Prevalence and clinical impact of germline pathogenic variants in breast cancer: a descriptive large single-center study

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BACKGROUND: Germline (likely) pathogenic variants (PVs) are identified in 5%-10% of patients with breast cancer (BC) and play a critical role in guiding clinical management, including the use of targeted therapies such as poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi). High-risk genes such as BRCA1, BRCA2, and PALB2, and moderate-risk genes such as CHEK2 and ATM, influence BC risk and treatment decisions. This study evaluates the prevalence and clinical impact of PVs in a large consecutive cohort. MATERIALS AND METHODS: A retrospective analysis was conducted on 912 individuals with BC who underwent germline testing at the Hospital Clinic of Barcelona from 2016 to 2023. Genetic testing for 14 BC and Lynch syndrome genes was carried out using the TruSight Hereditary Cancer Panel. Statistical analyses were carried out to assess associations between germline results and clinical characteristics, including eligibility for PARPi therapy. RESULTS: Of the 912 individuals, 129 (14.1%) had a PV, with BRCA2 (31.8%) and BRCA1 (24%) being the most frequently altered genes. Additionally, 16.2% carried variants of uncertain significance, most commonly in ATM and BRCA2 genes. Patients with PV were younger compared with PV-negative individuals (median age: 43.5 versus 48.2 years, P = 0.006), more likely to have bilateral BC (13.3% versus 5.8%, P = 0.002), and more frequently diagnosed with triple-negative BC (TNBC; 28.7% versus 20.8%, P = 0.046). Of those with PVs, 39.1% completed a bilateral mastectomy, 36.7% had a risk-reducing salpingo-oophorectomy, and 22.7% had both surgeries. PV detection was associated with higher stages at diagnosis (stage IV: 13.0% versus 5.9%, P < 0.001). In the metastatic cohort, 12.9% received PARPi therapy, with 80.7% harboring BRCA1/2 PVs. In early BC, 13.1% met the criteria for adjuvant PARPi. CONCLUSIONS: The identification of germline PVs significantly influences surgical decisions and systemic therapies. Genetic testing for patients with BC optimizes care, particularly in selecting candidates for PARPi in both early and advanced BC, improving management and prevention strategies.

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