Genomic correlations for clinical outcomes in HER2-positive advanced gastric cancers treated using trastuzumab-based therapy

Abstract Purpose Although trastuzumab-based chemotherapy improves survival in HER2-positive advanced gastric cancer, some patients demonstrate suboptimal efficacy and limited response durations. We examined the relationship between clinical outcomes and genomic features, including co-mutations and the length of the ERBB2-amplified segment. Methods We retrospectively analyzed 151 patients who had received first-line trastuzumab-based chemotherapy. Targeted next-generation sequencing was employed to assess genomic alterations. Progression-free survival (PFS) was defined as time from treatment initiation to disease progression or death. Results The median patient age was 62 years, and 73.5% were male. The median follow-up period was 45.8 months, and the median PFS was 8.2 months (95% confidence interval (CI), 6.5–9.4). Patients with a focal amplification of ERBB2 (≤ 879 Kb) had significantly longer PFS compared to those with non-focal amplifications (> 879 Kb) (10.1 vs. 6.1 months; log-rank p = 0.01). NOTCH3 alterations were associated with shorter PFS (log-rank p = 0.002). Multivariate analysis confirmed that ERBB2 focal amplification is an independent prognostic factor associated with improved prognosis, whereas NOTCH3 alterations serve as an independent prognostic factor for poorer outcomes. Conclusions ERBB2 focal amplification is associated with improved outcomes in trastuzumab-treated patients with HER2-positive gastric cancer, whereas NOTCH3 alterations predict a poor prognosis. These genomic features may support risk stratification and therapeutic decisions.