Germline DNA repair gene variants in patients under active surveillance for low-grade bladder cancer: Implications for risk stratification.

849 Background: The growing interest in de-intensifying therapeutic strategies for low-grade bladder cancer (BC), including active surveillance (AS), highlights the imperative need for precise patient stratification criteria. The major clinical challenge is the identification of patients at risk for progression to high-grade disease. To address this unmet need, we investigated the role of germline pathogenic variants (PVs) and variants of unknown significance (VUS) in DNA repair genes (DRG) to refine patient selection for AS. Methods: This ongoing prospective study includes patients with bladder cancer who have been enrolled in an AS protocol for a minimum of 12 months. Whole-exome sequencing was performed to screen for PVs and VUS in DRG (including TM, ATR, MRE11A, BAP1, BARD1, BRCA1, NBN, BRCA2, PALB2, BRIP1, CHEK2, RAD51C, FAM175A, RAD51D, GEN1, XRCC1, and the mismatch repair genes MLH1, PMS2, MSH2, and MSH6). The inclusion criteria for AS include suspicious recurrence at follow-up cystoscopy following a histopathologically confirmed diagnosis of low-grade pTa/pT1a NMIBC, with a maximum of five suspicious lesions, each no larger than 1 cm in diameter, absence of gross hematuria, and negative urinary cytology (UC). The primary endpoint was to describe the prevalence of PVs and VUS in AS patients. Patients with high-grade NMIBC and muscle-invasive bladder cancer (MIBC) were included as positive controls and screened for the same set of genes. This study is funded by the Associazione Italiana per la Ricerca sul Cancro (AIRC) under Protocol ICH-2812, code IG 2020-ID-25027. Results: From January to June 2024, a total of 15 patients under AS were tested. The median duration of surveillance at the time of testing was 16 months. All patients had a history of low-grade bladder cancer, with a median interval of 23 months between initial diagnosis and entry into the active surveillance protocol. None of the patients in the AS cohort harbored pathogenic variants in the targeted genes analyzed. In the positive control group, consisting of 10 patients with HG-NMIBC and 16 with MIBC, a total of 18 variants were identified, including 17 VUS and 1 PV. The distribution of variants was as follows: ATM (N=4), ATR (N=3), BARD1 (N=3), PMS2 (N=2), with one variant each in BRCA2, MSH6, NBN, PALB2, and GEN1. The single risk variant was detected in the CHEK2 gene. Conclusions: Our study indicates that none of the patients under AS with NMIBC harbored PVs or VUS the targeted genes. On the contrary, in the positive control group (NMIBC and MIBC), multiple VUS and one risk variant were identified, suggesting that germline DNA repair gene analysis may be more relevant in higher-risk bladder cancer cohorts. These findings underscore the need for further investigation into the utility of genetic screening, which might play a crucial role in refining patient selection for AS protocols in the future.