Somatic BRCA alterations in breast cancer are associated with distinct biological and clinical patterns according to germline BRCA status

Background Comprehensive genomic profiling increasingly identifies BRCA alterations in breast cancer (BC). While germline BRCA mutations are well established as biologically and clinically relevant, the significance of somatic BRCA alterations remains unclear. We hypothesized that the implications of BRCA alterations may differ according to germline BRCA alterations. Patients and methods Among 5411 BC cases registered in the Center for Cancer Genomics and Advanced Therapeutics database, we analyzed 2978 BC cases with available germline (g) and somatic (s) BRCA status. Patients were categorized into four groups (g + /s + , g + /s − , g − /s + , and g − /s − ). Mutational landscapes, homologous recombination deficiency (HRD)-related alterations, specimen origin, and time to treatment discontinuation (TTD) were evaluated, focusing on estrogen receptor (ER)-positive/HER2-negative and triple-negative breast cancer (TNBC). Results g − /s + tumors were more prevalent than g + /s + tumors, and concordance between germline and somatic BRCA status was limited. Somatic BRCA alterations were more frequently detected in metastatic lesions and were more frequently observed in metastatic specimens. Genomically, g − /s + tumors were enriched for oncogenic signaling mutations, including PIK3CA and TP53 , whereas g + /s + tumors showed HRD-related features dominated by BRCA alterations. Non- BRCA HRD-related alterations were most frequent in g − /s + tumors (52%; P = 0.004). In ER-positive/HER2-negative BC, germline BRCA positivity was associated with shorter cyclin-dependent kinase 4 and 6 inhibitor TTD, and g + /s + status remained independently associated with shorter TTD (hazard ratio 1.3, P < 0.001), whereas g − /s + tumors were comparable with g − /s − tumors. In contrast, g − /s + tumors showed TTD comparable with g − /s − tumors. In TNBC, immune checkpoint inhibitor outcomes were not associated with BRCA status. Conclusions BRCA alteration groups defined by combined germline and somatic status showed distinct genomic and clinical patterns in BC. Somatic BRCA alterations should not be interpreted in isolation and require integration with germline status and broader genomic context.