HER2 Over-Expression and Gastric Cancer: Molecular Mechanisms and Target Therapies
Pp. 3-31 (29)
Michael Luis and Ramon A. de Mello
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.
Gene amplification, monoclonal antibodies, biomarkers, erbB-2,
HER2 protein, stomach neoplasms, trastuzumab, lapatinib.
Department of Medical Oncology, Portuguese Oncology Institute, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.