New Strategies in Esophageal Carcinoma: Translational Insights from Signaling Pathways and Immune Checkpoints

Esophageal cancer remains a highly lethal malignancy in which relatively modest therapeutic advances have been made over the past several decades. Cytotoxic therapy remains the mainstay of treatment for both advanced esophageal adenocarcinoma and squamous cell carcinoma (SCC), with incremental benefit conferred by antibodies targeting HER2 and VEGFR in selected patients. However, intrinsic or acquired resistance in this disease almost invariably occurs and remains a major challenge. Moreover, although large-scale exome and whole-genome sequencing efforts have identified a variety of somatic mutations and copy number variations, particularly amplifications, in esophageal cancer, the ability to translate these findings successfully into actionable therapeutic approaches has been elusive. More recently, immunotherapeutic strategies, most notably immune checkpoint inhibitors, have demonstrated benefit to a subset of patients with both esophageal adenocarcinoma and SCC and represent an area of active clinical investigation. In this article, we discuss some of the insights derived from past trials of esophageal cancer, highlight ongoing research efforts in this arena, and emphasize the need to refine our approach to treating patients based on distinct anatomic, histologic, and molecular features. Clin Cancer Res; 22(17); 4283-90. ©2016 AACR.