Molecular profiling of male breast cancer in Brazil: Comprehensive genomic characterization of a Latin American cohort.

Abstract

571 Background: Male breast cancer (MBC) is a rare disease, accounting for < 1% of all breast cancers. Current treatment recommendations are largely extrapolated from female breast cancer data, which may not reflect the distinct biological features of MBC. Notably, MBC is associated with higher mortality rates than female breast cancer. Molecular data from Latin America are scarce. This study aimed to characterize the clinicopathological and molecular features of MBC in a Brazilian cohort, addressing an important knowledge gap in an underrepresented population. Methods: Medical records of 106 men diagnosed with breast cancer at three Brazilian cancer centers between 2000 and 2022 were reviewed. Tumor samples from 48 patients were available for molecular analysis after centralized histopathological review. FFPE samples with ≥10% tumor cellularity were included. DNA and RNA were extracted using the AllPrep kit (Qiagen). Libraries were prepared using the Oncomine Focus Assay (Thermo Fisher Scientific) and sequenced on the Ion S5 platform. Bioinformatic analysis for single nucleotide variants (SNVs), insertions/deletions, copy number variations (CNVs), and gene fusions was performed using Ion Reporter software. Results: The median age at diagnosis was 58.5 years (range: 33–84). A family history of cancer was reported in 64% of patients, including female breast cancer in 32%. Most tumors were invasive ductal carcinomas (87.7%), high grade (grades 2–3; 90%), and hormone receptor–positive (93%). HER2+/HR– and triple-negative subtypes accounted for 0.9% and 3.9%, respectively. Most patients (88.5%) presented with localized or locally advanced disease. The most frequent pathogenic variants were PIK3CA (28%), followed by MAP2K1, BRAF, and AKT1 (6% each), and EGFR, JAK3, and MTOR (3% each). The most common CNV amplifications involved MYC (24%), FGFR1 (20%), CCND1 (16%), and ERBB2 (4%). No gene fusions were identified. Pathway analysis revealed alterations in PI3K/AKT/mTOR (37%), Cell Cycle (40%), FGF signaling (20%), and MAPK (12%) pathways. Overall, 46% of patients harbored potentially actionable SNVs, and 24% harbored potentially actionable CNVs. Conclusions: This is the first comprehensive molecular characterization of MBC in Brazil. Our findings confirm PIK3CA as the most frequent alteration, consistent with international cohorts, supporting the central role of the PI3K/AKT/mTOR pathway in MBC. Additional alterations in Cell Cycle and FGF signaling pathways highlight distinct oncogenic drivers. The high prevalence of potentially actionable genomic alterations suggests that molecular profiling may inform treatment selection for a substantial proportion of patients. These findings underscore the limitations of extrapolating treatment guidelines from female breast cancer and support biomarker-driven clinical trials for men with breast cancer in Latin America.