HER2 copy number as predictor of disease-free survival in HER2-positive resectable gastric adenocarcinoma

Abstract

Purpose: The 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.

Methods: We 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.

Results: Of 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.

Conclusion: We 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.

Keywords: Copy number; HER2; Resectable gastric adenocarcinoma; Survival.

Fig. 1

Heatmap of patients harboring genetic mutations in tumor samples retrieved from targeted next-generation sequencing panel consisting of 41 gastrointestinal cancer-related genes

Fig. 2

Correlation of HER2 copy number with clinicopathologic features in HER2-positive resectable GA patients. (a), age; (b), gender; (c), stage; (d), Lauren’s classification; (e), histological grade; (f), tumor location; (g), perineural invasion; (h), lymphatic/venous invasion; (i), ulcer findings. GA gastric adenocarcinoma, CN copy number, HER2 human epidermal growth factor receptor 2

Fig. 3

Kaplan–Meier curves of HER2 CN-high and CN-low patients for DFS and OS. a Kaplan–Meier curves of HER2 CN-high and CN-low patients for DFS in stage I-III patients; b, Kaplan–Meier curves of HER2 CN-high and CN-low patients for DFS in stage III patients; c Kaplan–Meier curves of HER2 CN-high and CN-low patients for OS in stage III patients. DFS disease-free survival, OS overall survival, CN copy number, HER2 human epidermal growth factor receptor 2

Fig. 4

Kaplan–Meier curves of HER2 CN-high and CN-low patients for DFS in patients with intestinal-type GA. DFS: disease-free survival. CN: copy number; HER2: human epidermal growth factor receptor 2