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Barrett’s esophagus is the precursor of all esophageal adenocarcinomas

View ORCID ProfileKit Curtius, Joel H. Rubenstein, Amitabh Chak, View ORCID ProfileJohn M. Inadomi
doi: https://doi.org/10.1101/2020.05.14.096826
Kit Curtius
1Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
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  • For correspondence: k.curtius@qmul.ac.uk
Joel H. Rubenstein
2Barrett’s Esophagus Program, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA
3Center for Clinical Management Research, Ann Arbor Veterans Affairs Medical Center, Ann Arbor, Michigan, USA
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Amitabh Chak
4Division of Gastroenterology and Liver Diseases, Case Western Reserve University, Cleveland, Ohio, USA
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John M. Inadomi
5Division of Gastroenterology, University of Washington, Seattle, Washington, USA
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Abstract

Objective Barrett’s esophagus (BE) is a known precursor to esophageal adenocarcinoma (EAC) but current clinical data have not been consolidated to address whether BE is the origin of all incident EAC, which would reinforce evidence for BE screening efforts. We aimed to answer whether all expected prevalent BE, diagnosed and undiagnosed, could account for all incident EACs in the US cancer registry data.

Design We used a multi-scale computational model of EAC that includes the evolutionary process from normal esophagus through BE in individuals from the US population. The model was previously calibrated to fit SEER cancer incidence curves. Here we also utilized age- and sex-specific US census data for numbers at-risk. The primary outcome for model validation was the expected number of EAC cases for a given calendar year. Secondary outcomes included the comparisons of resulting model-predicted prevalence of BE and BE-to-EAC progression to the observed prevalence and progression rates.

Results The model estimated the total number of EAC cases in 2010 was 9,970 (95% CI 9,140 – 11,980), which recapitulates all EAC cases from population data. The model simultaneously predicted 8-9% BE prevalence in high-risk males age 45-55, and 0.1-0.2% non-dysplastic BE-to-EAC annual progression in males, consistent with clinical studies.

Conclusion There are no additional EAC cases that plausibly arise in the US population outside the BE pathway. Effective screening of high-risk patients could capture the majority of population destined for EAC progression and decrease mortality through early detection and curative removal of small (pre)cancers during surveillance.

Summary Box What is already known about this subject?

  • Barrett’s esophagus (BE) patients have a 40 to 50-fold higher risk of developing esophageal adenocarcinoma (EAC) than the general population yet many remain undiagnosed.

  • Identified BE patients receiving surveillance can have early cancers discovered endoscopically, which decreases the high overall EAC-associated mortality.

  • Currently around 90% of patients who develop EAC were never part of a BE surveillance program, and those BE patients on surveillance have a low annual progression rate of 0.1 - 0.3% to develop EAC.

What are the new findings?

  • By applying a model that incorporates the evolution from normal cells to BE to EAC in patients, we found that the numbers add up - the expected number of EAC cases in the US population are explained by the published rates of BE described above.

  • We cohesively examined the published estimates to determine that all EAC likely arises from both identified BE and occult, undiagnosed BE in the population.

How might it impact on clinical practice in the foreseeable future?

  • Based on current best estimates, our findings suggest there is no public health need to seek cases of a non-BE alternative pathway to EAC.

  • Increasing efforts for effective, sensitive screening and surveillance of the true BE population will decrease EAC mortality in the coming years.

Competing Interest Statement

KC, JHR, and JMI declare no potential conflicts of interest. AC has founders shares and stock options in LucidDx, serves as a consultant to LucidDx, has sponsored research with LucidDx, and has a royalty interest in patents licensed to LucidDx. He is also a consultant for Interpace Diagnostics and receives research support from C2 Therapeutics/Pentax Inc.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 16, 2020.
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Barrett’s esophagus is the precursor of all esophageal adenocarcinomas
Kit Curtius, Joel H. Rubenstein, Amitabh Chak, John M. Inadomi
bioRxiv 2020.05.14.096826; doi: https://doi.org/10.1101/2020.05.14.096826
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Barrett’s esophagus is the precursor of all esophageal adenocarcinomas
Kit Curtius, Joel H. Rubenstein, Amitabh Chak, John M. Inadomi
bioRxiv 2020.05.14.096826; doi: https://doi.org/10.1101/2020.05.14.096826

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