Abstract 6600: Dissecting genomic features of BCG unresponsive non-muscle-invasive bladder cancer identifies drivers of sensitivity to intravesical gemcitabine/docetaxel

Introduction: Intravesical Gemcitabine/Docetaxel (GemDoce) is an effective therapy in patients with Bacillus Calmette-Guérin (BCG) unresponsive non-muscle-invasive bladder cancer (NMIBC) with 50% response at 2 years. However, the genomic landscape of BCG-unresponsive NMIBC and whether distinct mutations are associated with response and resistance to sequential intravesical GemDoce is unknown. Our goal is to define mutational features of BCG-unresponsive NMIBC and nominate genomic drivers of response and resistance to GemDoce. Methods: We identified patients with BCG unresponsive NMIBC who subsequently received intravesical Gem/Doce. We performed whole-exome sequencing of BCG unresponsive bladder tumors (total tumors n=23; Tumor-normal pairs n=3; Tumor-only n=20) prior to GemDoce administration and classified patients in “responders” (recurrence free survival (RFS) > 18 mo) and “non-responders” (RFS < 18 mo). The Broad Institute’s CGA pipeline was used to account for mutation calls, ABSOLUTE was used to define copy number alterations (CNA) and PhylogicNDT was applied to model phylogenetic and evolutionary tumor trajectories. Results: Median follow-up was 45 months. Median time to HG-recurrence and cystectomy were longer in the responder group (33 mo, 28 mo) in comparison to the non-responder group (3.5 mo, 8 mo). We identified alterations in known bladder cancer genes including TP53 (10/20 tumors), KDM6A (9/20 tumors) and FGFR3 (5/20 tumors) in both responders and non-responders. Most alterations in TP53 and KDM6A were predicted loss-of-function mutations, consistent with the known tumor suppressor roles for these genes. Mutations in two genes that control cell division and chromosomal stability, CREBBP and STAG2, were exclusively present in responders to GemDoce. Both responders and non-responders harbor CNA in CDKN2A that characterize NMIBC. However, FGFR3, E2F2 and MDM2 amplifications were exclusively present in non-responders. Phylogenic analysis showed BRCA1 clonal mutations and subclonal BRCA2 mutations only in responders. Conclusions: BCG unresponsive NMIBC harbor mutational features that biologically explain response to GemDoce. Mutations in CREBBP and STAG2, and clonal BRCA1 mutations may sensitize tumors to GemDoce resulting in long-term responses to intravesical chemotherapy. Future efforts should focus on determining the presence of CREBBP and STAG2 using immunohistochemistry prior to GemDoce to improve intravesical treatment response in NMIBC. Citation Format: Matias Vergara, Kendrick Yim, Kevin R. Melnick, Brendan Reardon, Timothy N. Clinton, Matthew Mossanen, Graeme S. Steele, Michelle S. Hirsch, Natalie M. Rizzo, Kent W. Mouw, Matthew F. Wszolek, Keyan Salari, Adam S. Feldman, Adam S. Kibel, Eliezer M. Van Allen, Mark A. Preston, Filipe LF. Carvalho. Dissecting genomic features of BCG unresponsive non-muscle-invasive bladder cancer identifies drivers of sensitivity to intravesical gemcitabine/docetaxel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6600.