Genomic Correlations for Clinical Outcomes in HER2-positive Advanced Gastric Cancer Treated Using Trastuzumab-based Therapy

Abstract

Background/aim: 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.

Patients and 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% of patients 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=0.007). NOTCH3 alterations were associated with shorter PFS (log-rank p=0.003). 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.

Conclusion: 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.

Keywords: ERBB2 copy number amplification; ERBB2 focal amplification; HER2 positive; NOTCH3; advanced gastric cancer; trastuzumab.