Abstract 2515: Cation transport gene signature predicts overall and progression free survival in bacillus-calmette-guerrin-treated non-muscle invasive bladder cancer in The Cancer Genome Atlas

Abstract                Introduction: Bacillus Calmette-Guerrin (BCG) is a commonly used immunotherapy for non-muscle invasive bladder cancer (NMIBC), and there is limited understanding of its in vivo mechanisms. In vitro studies on patient-derived tumor cells suggest the role of calcium signaling as an effector of immune response. We aimed to elucidate further understanding of important signaling pathways implicated in BCG response using gene expression data. The goal is to identify a gene signature for predicting BCG response and survival post-BCG therapy.                Methods: Gene expression data for the BCG treated NMIBC cohort was downloaded from TCGA. Individual gene expression data analyzed with univariate cox proportional hazard models versus overall survival (OS) and progression-free survival (PFS) independently. The survival outputs were then fed into String DB network analysis. Overlapping genes in the 2 networks were combined into a Z- sum composite score for survival prediction. Correlation analysis was performed for the overlapping genes.                Results: Based on the selection criteria, 35 patients were available for the study. In OS analysis a total of 622 genes were filtered based on HR&amp;gt;2 or &amp;lt;0.5 with adjusted-p &amp;lt;0.05. Network analysis of those significant genes demonstrated significant calcium ion transmembrane transport upregulation in patients with better OS, showing a subnetwork of 16 genes. In the PFS analysis, 500 genes with HR&amp;gt;2 or &amp;lt;0.5 with adjusted-p&amp;lt;0.05 were subjected to network analysis. The main cluster was enriched in cation transmembrane transport upregulated in patients with better PFS, and consisted of a subnetwork of 39 genes. There were 295 shared genes between the genes associated with improved OS and PFS gene sets. A composite score constructed from these 295 genes revealed an optimized cutoff of the lower 70th percentile of expression versus the upper 30th percentile of normalized summed gene expression (HR = 0.192, p = 0.00048 for OS; and HR = 0.171, p &amp;lt; 0.0001 for PFS). Internal correlation reveals 3 sub-clusters of gene expression within our data set.                Conclusion: Similar to in vitro studies we report increased cation transport expression in vivo, that was significantly associated with improved OS after BCG immunotherapy. Our composite gene signature score was able to identify a poor survival subgroup—about 1/3 of patients—with 5-fold worse PFS and OS following BCG therapy. Increasing calcium signaling may potentiate BCG response in currently poor BCG-responders.                Citation Format: Lynn Kim Hoang Tran, Seth P. Lerner. Cation transport gene signature predicts overall and progression free survival in bacillus-calmette-guerrin-treated non-muscle invasive bladder cancer in The Cancer Genome Atlas [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(6_Suppl):Abstract nr 2515.