Evolution of germline testing, mutation spectrum and clinico-pathological features in male breast cancer: a 27-year retrospective cohort including 69 patients.

BACKGROUND

Male breast cancer (MBC) is rare, and its genetic basis remains poorly characterized. Over the past few decades, genetic screening strategies have evolved from analyses focusing solely on the BRCA1/2 genes to extensive multigene panels. Longitudinal data describing this transition in men remain scarce.

METHODS

All men diagnosed with breast cancer and referred for germline genetic testing between 1998 and 2025 at our institution were included. Clinical characteristics, test indications, genes analyzed, and pathogenic/probably pathogenic (P/LP) variants were extracted. Three periods covering the transition from Sanger sequencing to next-generation sequencing (NGS) were considered: between 1998 and 2015, 26 patients were tested for BRCA1/2 only. Between 2015 and 2018, 10 patients underwent limited multigene panel testing (6-8 genes). From 2018 onward, 29 patients were tested using a nationally validated 13-gene panel, and in the most recent two years, 4 patients underwent extensive genetic testing covering 17 genes, including non-consensus genes.

RESULTS

Sixty-nine men underwent genetic testing. Overall, P/LP variants were identified in 13% (9/69) of patients, in BRCA2 (n=4), PALB2 (n=2), ATM (n=2), and BRCA1 (n=1). The mean age at diagnosis was higher among variant carriers compared with non-carriers (69.9 (±7.4) years vs 65.7 (±12.3)), except for BRCA2 carriers, who were diagnosed at a younger age (63.8 (±5.0)). A family history suggestive of hereditary breast and ovarian cancer was absent in 71% of the overall cohort. One BRCA2-positive family included three cases of male breast cancer.

CONCLUSION

Over 27 years, germline testing in male breast cancer shifted from BRCA-focused strategies to multigene panels, revealing a broader spectrum of susceptibility genes. These findings support systematic genetic testing for all men with breast cancer, regardless of age and family history.