Abstract B021: Spatial dynamic transcriptomic characterization of response patterns to neoadjuvant chemotherapy in muscle-invasive bladder cancer

Abstract

Abstract Defined by a high mutational burden and a heterogeneous tissue landscape, muscle-invasive bladder cancer (MIBC) is an aggressive disease with a 5-year mortality rate of approximately 50%. To lower the risk of relapse and improve survival, cisplatin-based combination neoadjuvant chemotherapy (NAC) is recommended prior to radical cystectomy, but response rates are limited to only 30-50% of patients. Importantly, patients in whom NAC treatment induces a pathological downstaging of the primary tumor to pT0/pTis have a significantly increased 5-year mortality of 85% compared to 43% for patients with resistant ≥ pT2 tumors. Thus, the current inability to stratify patients who are most likely to benefit from NAC treatment results in a considerable overtreatment of non-responders. The effectiveness of chemotherapy can be influenced by numerous factors, including intrinsic or acquired tumor resistance mechanisms or the selection of pre-existing treatment-resistant clones. Previous literature on MIBC has recognized several tumor characteristics associated with chemosensitivity, including somatic mutations in DNA repair-associated genes, chromosomal alterations, immune cell infiltration, and distinct variant histologies, but no robust biomarkers have yet been implemented in clinical routine. Thus, further in-depth characterization of the tumor architecture of MIBC is highly needed. We aim to perform a comprehensive spatial mapping of the transcriptomic landscape of MIBC through analysis of longitudinal tumor tissue samples from patients (n=15) treated for MIBC at Skåne University Hospital, Sweden, with divergent response patterns to NAC. Multiregional sampling from pre-NAC tissue specimens derived from transurethral resection of the bladder tumor (TURBT) and post-NAC radical cystectomy will be performed and incorporated into tissue microarrays. GeoMx Digital Spatial Profiler Cancer Transcriptome Atlas panel (Nanostring Technologies) will be applied for high-plex compartment-specific expression of genes covering important aspects of tumor biology and tumor-immune interaction, as well as a customized panel including RNA-binding motif protein 3 (RBM3), a gene previously associated to cisplatin sensitivity in several cancer types including urothelial cancer. Gene expression will be quantified through next-generation sequencing and related to clinical and pathological data. Hereby, we aim to gain insights into mechanisms of chemosensitivity and durable response that could potentially refine treatment protocols towards more tailored approaches. Citation Format: Sara Wahlin, Karolina Boman, Björn Nodin, Gottfrid Sjödahl, Karin Jirström. Spatial dynamic transcriptomic characterization of response patterns to neoadjuvant chemotherapy in muscle-invasive bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B021.