Germline HRR alterations and ancestry-related outcomes in Brazilian triple-negative breast cancer patients: A comprehensive genomic and clinical study

Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous breast cancer subtype frequently associated with early-onset, African ancestry, and germline pathogenic variants (GPVs), particularly in BRCA1 . Loss of function germline mutation in homologous recombination repair (HRR) genes culminate in homologous recombination deficiency (HRD), a molecular phenotype that confers increased susceptibility to DNA-damaging agents such as platinum-based chemotherapy and PARP (poly ADP-ribose polymerase) inhibitors. While this mechanism is well-characterized in European and North American cohorts, studies in admixed populations remain limited. We conducted a comprehensive retrospective study of 320 unselected Brazilian TNBC patients, integrating multigene next-generation sequencing (NGS) panels, ancestry analysis, and clinical-pathological data. Germline variants were analyzed across cancer predisposition multi gene panels, and ancestry was determined in 248 patients using the Axiom Precision Medicine Diversity Array and ADMIXTURE (K=4). GPVs were detected in 29.1% of patients, with BRCA1 being the most frequently altered gene (14.7%), followed by BRCA2 (4.4%) and non- BRCA HRR genes (4.7%). Overall, 23.8% of patients harbored GPVs in HRR-related genes. BRCA1 carriers were significantly younger at diagnosis, more likely to present bilateral tumors, and showed improved 3-year progression-free survival (3y-PFS) compared to non-carriers (p = 0.0162). Carriers of other HRR genes also had superior 3y-PFS (p = 0.0398). Combined, HRR-carriers exhibited better 3y-PFS (p = 0.0025) and 5-year overall survival (5y-OS, p = 0.0260) than non-carriers. Ancestry analysis revealed a predominance of European ancestry (87.1%) but also substantial African and Native American components (≥1% in 68.5% and 81.4%, respectively), confirming Brazil's complex admixture. Patients with predominant African ancestry had significantly worse 3y-PFS (p = 0.0011) and 5y-OS (p = 0.0117) compared to those with European ancestry. Self-reported race only partially correlated with molecular ancestry. Local ancestry analysis focused on the BRCA1 locus showed that 25% of individuals carried African-derived haplotypes, but no significant associations were found between BRCA1 local ancestry and cancer type (p > 0.05). This is the largest TNBC germline study conducted in a Latin American population to date, uniquely integrating genetic, clinical, and ancestry data. Our findings reinforce the central role of HRR genes, particularly BRCA1 , in TNBC predisposition and prognosis, and reveal ancestry-related survival disparities that merit further investigation. Ongoing analyses of local ancestry components will provide additional insights into the genomic and clinical heterogeneity of TNBC in highly admixed populations.