The role of gastroesophageal reflux and other factors during progression to esophageal adenocarcinoma.

Publication Type:

Journal Article


Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology (2015)


US esophageal adenocarcinoma (EAC) incidence increased over five-fold between 1975 and 2009. Symptomatic gastroesophageal reflux disease (sGERD) elevates the risk for EAC. However, a simple calculation suggests that changes in sGERD prevalence can explain at most ~16% of this trend. Importantly, a mechanistic understanding of the influence of sGERD and other factors (OF) on EAC is lacking. Thus a multiscale model was developed to estimate temporal trends for sGERD and OF, and their mechanistic role during carcinogenesis. Model calibration was to Surveillance, Epidemiology, and End Results (SEER) incidence and age-dependent sGERD data using maximum likelihood and Markov chain Monte Carlo (MCMC) methods. Results suggest that 77.8% [95% Credibility Interval (CI) = 64.9 - 85.6%] of the male incidence trend is attributable to OF, 13.4% [95% CI = 11.4 - 17.3%] to sGERD, and 8.8% [95% CI = 4.2 - 13.7%] to sGERD-OF interactions. Among women, 32.6% [95% CI = 27.0 - 39.9%] of the trend is attributable to OF, 13.6% [95% CI = 12.5 - 15.9%] to sGERD, and 47.4% [95% CI = 30.7 - 64.6%] to interactions. The predicted trends were compared with historical trends for obesity, smoking, and proton pump inhibitor use. Interestingly, predicted OF cohort trends correlated most highly with median body mass index (BMI) at age 50, (r = 0.988 for men; r = 0.998 for women.) sGERD and OF mechanistically increase premalignant cell promotion, which increases EAC risk exponentially. Thus surveillance should target individuals with both long-duration sGERD and OF exposures.