Abstract PR-08: Impact of gut microbiota on response to Bacillus Calmette-Guérin immunotherapy in bladder cancer: Towards a predictive molecular model

Abstract Objectives: Bladder cancer is the fifth most frequently diagnosed cancer in Canada. Approximately 75% of cases are non-muscle invasive bladder cancer (NMIBC). Treatment of high-risk NMIBC involves transurethral tumor resection followed by intravesical immunotherapy with Bacillus Calmette-Guerin (BCG) instillations. Unfortunately, 40% of patients relapse within five years. Several studies showed that gut microbiota influence immunotherapy response and identified specific bacteria capable of improving systemic immunotherapy effectiveness in a variety of cancers. However, it is still unknown whether these bacteria also play a role in BCG response. Methods and Results: We performed metagenomic analyses on fecal DNA from 58 NMIBC patients collected before their BCG treatment to catalog gut microbiota composition. We first tested the TOPOSCORE, a gut microbiota-based predictive model for systemic immunotherapy response validated in various cancers (Derosa et al., Cell 2024). Although this predictive score identifies 100% of BCG non-responders (NR), it showed low specificity (57%) in predicting BCG response. Our preliminary data suggest that 50% of the NR bacteria are associated with antibiotic resistance. In parallel, we found a unique microbiota signature linked to BCG response using whole-genome sequencing. Several BCG response-associated bacterial species (RABS) were uniquely associated with improved recurrence-free survival of NMIBC patients. These RABS appear to harbor no antibiotic resistance genes, making them promising candidates as probiotic adjuvants to BCG therapy in bladder cancer. Conclusion: Our results suggest that gut microbiota associated with non-response to systemic immunotherapy is similar to that of BCG non-responders in NMIBC, while the bacteria linked to BCG response differ. Our current research aims to develop a unique predictive molecular test based on the microbiota signature of NMIBC patients, which will predict clinical response to BCG and optimize the patient care. Moreover, RABS identification supports the development of a BCG adjuvant treatment via a probiotic supplementation to improve BCG response. Citation Format: Marine Boireau, Jalal Laaraj, Gabriel Lachance, Roxane Tourigny, Sandra Isabel, Yves Fradet, Karine Robitaille, Vincent Fradet. Impact of gut microbiota on response to Bacillus Calmette-Guérin immunotherapy in bladder cancer: Towards a predictive molecular model abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Mechanisms of Cancer Immunity and Cancer-related Autoimmunity; 2025 Sep 24-27; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(9 Suppl):Abstract nr PR-08.