The mutational pattern of homologous recombination (HR) related genes and its relevance to response to immunotherapy in gastric cancer.

Abstract

e16579 Background: Although therapeutic strategies based on immune checkpoint inhibitors (ICIs) have been introduced for gastric cancer (GC), there is still a pressing need to find potential predictive therapeutic biomarkers beyond PD-L1 expression to help patients to derive more benefit from these therapies. Homologous recombination deficiency (HRD) could modify tumor immune microenvironment by increasing the presence of tumor-infiltrating lymphocytes (TILs) indicating that HRD might be a biomarker of immunotherapies. Our aim was to analyze the mutational pattern of HR related genes in a large Chinese GC cohort and its relevance to tumor immune profile and clinical response to immunotherapy. Methods: A panel of 543 cancer related genes was used to analyze the genomic profiling of Genecast cohort which is consisted of 484 Chinese patients with GC. The correlation between HR-gene mutations and tumor immunity or clinical outcome using two GC genomics datasets (TCGA and MSK-GC) by the bioinformatic approach. Results: Fifty-one of 484 (10.54%) patients had at least one somatic mutation in HR-gene, ATM (16/484, 3.31%), ATRX (14/484, 2.89%), and ATR (13/484, 2.69%) were among the top mutated HR-gene in Genecast cohort. Mutations in HR-gene are associated with elevated TMB, enhanced immune activity, and microsatellite instability (MSI) status. In MSK-GC cohort, including a total of 49 patients who had stomach adenocarcinoma (STAD) or gastroesophageal junction adenocarcinoma (GEJ) and treated with ICIs, HR-mut GC (n = 12) had a significantly better OS than HR-wt GC (n = 37) (log-rank test, P = 0.034). Conclusions: Our data suggests that detection of somatic mutations of HR-gene could expand the proportion of patients who might get benefit from immune checkpoint blockade therapy response.