Absence of prostate cancer events after 3 years of tailored screening in high-risk individuals with germline pathogenic variants in DNA repair genes.
Authors: Fasulo Vittorio , Chiarelli Giuseppe , Buffi NicolòMaria , Avolio Pier Paolo , Garofano Giuseppe , Aljoulani Muhannad , Asselta Rosanna , Soldà Giulia , De Simone Ilaria , Colombo Piergiuseppe , Cieri Miriam , Hurle Rodolfo , Paciotti Marco , Casale Paolo , Maura Federica , Cavalli Pietro , Lughezzani Giovanni , Lazzeri Massimo 
Published: February 2025

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Background:
The increasing focus on patient-centered care and the development of precision medicine emphasize the need for alternative screening pathways for high-risk individuals. Family history is a significant risk factor for prostate cancer (PCa), and identifying patients with a genetic predisposition is crucial. The discovery of germline pathogenic variants (PVs) in DNA repair genes (DRGs) underscores the importance of a dedicated screening approach. This study aimed to evaluate the effectiveness and compliance of a tailored screening protocol in that population, incorporating the Prostate Health Index (PHI) and multiparametric MRI (mpMRI).
Methods:
This prospective study, based on a novel concept of a dedicated screening protocol and funded by AIRC (project IG 2020 ID 25027), was conducted at a tertiary hospital in collaboration with department of Oncology, Urology, Pathology, Radiology, and Medical Genetics. The study included men aged 35-69 with documented PVs in DRGs who consented to participate in the screening protocol. Probands were recruited in two categories: Male relatives of women with PVs in DRGs who were affected by breast or ovarian cancer; Male relatives of men with PVs in DRGs diagnosed with high-grade PCa (ISUP >2). Participants underwent annual PSA testing, PHI assessments, digital rectal examinations (DRE), and mpMRI based on individual risk stratification (PHI<20, 20<PHI<40, PHI>40).
Results:
Between 2021 and 2024, 102 patients were enrolled, with a median age of 52 years (IQR 46-61). Of these, 100 were from the women’s cohort, and 2 were from the men’s cohort. The median PSA level was 0.9 ng/mL (IQR 0.5-1.7), and the median PHI was 17 (IQR 12.0-23.2). The distribution of pathogenic variants (PVs) included BRCA2 (56.1%), BRCA1 (18.6%), ATM (4.92%), PMS2 (2.94%), and other less frequent PVs. Screening compliance was high, with 95% of patients completing the T1 visit, 86% completing the T2 visit, and 100% completing the T3 visit. Among patients with PHI >20 and <40, 81.5% underwent mpMRI. Only one patient had a positive mpMRI result and underwent a biopsy, which was negative for PCa. An additional three patients underwent biopsy due to clinical suspicion, with all resulting negative. Of those with PHI >40, 66.7% underwent mpMRI and, as per protocol, a biopsy, which also resulted negative for PCa. Interestingly, at T2, 33.3% of patients with PSA >3 had a PHI <20, thereby avoiding the need for mpMRI. Despite no cases of PCa being detected after three years of follow-up, two patients were diagnosed with bladder cancer (BC).
Conclusions:
This study demonstrated, so far, a low effectiveness in diagnosing prostate cancer (PCa), with no cases identified, in contrast to the results of the referral IMPACT study. However, compliance with the screening protocol was high, and the two cases of bladder cancer (BC) raise new perspectives on the role of PVs in DRGs and their relationship with urological neoplasms. Enrollment in the study is ongoing, and further follow-up may provide additional insights.