Germline Mutational Profile of Triple-Negative Breast Cancer in Portugal: A Multicenter Retrospective Cohort Study

Background/Objectives: Triple-negative breast cancer (TNBC) carries a poor prognosis; while PARP inhibitors (PARPi) are approved for BRCA-mutated disease, other homologous recombination deficiency (HRD) pathways may be actionable targets. This study characterizes germline mutations in Portuguese TNBC and explores exploratory associations with clinicopathologic features and outcomes. Methods: A multicentric retrospective cohort of women diagnosed with TNBC (2022–2024) that harbored a pathogenic variant (PV), likely pathogenic variant (LPV), or variant of uncertain significance (VUS) across six Portuguese institutions. Clinicopathologic variables were compared between groups. Overall (OS) and progression-free survival (PFS) were estimated in patients eligible for curative-intent therapy with PV/LPV, using Kaplan–Meier and log-rank methods. Results: Among 109 patients, 38.5% carried a PV and 11.0% an LPV. BRCA1/2 predominated among PV carriers (59.5%), followed by PALB2 (9.5%), RAD51C (7.1%), and RAD51D (4.8%). Additionally, 53.2% harbored a VUS, mainly ATM (22.4%), CHEK2/BRCA2 (8.6% each), and NF1 (6.9%). Mean age was 49.7 ± 12.1 years; 49.5% had advanced-stage disease (>cT2/N+); 61.5% received neoadjuvant immunotherapy; 1.8% received adjuvant PARPi. For efficacy analysis, BRCA (n = 26) and non-BRCA (n = 25) carriers were well balanced. Pathologic complete response occurred in 60.9% of non-BRCA versus 82.6% of BRCA carriers (p = 0.190). BRCA carriers had numerically higher PFS (p = 0.09): 92.3% versus 69.7% at 24 months. OS was comparable (p = 0.16); median OS not reached. Conclusions: This study characterizes the germline landscape of Portuguese TNBC, revealing diverse HRD-pathway mutations beyond BRCA. In this small exploratory analysis, BRCA status was not associated with a statistically significant difference in PFS, pathologic response, or OS.