Barrett's oesophagus and oesophageal adenocarcinoma: time for a new synthesis

The paradigm that Barrett's oesophagus develops as a consequence of symptomatic gastroesophageal reflux disease and predisposes to oesophageal adenocarcinoma has dominated clinical thought for more than three decades. However, current approaches for controlling the incidence and mortality of oesophageal adenocarcinoma, which are largely based on endoscopic investigation of individuals with symptomatic gastroesophageal reflux disease, and histology-guided surveillance and treatment of individuals with Barrett's oesophagus, have considerable limitations.Barrett's oesophagus rarely progresses to oesophageal adenocarcinoma, and a theory has recently been proposed that mucosal defences in most patients with Barrett's oesophagus represent successful adaptations to the harsh intra-oesophageal environment of chronic gastroesophageal reflux disease. Several mucosal defences that arise in Barrett's oesophagus have been identified, including the secretion of bicarbonate and mucous, expression of claudin 18 tight junctions, overexpression of defence and repair genes, and resistance to prolonged and repeated acid exposure.The incidence of oesophageal adenocarcinoma has been rising at an alarming rate in the United States, Western Europe, Australia and in other developed countries over the past four decades, and there is disquieting evidence of increased incidence of oesophageal adenocarcinoma in some Asian populations.Four risk factors — gastroesophageal reflux disease, obesity, cigarette smoking and poor diet — account for most oesophageal adenocarcinomas. The effects of obesity might influence both early and late stages of progression and interact biologically with gastroesophageal reflux disease, although a substantial proportion of the effect of obesity is likely to be through other pathways.Neoplastic progression to oesophageal adenocarcinoma is characterized by genomic instability (including chromosomal instability in most cases), disruption of regulatory pathways and temporal evolution of clones that might be modulated by host and environmental risk and protective factors. Proper measurement and quantification of the complexity of these alterations creates opportunities and challenges for improved risk stratification, prevention and early detection.Aspirin and other non-steroidal anti-inflammatory drugs have been consistently reported to have a protective association with oesophageal adenocarcinoma in case–control and cohort studies as well as meta-analyses; they might be useful in patients at both early and late stages of progression.No intervention, whether based on lifestyle modification, chemoprevention or medical and surgical treatments, has yet been convincingly demonstrated in a randomized trial to reduce the incidence and/or mortality of oesophageal adenocarcinoma; this remains a particularly crucial area of unmet research need. New oesophageal adenocarcinoma prevention strategies are proposed to overcome these limitations.