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Esophageal adenocarcinoma (EAC) is a highly lethal malignancy. Due to its rising incidence, EAC has become a severe health challenge in Western countries. Current treatment strategies are mainly chosen based on disease stage and clinical features, whereas the biological background is hardly considered. In this study, we performed a comprehensive review of existing studies and discussed how etiology, genetics and epigenetic characteristics, together with the tumor microenvironment, contribute to the malignant behavior and dismal prognosis of EAC. During the development of EAC, several intestinal-type proteins and signaling cascades are induced. The anti-inflammatory and immunosuppressive microenvironment is associated with poor survival. The accumulation of somatic mutations at the early phase and chromosomal structural rearrangements at relatively later time points contribute to the dynamic and heterogeneous genetic landscape of EAC. EAC is also characterized by frequent DNA methylation and dysregulation of microRNAs. We summarize the findings of dysregulations of specific cytokines, chemokines and immune cells in the tumor microenvironment and conclude that DNA methylation and microRNAs vary with each different phase of BE, LGD, HGD, early EAC and invasive EAC. Furthermore, we discuss the suitability of the currently employed therapies in the clinic and possible new therapies in the future. The development of targeted and immune therapies has been hampered by the heterogeneous genetic characteristics of EAC. In view of this, the up-to-date knowledge revealed by this work is absolutely important for future EAC studies and the discovery of new therapeutics.

Esophageal adenocarcinoma (EAC) is a highly aggressive cancer and its response to chemo- and radiotherapy is unpredictable. EACs are highly heterogeneous at the molecular level. The aim of this study was to perform gene expression analysis of EACs to identify distinct molecular subgroups and to investigate expression signatures in relation to treatment response. In this prospective observational study, RNA sequencing was performed on pre-treatment endoscopic EAC biopsies from a discovery cohort included between 2012 and 2017 in one Dutch Academic Center. Four additional cohorts were analyzed for validation purposes. Unsupervised clustering was performed on 107 patients to identify biological EAC subgroups. Specific cell signaling profiles were identified and evaluated with respect to predicting response to neo-adjuvant chemo(radio)therapy. We identified and validated three distinct biological EAC subgroups, characterized by (1) p38 MAPK/Toll-like receptor signaling; (2) activated immune system; and (3) impaired cell adhesion. Subgroup 1 was associated with poor response to chemo-radiotherapy. Moreover, an immune signature with activated T-cell signaling, and increased number of activated CD4 T memory cells, neutrophils and dendritic cells, and decreased M1 and M2 macrophages and plasma cells, was associated with complete histopathological response. This study provides a novel molecular classification for EACs. EAC subgroup 1 proved to be more therapy-resistant, while immune signaling was increased in patients with complete response to chemo-radiotherapy. Our findings give insight into the biology of EACs and in cellular signaling mechanisms underlying response to neo-adjuvant treatment. Future implementation of this classification will improve patient stratification and enhance the development of targeted therapies.

Esophageal cancers confer a major health challenge and are highly aggressive malignancies with poor prognosis. Esophageal adenocarcinoma (EAC) is one of the two major histopathological subtypes of esophageal cancer. Despite advances in treatment modalities, the prognosis of patients with EAC remains poor, with a 5-year survival rate that rarely exceeds 30% in patients treated with curative intent. Chemoradiotherapy followed by resection is the treatment of choice for EAC patients, which are deemed to be curable. Current patient stratification and treatments are based on outcomes from clinical trials. Unfortunately, the molecular heterogeneity of EAC which determines the chemo- and radiosensitivity of these cancers are not taken into account. A more personalized approach in the treatment of EAC could improve patient outcomes. This review aims at summarizing literature on translational and clinical research in the field of EAC which could be of importance to develop personalized approaches. As suggested by the TCGA, expression data features molecular classifications by different platforms, including miRNA, genomic mutations and reverse-phase protein arrays. Here, we summarize literature on transcriptomic, data-driven approaches to identify distinct subtypes of EAC associated with molecular features. These novel classifications may determine the responsiveness to chemo(radio)therapy and help to identify novel molecular targets within cell signaling pathways. Moreover, we discuss the current clinical research efforts on tailored treatment regimens for patients with EAC taking into account the heterogeneous response to chemoradiotherapy. We summarize the evidence regarding active surveillance instead of immediate surgical resection after application of neoadjuvant chemo(radio)therapy in EAC. We consider that in future patients with complete response to chemo(radio)therapy, predicted by (transcriptomic) biomarkers, might benefit most from this approach. Finally, challenges to overcome for current findings to be implemented in clinical practice and move the field forward are being discussed.