Topography of Tumor Mutational Burden (TMB) and Immune-related Genomic Alterations (GA) Across Gastrointestinal Malignancies (GIm): A Study of 22,570 Cases

Abstract

Background: Response to immune checkpoint inhibitors (ICPIs) is mediated in part by tumor neoantigens. TMB has emerged as a predictive biomarker, but data is lacking in GIm. We examined TMB and concurrent GA across GIm to identify patient subsets for further study. Methods: Comprehensive genomic profiling was used to determine TMB, microsatellite instability (MSI), and additional GA using previously described methods. GA were compared among anatomically defined tumor types and stratified by TMB status (mutations/ DNA megabase), and those associated with response or resistance to ICPIs were compared to identify patient subsets. Results: Median TMB was higher for tubular vs. non-tubular GIm (p=0.032). Among the entire cohort, 3.5% and 7.4% of samples had a TMB >20 and>10, respectively. The proportion of tumors with TMB≥10 was greatest within tubular foregut structures (esophagus, stomach, duodenum; 11.2%). MSI was observed across all anatomic subtypes (range: 0.2-6%). Overall 1.2% of cases harbored receptor tyrosine kinase (RTK) fusions; colon and biliary tumors with RTK fusions had high (11) and low (2.5) median TMB, respectively. Validated immunoresponsive GA including PD-L1 amplification and POLE mutations were mutually exclusive and enriched in tubular GI structures [esophagus (0.5%), stomach (0.8%), colon (0.9%), duodenum (1.3%) and rectum (0.9%)]. POLE mutation, but not PD-L1 amplification, correlated with high TMB (median 100 and 5.4, respectively). PIK3CA catalytic (H1047R) vs. helical (E545K) domain GA were strongly associated with high TMB (p<0.0001), and similar findings were observed within MSI vs. MSS samples (p<0.0001). Pre-existing GA that may decrease ICPI responsiveness including or JAK1 inactivating GA were rare (4.7% and 0.3% of cases, respectively). Representative clinical cases will be presented. Conclusions: GAs associated with increased sensitivity and/or resistance to ICPIs are observed across GI cancers. Baseline genomic profling may inform rational patient selection for immunotherapy treatment. The observation that high TMB and MSI are strongly enriched for PIK3CA H1047R, and whereas low TMB and MSS are enriched for E545K, warrants further study.