323 Background: A positive family history is a well-established risk factor for prostate cancer (PCa), making the identification of individuals with inherited susceptibility particularly relevant. The detection of germline pathogenic variants (PVs) in DNA-repair genes (DRGs) further supports the implementation of targeted screening strategies. The present study aimed to investigate the performance and adherence of a personalized screening protocol designed for this high-risk population, integrating both the Prostate Health Index (PHI) and multiparametric magnetic resonance imaging (mpMRI). Methods: This ongoing prospective study, supported by AIRC-(ID-IG-25027-V1.3), is based on the concept of a dedicated PCa screening protocol. It was conducted at a tertiary referral center in collaboration with multiple departments. The study enrolled men aged 35–69 years carrying documented PVs in DRGs who provided informed consent to participate in the screening program. Probands were classified into two groups: (1) male relatives of women harboring DRG PVs associated with breast or ovarian cancer, and (2) male relatives of men with DRG PVs diagnosed with high-grade PCa (ISUP grade group >2). Participants underwent annual assessments including PSA testing, PHI measurement, DRE, and mpMRI, according to individual risk stratification (PHI 40). Results: Between 2021 and 2025, a total of 129 patients were enrolled, with a median age of 52 years (IQR 47–64). Among them, 118 belonged to the group 1 and 11 to the group 2. The most prevalent PVs was BRCA2 (56.0%), followed by BRCA1 (21.6%), ATM (3.4%), PMS2 (2.6%), MSH2 (2.6%), MLH1 (2.6%), PALB2 (2.6%), and MSH6 (1.7%). Screening compliance was high: 95% of participants completed the T1 visit, 86% completed T2, 90% completed T3, and 100% completed T4. Among patients with PHI values between 20 and 40, 85% underwent mpMRI. Three of these showed a positive mpMRI and proceeded to biopsy, which was negative two cases and positive in one. An additional 3 patients underwent biopsy due to clinical suspicion, all yielding negative results. Among those with PHI >40, 75.5% underwent mpMRI followed by biopsy according to protocol, all of which were negative for prostate cancer. At the fourth year of follow-up, the screening program detected its first case of PCa: a BRCA2 carrier with a PVs, whose biopsy confirmed ISUP 4 PCa. The patient has been scheduled for surgery. Conclusions: The screening program detected the first case of PCa in a 57-year-old man. Despite this finding, the overall incidence of PCa in our cohort remains notably lower than reported in international studies, including the IMPACT trial. This unexpected result may suggest the presence of a population-specific protective factor, a phenomenon we refer to as the “Italian paradox.” Nevertheless, given the limited sample size and short follow-up, this observation should be interpreted cautiously.
Fasulo et al. (Sun,) studied this question.