Prognostic implications of tissue-based homologous recombination deficiency in metastatic gastric cancer treated with immune checkpoint inhibitor plus chemotherapy.

Abstract

Background: Homologous recombination deficiency (HRD), a genomic instability phenotype resulting from impaired DNA repair, has been associated with increased tumor immunogenicity in several solid tumors. However, its clinical relevance in metastatic gastric cancer (mGC), particularly in the context of immunotherapy-containing regimens, remains unclear.

Methods: This study included 139 GC patients with nivolumab plus chemotherapy as first line between May 2022 and May 2024 and underwent tissue-based NGS (n = 116); a smaller subset additionally underwent ctDNA-based NGS (n = 24). HRD was defined by the presence of pathogenic or likely pathogenic variants in predefined homologous recombination repair (HRR) genes. Treatment outcomes, and molecular characteristics were compared according to HRD status based on tissue- and/or circulating tumor DNA (ctDNA) NGS results.

Results: Among 116 patients who underwent tissue-based NGS, HRD-positive tumors (14.7%) were significantly associated with longer progression-free survival (PFS; median 23.1 vs. 9.6 months; p = 0.032) to immune checkpoint inhibitor (ICI) plus chemotherapy and overall survival (OS; median not reached vs. 17.9 months; p = 0.027). HRD positivity remained an independent favorable prognostic factor for OS in multivariate analysis (HR: 0.247; 95% CI 0.071-0.859; p = 0.028). HRD-positive tumors showed higher frequencies of high tumor mutational burden (TMB) and microsatellite instability (MSI)-high tumors. However, exploratory analysis of ctDNA-based HRD in a small subset did not demonstrate a statistically significant association with survival outcomes.

Conclusion: Tissue-based HRD positivity was associated with favorable survival outcomes and may provide complementary prognostic information in mGC patients with nivolumab plus chemotherapy as first line.