Comparative Study on Overexpression of HER2/neu and HER3 in Gastric Cancer

Abstract

Owing to the special importance of the HER family in tumorigenesis, the downstream signaling pathways and effectors have become the key molecules in the strategy of carcinoma-targeted therapy. Recent evidence that HER3 is responsible for tumor resistance to therapeutic agents targeting EGFR or HER2/neu, along with the new findings that HER3 is involved in the process of dedifferentiation of gastric cancer (GC) have highlighted the critical role of HER3 in cancer research. HER3 is becoming a new targeted molecule in cancer treatment. Here, we comparatively investigated the expression of HER2/neu and HER3 in gastric cancer of two pathologic types (intestinal type and diffuse type) using immunohistochemistry (IHC) and analyzed the correlation between overexpression of HER2 and HER3 and clinicopathologic parameters. An IHC study for HER2 and HER3 was performed on 102 formalin-fixed, paraffin-embedded specimens of GC-60 intestinal and 42 diffuse types. The correlation between overexpression of HER2 and HER3 and clinicopathologic parameters was statistically analyzed. In the GC group, overexpression of HER2 and HER3 was detected in 19 (18.6%) and 14 (13.7%) of 102 GC patients, respectively. In a nontumorous group of 102 specimens, 5 were HER2-positive (4.9%) (18.6% vs. 4.9%, p < 0.01), and 2 were HER3-positive (2.0%) (13.7% vs. 2.0%, p < 0.01). No co-overexpression of HER2 and HER3 was observed. The intestinal type of GC exhibited a higher rate of HER2 overexpression than did the diffuse type (26.7% vs. 7.1%, p < 0.05), whereas the diffuse type of GC exhibited a significantly higher rate of HER3 overexpression than did the intestinal type (26.2% vs. 5.0%, p < 0.01). The overexpression rates of HER2 and HER3 in phase III-IV (TNM stage) disease were significantly higher than that in phase I-II disease (24.0% vs. 7.7%, p < 0.05 and 22.0% vs. 5.8%, p < 0.05, respectively). HER2 and HER3 overexpression was also correlated with a significantly worse survival (p = 0.046 and 0.024, respectively). The selective overexpression of HER2 and HER3 in the two histologic types of gastric cancer is strongly associated with a poor prognosis. Being an important member of the HER family, HER3 may become another candidate for molecular-targeted therapy in gastric cancer, especially for the diffuse histologic type.