Abstract 531: Germline HRR alterations and ancestry-related outcomes in Brazilian triple-negative breast cancer patients: A comprehensive genomic and clinical study.

Abstract 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. Citation Format: Rafael C. Brianese, Karina M. Santiago, Gabriel Bandeira do Carmo, Leticia S. Pimentel, Diego Ortunes, Rafaella Ormond, Marcos L. Santoro, Giovana T. Torrezan, Marcelo Moreno Ândrea R. dos Santos, Marina de Brot, Fabiana B. Makdissi, Solange M. Sanches, Jose C. Rocha, Dirce Maria Carraro. Germline HRR alterations and ancestry-related outcomes in Brazilian triple-negative breast cancer patients: A comprehensive genomic and clinical study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 531.