These results reveal that all members of the HER family are expressed in GC. Furthermore, expression of HER2 and HER3 is a significant predictor of poor survival in GC. Therefore, the development of HER-targeted agents and agents targeting downstream signaling pathways provides new possibilities in the treatment of GC.

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The human epidermal growth factor receptors (EGFR) family consists of four members: ErbB-1 (HER1), ErbB-2 (HER2), ErbB-3 (HER3) and ErbB-4 (HER4). These receptors activate numerous downstream pathways in response of extracellular ligands, regulating diverse processes including differentiation, migration, proliferation, and survival. Alterations in EGFR family members play a role in the development and progression of many human cancers. In gastric carcinomas (GC), HER1 and HER2 overexpressions are thought to be prognostic factors and targets of novel biological agents. The effect of HER3 or HER4 expression in GC has not been sufficiently studied. HER3 expression is observed frequently in advanced GC with poor prognosis and HER4 gene expression seems to be higher in GC tissue in comparison with adjacent gastric mucosa. In this study, we explored gene and protein expression of the EGFR family in GC in order to establish new potentially prognostic factors. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) were carried out in 221 GC using tissue microarray. IHC positivity for EGFR was defined by score 2+ or 3+ according with intensity and frequency of membranous staining. In addition, the intensity of the cytoplasm staining was also determined for HER3 and HER4 overexpression. HER1, HER2, HER3, and HER4 overexpression was found in 3/197 (1.5%), 24/207 (12%), 121/193 (64%) and 41/183 (22%) cases respectively. FISH assay was performed according to the protocol previous described. In each case, 100 tumor nuclei were evaluated. Cases showing a gene/CEN fluorescence ratio ≥ 2 were considered positive for gene amplification. FISH detected HER1 and HER2 amplification in 1.3% and 8% of the cases. Amplifications for HER3 and HER4 were not observed. Overall, alterations of the 4 members of EGFR were significantly associated with parameters involved with tumor progression, including the depth of tumor invasion, involved lymph nodes, and tumor stage. We herein showed a strong correlation between HER2, HER3 and HER4 overexpression and low-grade tumors, corresponding to the intestinal type GC according to Lauren's classification. In addition, HER2 amplification was significantly related with worse survival. These results reveal that members of EGFR family are activated in GC. The exact molecular mechanisms involved in the HER3 or HER4 alterations in gastric cancer, especially in the intestinal type, remain unclear since amplifications of these genes were not found. Gaining further understanding into the oncogenic mechanism of EGFR family may not only help in the development of targeted therapy in gastric patients but might accelerate the acceptance of a novel taxonomy of cancer which is based on the genomic perturbations in cancer genes and cancer gene families and their response to targeted agents. Citation Information: Clin Cancer Res 2010;16(14 Suppl):A3.