Identification of Novel Molecular Subgroups in Esophageal Adenocarcinoma to Predict Response to Neo-Adjuvant Therapies

Abstract

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.

Molecular Biology and Clinical Management of Esophageal Adenocarcinoma

“…In this study, 71 out of 72 EAC cases were identified to have CIN indicating similarities between EAC and gastric cancers with CIN [1]. More recently, our research group was able to further differentiate EAC into three molecular subgroups, characterized by (i) p38 MAPK/Toll-like receptor signaling, (ii) an activated immune system and (iii) impaired cell adhesion, and this classification was associated with response to neo-adjuvant treatment [143].…”

“…In different studies, it has been demonstrated that EAC can be divided into various molecular subgroups. One subclassification of EAC can be used to predict response to neoadjuvant treatment for EAC patients [143]. However, the subclassifications in several studies seem to have less clinical significance [108,123].…”

“…Next to genomic abnormalities, transcriptomic profiling by microarray or RNA sequencing has been an important topic of research [143]. Based on RNA profiling, the TCGA research group investigated gastric adenocarcinoma and proposed a new classification with four subtypes: chromosomal instability (CIN), microsatellite instability (MSI), genomic stability (GS) and Epstein-Barr-virus-positive cancers [144].…”

miRNA profiling of esophageal adenocarcinoma using transcriptome analysis

“…In EAC, M2 macrophage polarization appears to occur in response to tumor upregulation of Th2 pathways, leading to increased IL-4 and IL-13 [ 82 ]. Like other cancers, EAC treatment success is partially dictated by relatively low levels of infiltrating macrophages compared to other immune constituents [ 83 ]. Taken together, M2 macrophages may become an attractive target in the emerging treatment of EAC.…”