Molecular
therapies targeting HER2 are part of the established
drug armamentarium in
breast carcinoma. Now the ToGA trial, an international multicenter phase III clinical study, involving 24 countries globally, has shown that the anti-HER2 humanized
monoclonal antibody Trastuzumab is effective in prolonging survival in HER2-positive
carcinoma of the stomach and the gastroesophageal junction (GEJ). Similarly to
breast carcinoma, >20% of
gastric cancers show HER2 overexpression and/or amplification, and this percentage increases to 33% in GEJ
tumors. Thus, as in
breast carcinoma, pathologists are now asked to evaluate HER2 status in gastric
carcinoma samples. As validated in the ToGA trial, the HER2 testing criteria that must be used in evaluating both gastric
carcinoma biopsies and surgical specimens significantly differ from those routinely applied in
breast carcinoma. The main variations with regard to the pattern of reactivity in HER2-expressing cells are as follows: the completeness of membrane staining is not a "conditio sine qua non" and the number of stained cells necessary to consider a case as positive is different. We must also take note of the much more frequent heterogeneity of HER2 positivity in
gastric cancer compared with
breast carcinoma and the less stringent correlation between HER2 amplification and
protein overexpression that is observed in gastric
carcinoma, where more than 20% of cases may carry HER2 amplification, although of low level, without HER2 expression. In these patients, in the ToGA trial, there was no apparent benefit from adding
Trastuzumab to
chemotherapy: for this reason the European Medicines Agency, while approving usage of
Trastuzumab for metastatic
adenocarcinoma treatment, indicated HER2 testing by immunohistochemistry as first evaluation assay, followed by fluorescence in situ hybridization in 2+ equivocal cases. HER2 testing in gastric
carcinoma is a new field, opening several opportunities: for patients with
gastric cancer, this is a new promising therapeutic option; for pathologists, strengthening our role in
therapy selection and emphasizing our duty of providing accurate and reproducible HER2 testing results; for all interested in understanding the biology of gastric and GEJ
cancer and in discovering new possible molecular
therapy targets.