BRCA1 and HRR pathway genes in triple-negative breast cancer patients: clinical outcomes in an admixed Brazilian cohort

Abstract Background Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer, frequently associated with early-onset disease, hereditary susceptibility and African ancestry. A substantial proportion of TNBC cases are linked to germline pathogenic variants (gPVs) in BRCA1 , a key gene in the homologous recombination repair (HRR) pathway. Disruption of this pathway due to gPV in BRCA1 and other HRR genes results in homologous recombination deficiency, a phenotype associated with sensitivity to PARP inhibitors. In admixed populations, such as Brazil, the combined impact of hereditary predisposition and ancestry on TNBC clinical outcomes remains insufficiently characterized. Methods We analyzed 320 Brazilian TNBC patients using NGS panels and assessed molecular ancestry in 248 patients using a microarray assay. Both global and local ancestry at the BRCA1 locus were evaluated. Results We identified gPVs in 29.1% of patients, with the highest frequency in BRCA1 (14.7%), followed by other HRR pathway genes. BRCA1 carriers were diagnosed at a younger age and were more likely to present bilateral tumors. Carriers of BRCA1 and other-HRR gPVs showed significantly improved 3-year progression-free survival (3y-PFS). Predominant African global ancestry was associated with worse 3y-PFS, whereas local ancestry at the BRCA1 locus was not associated with gPV status or prognosis. Conclusions gPVs in BRCA1 and other HRR genes define distinct clinical characteristics and improved short-term outcomes, supporting the relevance of HRD-guided therapeutic strategies beyond BRCA1/2 . Associations between ancestry and survival indicated survival disparities in the Brazilian population, warranting further validation in larger and more diverse cohorts.