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

Abstract

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.