with aggressive phenotypes and gHRRm, but not sHRRm. Our findings suggested that HRD scores might be useful in predicting response to P-FEC in the luminal subtype.