HER2 Over-Expression and Gastric Cancer: Molecular Mechanisms and Target Therapies

Gastric cancer is the second leading cause of cancer related-death worldwide. In 2008, it was estimated 990.000 new cases and 738.000 related-deaths. Considering the poor prognosis of advanced gastric cancer, new therapeutic regimens with acceptable toxicity have been pursued. Interesting insights have emerged from the investigation of human epidermal growth factor receptor 2 (HER2) as a potential therapeutic target. HER2 is a transmembrane tyrosine kinase receptor which is activated through dimerization, leading to a cascade of events that involves the activation of molecular pathways concerning regulation of cell proliferation, differentiation and survival, including the MAPK and PI3K pathways. The importance of addressing HER2 as a therapeutic target is underscored by consistent molecular and pathological findings: upregulated HER2/neu relates to carcinogenesis and is found in both primary tumours and metastasis. HER2 over-expression has been reported in breast, stomach, lung, salivary gland, ovary, colon, prostate and pancreatic cancers. In the particular case of breast cancer, recognition of the molecular signature of HER2 over-expression is widely used to tailor therapeutics involving molecular therapies with antibodies targeting HER2, therefore establishing HER2 status as a prognostic factor and a predictor of response to therapy. However, the correlation between the expression of HER2 and the prognosis of gastric cancer is still controversial. HER2 over-expression is currently estimated to occur in about 7-34% of gastric cancers. In this behalf, it is important to stress the recent development of validated methods in identifying HER2 overexpression in gastric cancer. In this chapter the authors will address the molecular mechanisms of HER2's oncogenicity, the assessment of HER2 over-expression and its clinico-pathological significance, resistance mechanisms and future perspectives emanating from clinical trials in this regard.

Keywords: Gene amplification, monoclonal antibodies, biomarkers, erbB-2, HER2 protein, stomach neoplasms, trastuzumab, lapatinib.