Current status of novel agents in advanced gastroesophageal adenocarcinoma.

Gastroesophageal (GE) adenocarcinomas are highly lethal malignancies and despite multiple chemotherapy options, 5-year survival rates remain dismal. Chemotherapy is the mainstay of treatment but patients are often limited by toxicity and poor performance status. Because of molecular heterogeneity, it is essential to classify tumors based on the underlying oncogenic pathways and develop targeted therapies that act on individual tumors. Trastuzumab, a human epidermal growth factor receptor type 2 (HER2) monoclonal antibody, was the first such agent shown to improve response rate, progression free survival (PFS), and overall survival (OS) when added to cisplatin based chemotherapy in patients with HER2 over-expressing GE junction (GEJ) and gastric adenocarcinomas. However, HER2 over expressing GE tumors are in the minority and the need for additional targeted agents is urgent. Though many agents are in development, incorporating targeted therapy in the treatment of GE cancers comes with a unique set of challenges. In this review, we outline oncogenic pathways relevant to GE adenocarcinomas, including HER2, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), and c-Met, and discuss recent trials with agents targeting these pathways.