Abstract A003: Exploring the molecular landscape of urothelial carcinoma leveraging GENIE: Identifying biomarkers for targeted therapy and precision medicine

Abstract Introduction: At the 9th most common cancer globally, bladder cancer (BC) poses a significant burden to healthcare. Treatments for BC are largely confined to surgical resection and chemotherapy for the muscle-invasive subtype, while BCG immunotherapy can be beneficial for the non-muscle-invasive subtype. However, these approaches generally have limited efficacy and are associated with high recurrence rates. To address these challenges and improve patient outcomes, a deeper understanding of the molecular landscape of BC is essential to aid-in classification and tailoring of targeted therapies. Methods: Data was retrieved from an open-source AACR Project GENIE cancer genomics database of 184,988 patients, of which 3814 patients with BC, specifically Urothelial Carcinoma (UC) patients were filtered out. This cohort was then studied on the molecular level, using the portal's “gene query” tool to analyze NGS data in order to understand the genetic landscape and identify significant biomarkers as potential therapeutic targets for BC. Results: A comprehensive list of reliable biomarkers which could serve as potential targets for therapy were retrieved and analyzed at the molecular level. The 9 most commonly mutated genes in our cohort were investigated: TP53, TERT, KMT2D, ARID1A, KDM6A, FGFR3, PIK3CA, RB1, & ERBB2. Using OncoKB, each gene was individually validated for its predictive potential as a target for therapy. Amongst these, only FGFR3 has an FDA-approved therapy, Erdafitinib. In a clinical trial that was conducted comparing its efficacy to chemotherapy in advanced UC, Erdafitinib therapy resulted in significantly increased OS and response rate, highlighting its established therapeutic relevance. While the remaining eight genes have FDA-approved drugs for cancers other than UC, evidence of their efficacy in UC is unknown; emphasizing the need for further research exploring their potential as therapeutic targets to develop effective targeted treatments. Integrating predictive biomarkers from existing therapies into gene mutations without approved treatments, supported by strong evidence of their potential effectiveness, holds significant potential for advancing BC treatment. By applying these well-researched biomarkers to uncharted genetic territories, further research can identify new therapeutic targets and develop more personalized treatment plans. This can expand treatment options for BC patients, leveraging existing knowledge to discover effective therapies, improve outcomes, and address unmet clinical needs. Conclusions: Current challenges in BC treatment necessitate a transformative shift towards a new treatment paradigm. Embracing molecular profiling marks a new era of precision medicine by standardizing approaches that enhance treatment efficacy and clinical outcomes. This advancement represents a crucial step towards addressing the complexities of BC and revolutionizing patient care. Citation Format: Osama Alsmadi, Ayah S Alsmadi, Nour Ibrahim, Mohammed Alarayedh, Yusra Bdair, Haneen Elhuneidi, Sinan Alsmadi, Leen Musleh. Exploring the molecular landscape of urothelial carcinoma leveraging GENIE: Identifying biomarkers for targeted therapy and precision medicine [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A003.