HER2 and gastric cancer: a novel therapeutic target for trastuzumab

HER2 protein overexpression by immunohistochemistry (IHC) and/or erB2 gene amplification by in situ hybridization (ISH) was detected in 4-28% of gastric or gastro-oesophageal junction (GOJ) cancers. Most studies have shown that HER2-overexpressing gastric cancers were worse prognosis. Trastuzumab is a humanized monoclonal antibody directed against HER2 with known efficacy in patients with HER2+ early or metastatic breast cancer. The international randomized trial ToGA study showed the superiority of the combination of trastuzumab with chemotherapy doublet fluoropyrimidine (5-FU or capecitabine) plus cisplatin (FP) every three weeks compared with chemotherapy alone in terms of overall survival : 13.8 versus 11.1 months (HR: 0.74, 95% CI: 0.60-0.91, P = 0.0046) in HER2+ advanced gastric cancers. The benefit was even greater in the subgroup with HER2 overexpression (16% of the screened population) as defined by IHC3+ or IHC2+ confirmed by positive ISH test. Trastuzumab plus FP chemotherapy has become the standard treatment for patients with HER2+ non-pretreated metastatic adenocarcinoma of the stomach or GOJ cancer. All these cancers should be tested for HER2 on paraffin block resection or biopsy specimens of the primary tumour or metastases. Endoscopic gastric biopsies should be multiple. The IHC should be the initial test. The standardized immunohistochemical scoring system differs from that recommended for breast cancer given the heterogeneity of HER2 expression and the frequency of incomplete membranous staining in gastric cancers. Equivocal IHC2+ tumours should be tested by ISH with two tools: fluorescence in situ hybridization (FISH) or bright field in situ hybridization (SISH). The perspectives are the assessment of trastuzumab in the perioperative and adjuvant setting, the development of novel anti-HER2 drugs and research into mechanisms of resistance and predictive molecular markers.