The Role of Gastroesophageal Reflux and Other Factors during Progression to Esophageal Adenocarcinoma

Abstract

Background: U.S. esophageal adenocarcinoma (EAC) incidence increased over 5-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 approximately 16% of this trend. Importantly, a mechanistic understanding of the influence of sGERD and other factors (OF) on EAC is lacking.

Methods: 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: Among men, 77.8% [95% credibility interval (CI), 64.9%-85.6%] of the 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).

Conclusions: sGERD and OF mechanistically increase premalignant cell promotion, which increases EAC risk exponentially with exposure duration.

Impact: Surveillance should target individuals with long-duration sGERD and OF exposures.

Figure 1

Annual observed (black circles) and expected EAC incident cases (stacked bars) among men due to direct effects of sGERD (red), direct effects of OF (violet), sGERD-OF interactions (green), and Background (black), shown by five-year periods ranging from 1975–1979 in panel a), to 2005–2009 in panel f). Panel h) shows results of model extrapolation of the expected cases in years 2025–2029.

Figure 2

Annual observed (black circles) and expected EAC incident cases (stacked bars) among women due to direct effects of sGERD (red), direct effects of OF (violet), sGERD-OF interactions (green), and Background (black), shown by five-year periods ranging from 1975–1979 in panel a), to 2005–2009 in panel f). Panel h) shows results of model extrapolation of the expected cases in years 2025–2029.