Abstract
PurposeThe identification of HER2 overexpression in a subset of gastric adenocarcinoma (GA) patients represents a significant step forward in unveiling the molecular complexity of this disease. The predictive and prognostic value of HER2 amplification in advanced HER2 inhibitor-treated GA patients has been investigated. However, its predictive value in resectable patients remains elusive.MethodsWe enrolled 98 treatment-naïve resectable Chinese GA patients with HER2 overexpression assessed using IHC. Capture-based targeted sequencing using a panel consisting of 41 gastrointestinal cancer-related genes was performed on tumor tissues. Furthermore, we also investigated the correlation between HER2 copy number (CN) and survival outcomes.ResultsOf the 98 HER2-overexpressed patients, 90 had HER2 CN amplification assessed using next-generation sequencing, achieving 92% concordance. The most commonly seen concurrent mutations were occurring in TP53, EGFR and PIK3CA. We found HER2 CN as a continuous variable was an independent predictor associated with DFS (p = 0.029). Our study revealed HER2 CN-high patients showed a trend of intestinal-type GA predominant (p = 0.075) and older age (p = 0.07). The median HER2 CN was 15.34, which was used to divide the cohort into CN-high and CN-low groups. Patients with high HER2 CN had a significantly shorter DFS than patients with low HER2 CN (p = 0.002). Furthermore, HER2 CN as a categorical variable was also an independent predictor associated with DFS in patients.ConclusionWe elucidated the mutation spectrum of HER2-positive resectable Chinese GA patients and the association between HER2 CN and DFS. Our work revealed HER2 CN as an independent risk factor predicted unfavorable prognosis in HER2-positive GA patients and allowed us to further stratify HER2-positive resectable GA patients for disease management.
Highlights
Gastric cancer (GC) is the fifth most frequently diagnosed cancer and the third leading cause of cancer death in the world (Bray et al 2018)
Our work demonstrated that HER2 copy number (CN) as a continuous variable was significantly associated with Disease-free survival (DFS) in the univariable Cox proportional hazards regression model (HR: 1.02, 95% CI 1.00–1.04, p = 0.025) and it retained the significant association with DFS in the multivariate Cox proportional hazards regression model (HR: 1.05, 95% CI 1.01–1.09, p = 0.029) (Table 2)
Our work revealed that HER2 CN either as a categorical variable or as a continuous variable was the independent risk factor associated with DFS in HER2-positve resectable gastric adenocarcinomas (GA) patients
Summary
Gastric cancer (GC) is the fifth most frequently diagnosed cancer and the third leading cause of cancer death in the world (Bray et al 2018). It is well known that 8–30% gastric adenocarcinomas (GA) show HER2 overexpression or gene amplification (Aditi et al 2016; Bang et al 2010; Cordero-García et al 2019; Qiu et al 2017; Shen et al 2016; Shitara et al 2013). The ToGA (Trastuzumab for Gastric Cancer) trial reveals that HER2- positive patients experienced longer overall survival (OS) after treated with trastuzumab plus chemotherapy compared with HER2-positive patients treated with chemotherapy alone (Bang et al 2010). The prognostic value of HER2 overexpression or gene amplification in resectable GA patients remains controversial. HER2 amplification was assessed by targeted next-generation sequencing (NGS) using a panel consisting of 41 gastrointestinal cancer-related genes, and the predictive and prognostic value of HER2 amplification in patients with HER2-positive resectable GA was investigated
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