Molecular analysis has identified a number of potential mechanisms and genes of interest, for which targeted therapy may be feasible. Amplification of one such therapeutic target, ERBB2, appears to be a frequent event in EAC,8,10 and such amplification also has been associated with worse overall prognosis.39 The HER2 gene encodes a receptor tyrosine kinase transmembrane receptor, p185HER2, that is targeted by the humanized anti-p185HER2monoclonal antibody, trastuzumab (Herceptin, Genentech, South San Francisco, CA).
Although a panoply of genetic changes in genes such as cyclin D1, p16INK4 A, p27KIP1, p53, EGFR, and c-ErbB2 (HER2/neu) have been associated with the development of esophageal carcinoma, measurement of altered expression in such genes of interest or their protein products does not appear to provide any prognostic advantage over standard measures such as tumor stage or regional lymph node involvement.40 Such potential markers still can be utilized in directing targeted therapy as such pharmacologic agents become available, as demonstrated by an ongoing cooperative group study of patients diagnosed with HER2/neu-overexpressing esophageal carcinomas. For this phase III study, patients with documented HER2/neu overexpression will receive the receptor tyrosine kinase inhibitor, trastuzumab (Genentech, San Francisco, CA) in addition to preoperative chemotherapy (cisplatin, 25 mg/m2 and paclitaxel, 50 mg/m2 weekly for 6 weeks) with thoracic radiation (50.4 Gy), followed by esophageal resection. In the phase I/II study preceding this phase III trial, 14 of 19 patients (74%) had either 3+ HER2 expression by immunohistochemistry, or an increase in HER2 gene copy number (HER2 gene amplification or high polysomy) by fluorescence in situ hybridization. Enrolled patients had T3N0 or T3N1 (AJCC, 6th edition) esophageal cancers. Of the fourteen patients with HER2 overexpression, eight were found to have a complete clinical response, defined as no evidence of tumor at posttreatment esophagoscopy with biopsies. Of the five patients who had HER2 expression less than 3+ by immunohistochemistry and no evidence of gene copy number increase, one patient was found to have a complete clinical response. The median survival of all patients was 24 months and the 2-year survival was 50%.41
Among patients with unresectable gastric cancer, including subjects with esophagogastric junction (cardia) carcinomas, whose tumors had overexpression of HER2/neu, an open label, randomized phase III trial demonstrated that the addition of trastuzumab to standard regimens of cisplatin and 5-fluorouracil or capecitabine improved overall survival without any observed difference in the number of grade 3 or 4 adverse events.42