Targeting the HER2 pathway for the therapy of lower esophageal and gastric adenocarcinoma.

INTRODUCTION: The mysteries of complex molecular pathways of tumorigenesis are only beginning to be unraveled. Overexpression of HER2 receptors has been associated with adverse outcomes in certain malignant solid tumors. AREAS COVERED: The authors give a focused review of the HER2 pathway and its importance for cancer cell survival. Similar to the situation in breast cancer, HER2 overexpression is seen in up to one-quarter of all gastric and gastroesophageal junction adenocarcinomas. The audience will also be familiarized with the existing HER2 targeted agents (both at the bench and at the bedside) for the therapy of gastric and gastroesophageal cancers. EXPERT OPINION: Despite recent advances, treatment of upper gastrointestinal malignancies remains a significant challenge. Trastuzumab in combination with chemotherapy is the current standard of therapy for patients with metastatic HER2-overexpressing esophageal and gastric cancers. The activity of lapatinib, an active agent in advanced HER2-positive breast cancer, is now being tested in HER2-overexpressing esophageal and gastric adenocarcinomas. A variety of monoclonal antibodies and tyrosine kinase inhibitors with affinity for HER2 are in development and may improve further the outcomes of these malignancies.