Esophageal cancer has a poor prognosis, with 5-year survival rates ranging from 20% to 35% in the nonmetastatic setting. Despite advances in surgical techniques and optimization of chemoradiotherapy regimens, overall survival benefits have been incremental at best. Esophageal cancer requires a concerted multidisciplinary approach, perhaps more so than any other tumor type given the integral role played by the esophagus in maintaining calorific intake and the propensity for early spread through the lymphatics. This review describes the latest in surgical techniques to minimize postoperative complications and examines previous and ongoing systemic therapy approaches. Strategies that harness a patient’s own immune system hold great promise, and shifting checkpoint inhibitors from the metastatic setting to the neoadjuvant/adjuvant setting is currently being evaluated in phase II and III clinical trials. In addition, a much better understanding of the interplay between tumors and their immune microenvironment is clearly needed to better judge how best to engage each patient’s immune system, and there will be likely demonstrable differences between early-stage tumors and metastatic disease. This review highlights emerging data, which demonstrate that, in addition to The Cancer Genome Atlas classification of esophageal squamous cell carcinoma having a distinct molecular makeup compared with esophageal adenocarcinoma, there are also differing responses to PD-1 inhibitors. Histology and the underlying immune milieu may have important ramifications for the management of localized disease in the future, above and beyond PD-L1 expression, microsatellite instability status, and tumor mutational burden.
Ronan J. Kelly
A better understanding of the biology of both thymomas and thymic carcinomas has occurred in recent years thanks to advanced technologies such as comparative genomic hybridization, expression array analysis, and next-generation sequencing. Gene expression profiling and genomic clustering studies have shown that thymic tumors as classified by the 2004 WHO system do have different molecular features. Because of the rarity of these tumors, there is a paucity of high-quality clinical research data, and treatment decisions are often guided by the small amount of prospective trial data, retrospective series, and individual case reports. The literature does report on several advanced thymic tumors that have responded to new targeted agents, indicating that across the spectrum of thymic malignancies there may be clinically relevant molecular subsets. Genomic profiling distinguishes type B3 thymoma and thymic carcinoma from type A and B2 thymomas. Furthermore, type B2 thymomas can be separated from other subgroups in that it has a more distinctly lymphocytic component than the other groups in which epithelial cells predominate. The presence of KIT mutations in thymic carcinomas rather than in thymomas further adds to a growing body of evidence showing that underlying tumor biology may in the future lead to molecular classifications, which may enhance therapies for these rare tumors.