Abstract
The incidence of gastro-esophageal disease and associated rate of esophageal adenocarcinoma (EAC) is rising at an exponential rate in the United States. However, research targeting EAC is lagging behind, and much research is needed in the field to identify ways to diagnose EAC early as well as to improve the rate of pathologic complete response (pCR) to systemic therapies. Esophagectomy with subsequent reconstruction is known to be a morbid procedure that significantly impacts a patient's quality of life. If indeed the pCR rate of patients can be improved and those patients destined to be pCR can be identified ahead of time, they may be able to avoid this life-altering procedure. While cancer-specific biological pathways have been thoroughly investigated in other solid malignancies, much remains unexplored in EAC. In this review, we will highlight some of the latest research in the field in regards with EAC, along with new therapeutic targets that are currently being explored. After reviewing conventional treatment and current changes in medical therapy for EAC, we will focus on unchartered grounds such as cancer stem cells, genetics and epigenetics, immunotherapy, and chemoradio-resistant pathways as we simultaneously propose some investigational possibilities that could be applicable to EAC.
Highlights
Esophageal cancer remains the sixth most commonly occurring form of cancer and continues to be an aggressive cancer due to its diagnosis in late stages
While patients with early stage tumors (T1a-T1b) are appropriate candidates for resection, locally advanced tumors (T2-T3, node positive, of either histologic subtype) are treated with upfront chemoradiation followed by surgical resection after restaging as per the CROSS group recommendations [4]
With the rising incidence of gastroesophageal reflux and an epidemic in Barrett’s esophagus and esophageal adenocarcinoma (EAC) in the United States, it is imperative that we understand the molecular biology of this disease in order to strategically develop biological therapies and to simultaneously develop an effective pre-symptomatic screening tool
Summary
Esophageal cancer remains the sixth most commonly occurring form of cancer and continues to be an aggressive cancer due to its diagnosis in late stages. Whereas genetic mutations are fixed, epigenetic abnormalities can potentially be modified and corrected without targeting the genome itself They can affect many of the molecular mechanisms involved in tumor growth such as cell cycle, DNA repair, survival and apoptosis, tumor suppressors, and epithelial to mesenchymal transformation affecting cell adhesion and invasion. When these differentially methylated CpG sites were mapped to biological processes, pathways related to cell proliferation and migration were over-represented in EAC and those regulating cell cycle and immune system processes were under-represented, suggesting their role in tumor development [79] Epigenetic modifiers, such as DNA cytosine5-methyltransferase I (DNMT1) and class I histone deacetylase 1 and 2 (HDAC1/2), are associated with EAC and combined inhibition of both DNMT and HDAC has been demonstrated to be an effective strategy to induce www.impactjournals.com/oncotarget. Telomerase inhibition alone does not affect tumor growth in EAC unless combined with HR inhibition with knockdown or inhibition of RAD51, which leads to enhanced radiosensitivity [63, 108]
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