This study examined 2,978 breast cancer cases from the C-CAT database, categorizing patients into four groups based on combined germline (g) and somatic (s) BRCA status (g+/s+, g+/s−, g−/s+, g−/s−) to assess differences in genomic landscape, HRD features, and clinical outcomes (TTD) across ER+/HER2− and TNBC subtypes.
g−/s+ tumors had distinct biology from g+/s+ tumors: they were enriched for PIK3CA/TP53 mutations and non-BRCA HRD alterations (52%), while g+/s+ tumors showed classical HRD signatures. In ER+/HER2− BC, germline BRCA positivity was linked to shorter CDK4/6 inhibitor TTD (g+/s+ HR 1.3, P<0.001), but g−/s+ tumors performed similarly to g−/s− tumors. In TNBC, immune checkpoint inhibitor outcomes were not associated with any BRCA group.
Retrospective database design limits causal inference; time to treatment discontinuation is a surrogate endpoint, not overall survival; germline–somatic concordance may be affected by tumor heterogeneity and biopsy site (somatic alterations more common in metastatic specimens).
Do not interpret somatic BRCA alterations in isolation — a g−/s+ result does not carry the same therapeutic or prognostic meaning as a germline BRCA mutation. Always integrate germline status and broader genomic context (e.g., HRD landscape, PIK3CA/TP53 co-mutations) when counseling patients and selecting therapy.
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