Predictive value of homologous recombination-related gene mutations in survival outcomes of first-line nivolumab plus chemotherapy for gastric cancer

Abstract

Background: Homologous recombination repair (HRR) gene mutations contribute to genomic instability. However, their clinical value in immune checkpoint inhibitor (ICI)-based treatments in gastric cancer remains unclear. Therefore, this study aims to investigate the efficacy of nivolumab plus chemotherapy according to the HRR mutation status in patients with advanced gastric cancer.

Methods: This single-center study included patients with gastric cancer with available panel sequencing results who were treated with first-line nivolumab plus chemotherapy (n = 115) or chemotherapy alone (n = 172). Mutation status of 17 HRR genes (BARD1, BLM, BRCA1, BRCA2, BRIP1, MRE11A, NBN, PALB2, PARP1, POLD1, RAD50, RAD51, RAD51C, RAD51D, RAD52, RAD54L, and XRCC2) was assessed using targeted next-generation sequencing.

Results: Among patients treated with nivolumab plus chemotherapy, 36.5% had HRR mutations, with BRCA2 mutation being the most common mutation (11.3%). Compared to those of the no-HRR mutation group, the HRR mutation group exhibited a higher objective response rate, longer progression-free survival (PFS) (median 12.8 vs. 6.5 months; hazard ratio HR 0.57), and overall survival (OS) (median not reached vs. 14.2 months; HR 0.40) with nivolumab plus chemotherapy. Patients with HRR mutations treated with nivolumab plus chemotherapy showed favorable PFS and OS compared to those treated with chemotherapy alone. However, this difference was not observed in patients without HRR mutations.

Conclusions: HRR mutations were associated with favorable survival outcomes in patients treated with nivolumab plus chemotherapy. Our findings suggest that HRR mutations may serve as a potential predictive biomarker for first-line ICI-based chemotherapy in gastric cancer.

Keywords: Gastric cancer; HRR mutation; Nivolumab plus chemotherapy; Predictive biomarker.