The clinical impact of germline variants in DNA repair genes in patients who underwent curative surgery for localized prostate cancer.

321 Background: Family history represents a significant risk factor for prostate cancer (PCa), emphasizing its genetic basis. Early identification of germline pathogenic variants (PVs) in DNA repair genes (DRGs) is crucial for timely PCa diagnosis, prognosis, and for informing at-risk relatives. Conversely, the presence of variants of uncertain significance (VUS) has been associated with worse clinical outcomes. This study aimed to assess how the presence of germline PVs and VUS affect clinical and pathological outcomes in a monocentric cohort of patients who underwent robot-assisted laparoscopic prostatectomy (RALP) for PCa. Methods: This prospective study, supported by AIRC - Fondazione AIRC per la Ricerca sul Cancro (registered and emended with the number ID-IG-25027-V1.3), was conducted at a tertiary referral center in collaboration with the Departments of Oncology, Urology, Pathology, Radiology, and Medical Genetics. A total of 179 men aged 58–70 years who underwent RALP for localized PCa were screened for germline PVs and VUS in DRGs prior to surgery. Patients were enrolled if they had an ISUP grade ≥3 at biopsy and/or a confirmed PCa diagnosis at ≤50 years of age. Individuals harboring a VUS or PVs were compared to those with negative genetic results. Results: Of the 179 patients screened between 2021 and 2024, 163 shared the results of genetic testing. Median age at surgery did not differ between groups (65 years, IQR 59–70). Among them, 114 (69.9%) tested negative, while 39 (29.4%) and 9 (5%) carried a VUS or PVs in DRGs, respectively. The most frequent VUS involved ATM (22.2%), CHEK2 (15.6%), BRCA2 (13.3%), ATR (6.7%), NBN (6.7%), RAD51D (6.7%), and MSH6 (4.4%). The nine PVs identified were: BRCA2, PALB2 + NBN, PALB2 + BRCA2, BRCA1 PALB2, CHEK2 + PMS2, CHEK2, and ATM . A family history of cancer was reported in 50% of VUS/PV carriers compared to 34.6% of non-carriers. High-grade PCa (ISUP >3) was found in 46.3% of carriers versus 38.0% of non-carriers. A pathological stage ≥pT3a occurred in 53.6% of carriers versus 45.1% of non-carriers, while nodal involvement (pN1) was more frequent among carriers (21.4% vs 12.6%). Biochemical recurrence (BCR) occurred in 36.8% of carriers versus 30.4% of non-carriers. Conclusions: This study provides valuable insight into the role of germline VUS, by the first, and PVs in DRGs among PCa patients, suggesting that such variants may confer a less favorable disease course. Although differences did not reach statistical significance, carriers tended to present with higher-grade and more advanced disease at final pathology. Genetic screening for PCa may therefore aid not only in early detection among high-risk individuals but also in guiding clinical management and follow-up strategies.