Multicenter large-scale study of prognostic impact of HER2 expression in patients with resectable gastric cancer

Although some small-scale studies have suggested that human epidermal growth factor receptor 2 (HER2)-positive status in gastric cancer is associated with poor outcomes, the prognostic value of HER2 is still controversial. Since intratumoral HER2 heterogeneity is also an important issue, a multicenter large-scale study was conducted to evaluate the prognostic impacts of HER2 expression and intratumoral heterogeneity in gastric cancer. This study included 1,148 gastric cancer patients who underwent gastrectomy in 11 institutions. HER2 expression was centrally evaluated with immunohistochemistry and fluorescence in situ hybridization, and intratumoral HER2 heterogeneity was evaluated for HER2-positive tumors. Overall survival was compared between HER2-positive and HER2-negative patients and between the homogeneous and heterogeneous groups. The HER2-positive rate was 15.7 %, and HER2 expression was significantly associated with histological type. HER2 expression scores obtained by immunohistochemistry showed a distinct influence on survival, and HER2-positive patients showed much poorer survival than HER2-negative patients [hazard ratio (HR) 1.59, 95 % confidence interval (CI) 1.24-2.02; P < 0.001). The subgroup analysis by pathological tumor stage showed a similar trend of poor survival in HER2-positive patients. Both intestinal type and diffuse type showed significant poor survival in HER2-positive patients. Cox multivariate analysis revealed that HER2 expression was an independent prognostic factor (HR 1.96, 95 % CI 1.51-2.55; P < 0.001). HER2 heterogeneity was observed in 75.4 % of HER2-positive cases, but the prognosis in the heterogeneous group was similar to that in the homogeneous group. Our study demonstrated that HER2 overexpression is an independent prognostic factor in patients with any stage of resectable gastric cancer. Intratumoral HER2 heterogeneity did not affect prognosis.