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


CONCLUSIONS
Surveillance should target individuals with long-duration sGERD and OF exposures.
Program in Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. hazelton@fhcrc.org.
William D
WD
Hazelton
Department of Applied Mathematics, University of Washington, Seattle, Washington.
Kit
K
Curtius
Division of Gastroenterology, University of Washington, Seattle, Washington.
John M
JM
Inadomi
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. Department of Epidemiology, School of Medicine, University of Washington, Seattle, Washington.
Thomas L
TL
Vaughan
Department of Epidemiology, School of Public Health, University of Michigan Medical School, Ann Arbor, Michigan.
Rafael
R
Meza
Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan. Veterans Affairs Center for Clinical Management Research, Ann Arbor, Michigan.
Joel H
JH
Rubenstein
Institute for Technology Assessment, Massachusetts General Hospital, Boston, Massachusetts. Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
Chin
C
Hur
Program in Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
E Georg
EG
Luebeck
D000230:Adenocarcinoma / Q000453:epidemiology* / Q000209:etiology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000453:epidemiology* / Q000209:etiology; D005260:Female; D005500:Follow-Up Studies; D005764:Gastroesophageal Reflux / Q000150:complications*; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D012189:Retrospective Studies; D018570:Risk Assessment / Q000379:methods*; D012307:Risk Factors; D018426:SEER Program; D013997:Time Factors; D014481:United States / Q000453:epidemiology; D055815:Young Adult