The impact of BRCA1 and BRCA2 Mutations on Metastatic Prostate Cancer: Genetic, Diagnostic, Therapeutic and Prognostic perspectives. A Retrospective Mono-Institutional Study

Abstract Background: BRCA 1 and BRCA 2 gene mutations are linked to prostate cancer (PCa) development, influencing diagnosis, progression, therapeutic options and response, and prognosis. Poly (ADP-ribose) polymerase inhibitors (PARPi) were the first targeted therapy approved for the management of patients with metastatic castration resistant prostate cancer (mCRPC) with germline and/or somatic mutations of BRCA 1/2, who have already received a previous treatment with androgen receptor signaling inhibitors (ARSIs). Guidelines recommend BRCA testing in all metastatic PC patients. However, the diagnostic pathway is still under development. Objective: This study aims to understand how different factors in the diagnostic pathway might impact the effectiveness of NGS analysis. It also examines the clinical and pathological features associated with BRCA mutations and evaluates the response to PARPi in BRCAm patients within a real-world cohort from San Luigi Gonzaga Hospital. Materials and Methods: A retrospective analysis was conducted on 158 prostate cancer patients treated at San Luigi Gonzaga Hospital who were tested for BRCA1/2 somatic and/or germline mutation between November 2017 and June 2024. The data collected included clinical and biochemical factors, such as demographics, disease characteristics, treatment information, and outcomes. Kaplan-Meier curves were used to compare overall survival (OS) and progressionfree survival (PFS) between BRCAm and BRCA wild-type (BRCAwt) patients and between BRCA1m and BRCA2m patients. Results: BRCA status was confirmed in 127 patients, of which 105 were BRCAwt and 22 were BRCA mutated, divided in 7 with BRCA1 and 15 with BRCA2 mutations. Of the BRCAm cohort, 50% had germline mutations. We were able to determine the BRCA status in 68% of cases and our study revealed that a longer interval between histological sampling and DNA extraction had a negative impact on the validity of NGS results. BRCAm patients exhibited aggressive biologic features, as indicated by the high prevalence of patients with a Gleason Score at diagnosis above 7. However, they also had a lower tumor burden at diagnosis or recurrence, as indicated by fewer lymph node metastasis and lower alkaline phosphatase levels, compared to BRCAwt patients. Importantly, BRCAm patients had a better early prognosis, with no deaths registered in the first 4 years from diagnosis, compared to 33% in the BRCAwt group.Among those treated with PARPi, PFS and OS were registered to be higher in the BRCA2 mutated group with respect to BRCA1. Conclusions: Our study emphasizes the importance of the introduction of routine genetic testing for all prostate cancer patients, as well as genetic counselling for their relatives, given the high prevalence of germline mutations observed in our cohort. The differences in OS and PFS between BRCAm and BRCAwt patients in our cohort did not align with existing literature, likely due to a selection bias, given that our cohort is small and included patients already managed with PARPi (85% of BRCAm patients), which might have mitigated the disparities between the two groups. Consistent with previous studies, our cohort of BRCA2m patients had better response to PARPi in terms of OS and PFS, compared to BRCA1 patients, highlighting the need for tailored therapeutic approaches for the latter group.