Abstract 1610: Elucidating tumor evolution and heterogeneity in metastatic bladder cancer from rapid autopsies

Abstract Background: Bladder Cancer is a highly prevalent cancer with staggering mortality of about 20%. Metastatic BLCA (mBLCA) with variant histologies are aggressive and have a poor prognosis. The extent and impact of tumor heterogeneity in these variant subtypes are not fully understood. This work explores the intricate characterization of intra-patient and inter-patient tumor heterogeneity through genomic and transcriptomic analyses, drawing insights from a unique rapid autopsy cohort comprising 20 patients. The resulting revelations provide critical perspectives on heterogeneity and clonal evolution in mBLCA, underscoring the essential role of understanding these dynamics for the development of personalized treatment strategies. Approach: Our research focuses on the genetic and molecular characteristics of these tumors, including the vast landscape of tumor heterogeneity, clonal evolution, genomic alterations, mutational signatures, and structural variants. Within the tumor microenvironment, we identified diverse cell populations with distinct genetic profiles. A detailed examination of mutational signatures sheds light on the specific processes underlying genetic alterations, while the investigation of structural variants elucidates their consequential role in cancer development and progression. Advanced bioinformatics tools are deployed to process and interpret the vast genomic and transcriptomic datasets, facilitating the identification of clonal populations, their genetic features, and the trajectory of clonal evolution. Furthermore, statistical models are employed to discern correlations between mutational signatures, treatment responses, and clinical outcomes. Summary: The study unveils substantial inter-patient heterogeneity and discernible differences in mutational signatures, revealing intriguing correlations with treatment responses. These variations are intricately connected to underlying genomic alterations, copy number alterations, and gene expression patterns, offer a detailed perspective on the molecular landscape of mBLCA. Conclusion: This multi-omics exploration stands as the most extensive study of its kind, leveraging rapid autopsy samples of metastatic variant histology BLCA. The research provides unprecedented resolution of genomic alterations and intra- and inter-patient tumor heterogeneity. The exploration of clonal evolution enhances our appreciation of the temporal dynamics of tumor progression, establishing a robust foundation for future therapeutic interventions precisely targeting evolving tumor clones. As we advance into an era of personalized medicine, these findings pave the way for tailored therapeutic strategies in the challenging landscape of metastatic variant histology Bladder Cancer. Citation Format: Pushpa Itagi, Sonali Arora, Thomas Persse, Michael Yang, Patricia Galipeau, Yixin Lin, Funda Vakar-Lopez, John K. Lee, Petros Grivas, Robert B. Montgomery, Jonathan L. Wright, Hung-Ming Lam, Andrew Hsieh, Gavin Ha. Elucidating tumor evolution and heterogeneity in metastatic bladder cancer from rapid autopsies abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1610.