Abstract
Approximately 10% of breast cancer cases are hereditary and associated with germline BRCA1/2 mutations. To characterize the somatic alteration landscape and HRD-related genomic features, we analyzed next-generation sequencing and clinical data from 1,243 breast cancer patients treated at Tianjin Cancer Hospital Airport Hospital between October 2021 and November 2024. We compared mutation patterns and clinicopathological features between patients with and without germline BRCA (gBRCA) mutations and further assessed somatic alterations and homologous recombination deficiency (HRD) in those carrying pathogenic variants. PIK3CA mutations were significantly more frequent in the Non-Germline and non-gBRCA groups than in the Germline and gBRCA groups (49% vs. 6%; 47% vs. 0%; both P < 0.001), indicating mutual exclusivity with gBRCA mutations. Conversely, PTEN alterations co-occurred in 30% of gBRCA cases, while TP53 mutations were mutually exclusive with MDM2 and FGFR1. HER2 amplification was identified in 10% of gBRCA-mutated tumors, and somatic alterations in non-gBRCA tumors were enriched in endocrine-resistance pathways. HRD scores were markedly higher in gBRCA patients than in non-gBRCA patients (median 59 vs. 24.5, P = 0.015), driven by significant increases in large-scale state transitions (LST) and telomeric allelic imbalance (TAI). The overall gBRCA1/2 mutation frequency was 15.61%, and two previously unreported variants, BRCA1 NM_007294.3:c.4185G>A and BRCA2 NM_000059.3:c.439C>A, were identified in the Chinese population. These findings provide a biological rationale to explore AKT1/HER2-targeted combinations with PARP inhibition in future studies for gBRCA-mutated breast cancer and provide the first evidence of PIK3CA-gBRCA mutual exclusivity in Chinese patients. The elevated HRD scores further underscore the presence of homologous recombination deficiency in the gBRCA group.