HRD-positive breast cancer genomics: Cross-application of ovarian cancer HRD scores.

1037 Background: Homologous recombination deficiency (HRD) is a well-established biomarker for PARP inhibitor (PARPi) therapy in ovarian cancer and is increasingly being explored in breast cancer. However, current definitions of HRD positivity in breast cancer rely heavily on ovarian cancer–derived thresholds, raising questions about their biological relevance. Here, we characterize the genomic landscape of HRD-positive breast cancer and assess the applicability of ovarian cancer–based HRD scoring criteria. Methods: We performed next-generation sequencing on 1,159 breast cancer samples to evaluate HRD status, somatic alterations, and germline variants. HRD scores were calculated as the sum of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST), using established ovarian cancer cutoffs. These results were compared with HRD scores from 617 ovarian cancer cases analyzed using the same methodology. Results: Pathogenic or likely pathogenic BRCA mutations were detected in 105 breast cancer patients (9.1%), including 33 somatic and 80 germline events, all of which occurred in HRD-positive tumors. Overall, 26.2% (304/1,159) of breast cancer cases were classified as HRD-positive, with a median HRD score of 21. HRD scores were significantly higher in triple-negative breast cancer (TNBC) than in non-TNBC subtypes (P < 0.001). HRD-positive tumors exhibited elevated genomic instability, marked by significantly higher copy number variation burden (P < 0.001) and tumor mutational burden (TMB) (P < 0.001), along with enriched TP53 alterations. Comparative analysis revealed that ovarian cancers had significantly higher HRD scores than breast cancers (median: 43 vs. 21, P < 0.001), suggesting that applying ovarian cancer–derived thresholds may underestimate HRD positivity in breast cancer. Conclusions: HRD-positive breast cancer displays distinct genomic features, including increased genomic instability and TP53 alterations. However, HRD scores in breast cancer are markedly lower than those in ovarian cancer, indicating that ovarian cancer–based cutoffs may not be optimal for breast cancer. Future studies should refine breast cancer–specific HRD thresholds to improve patient selection for PARPi therapy.