Current state of prognostication, therapy and prospective innovations for Barrett's-related esophageal adenocarcinoma: a literature review

Abstract

Objective: Barrett's esophagus (BE) is the only known precursor to esophageal adenocarcinoma (EAC), which has one of the lowest 5-year survival rates in oncology. The reasons for poor survival are twofold: the large majority of diagnoses are in advanced stages (~80%) and limited treatment options, with a deficit of biology-guided therapies. As a rapidly growing public health concern with poor prognosis, research into the molecular progression for BE and novel therapeutics for EAC currently has high clinical utility. Review of the literature reveals that innovative analysis of metaplastic progression from BE to EAC at a molecular level can shed light on the underlying transformative probabilities of BE into malignant pathologies and may impact current of future therapeutic modalities for management of these diseases.

Background: EAC is the fastest increasing cancer in the United States with a 600% increase over the past 25 years. This cancer arises from dysplastic tissue of BE, a complication of gastroesophageal reflux disease (GERD). Chronic acid and bile reflux in the distal esophagus initiates a metaplastic conversion of normal squamous epithelium to premalignant intestinalized columnar epithelium. Patients with BE have a 125-fold higher risk of cancer compared to the general population.

Methods: We critically reviewed the current status of BE monitoring, and subsequent therapeutic strategies being used in patients who have progressed to cancer. Also, new diagnostic tools and therapeutic candidates for BE-related EAC are discussed. Highly-targeted searches of databases containing recent original peer-reviewed papers were utilized for this review.

Conclusions: Novel and well-described biomarkers analyzed in the patient's diseased tissue will provide for more powerful diagnostics, but also possess the potential to develop strategies for personalized management and identify targets for intervention to either cease disease progression or treat BE and/or EAC. Since millions of Americans develop BE without progressing to cancer, there is a critical need to identify the small percentage of Barrett's patients who possess hallmarks of disease progression or carcinogenesis with novel screening techniques. Incorporation of such tools into standard screening protocols for BE surveillance and/or therapy would be critical to detect malignant transformations before clinically obvious cancer ever develops.

Keywords: Barrett’s esophagus (BE); early cancer detection; esophageal adenocarcinoma (EAC); precision oncology; targeted therapy.

Figure 1

Cancer deaths relative to incidence annually (percentage). Esophageal adenocarcinoma is the deadliest cancer in terms of deaths relative to annual incidence. Strikingly, the rate of incidence of EAC is rising the faster than any cancer in the US, which could lead to major clinical implications in the future. EAC possess a higher deaths per incidence annually rate than some of the more publicized indications like pancreatic, lung, brain, breast, liver and colon cancer. EAC, esophageal adenocarcinoma.

Figure 2

A 10-year mortality rate (Barrett’s esophagus metaplasia vs. cancer). The 10-year mortality rate for Barrett’s esophagus (non-cancerous disease) is higher or within the range of some cancers in the United States. Although indications like GERD and Barrett’s esophagus are not considered very serious, it can be just as deadly as some of the well-described indications in oncology. Esophageal adenocarcinoma, which is linked to Barrett’s esophagus, has one of the highest mortality rates in oncology. GERD, gastroesophageal reflux disease.

Figure 3

Prevalence of Barrett’s esophagus in the US [2020]. A heatmap of the prevalence of BE by region within the US. The highest rates are found in the South, Southeast, and the Midwest. Some of the lowest rates of BE are seen on the West Coast and in the Northeast and New England. US, United States; BE, Barrett’s esophagus.