Genomic Landscape of Late-Stage Gastric Cancer: Analysis From KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 Studies

PURPOSE The Cancer Genome Atlas (TCGA) classifies gastric cancer (GC) into four molecular subtypes: Epstein-Barr virus–positive, microsatellite instability–high (MSI-H), genomically stable (GS), and chromosomal instability (CIN). This exploratory analysis compared the genomic landscape of late-stage GC from KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 studies with early-stage GC from TCGA and evaluated the genomic characteristics of late-stage GC in patients of Western and Asian origin. MATERIALS AND METHODS Using pretreatment tumor samples, bulk DNA was analyzed via whole-exome sequencing (WES; KEYNOTE-059/KEYNOTE-061) and FoundationOneCDx (KEYNOTE-062) to determine TCGA-defined molecular subtypes (only MSI-H is determinable from FoundationOneCDx), genomic alterations, homologous recombination deficiency (HRD), and tumor mutational burden (TMB); gene expression signatures were analyzed using RNA sequencing. RESULTS When comparing KEYNOTE-059/061/062 combined WES and FoundationOneCDx data with data from TCGA, the MSI-H subtype prevalence was numerically lower in patients of Western (5% v 22%) and Asian origin (5% v 19%). When comparing KEYNOTE-059/061 WES data with the TCGA data set, the GS subtype prevalence was numerically higher (36% v 21%) in patients of Western or Asian origin. Among subtypes in KEYNOTE-059/061, HRD scores and TMB trended highest in CIN and MSI-H subtypes, respectively. TP53 mutation was the most prevalent genomic characteristic per KEYNOTE-059/061/062 combined analysis in patients of Western or Asian origin. Gene expression signature distributions were generally similar between patients of Western and Asian origin. CONCLUSION Numerical differences in the prevalence of MSI-H and GS subtypes were observed between early-stage and late-stage GC. Genomic characteristics of late-stage GC were generally similar between patients of Western and Asian origin.