Introduction
Screening for Barrett’s esophagus (BE) could lead to earlier detection and improved survival of esophageal adenocarcinoma (EAC). In the Barrett’s Esophagus Screening Trial 3 (BEST3), an offer of the Cytosponge-Trefoil Factor 3 (TFF3) test led to 10x more BE diagnoses among a reflux population taking acid-suppressant medications. Utilising BEST3 data, we 1) estimate the proportion of missed BE or stage-1 EAC (BE/EAC) under the current primary care reflux referral pathway, 2) define a target screening population, and 3) calculate the trade-off between the enrichment criteria and the proportion of BE/EAC diagnosed.

Methods
The BEST3 study was a multicentre, pragmatic, randomised controlled trial across 109 general practices in England.¹ In this post-hoc analysis, we used the intervention (n=6834) and control arm (n=6388) to estimate the number of missed BE/EAC under the current reflux referral pathway (aim 1), determined which clinical risk factors predict a diagnosis of BE/EAC among the 1654 individuals who swallowed the Cytosponge, and modeled the probability of a diagnosis of BE/EAC (aim 2). We then used different probabilities cut-off (≥3%, ≥5%, and ≥10%) of a BE/EAC diagnosis to estimate the starting age to screen and the trade-off between the population to screen and the proportion of BE/EAC that would be diagnosed using population data from the Office of National Statistics (ONS) of England as a reference (aim 3). We set an upper age limit of 74 years for practical considerations.

Results
In the control arm receiving usual care, the prevalence of BE/EAC was 0.2% (13/6388), compared to 10.6% (680/6388) in the Cytosponge arm, suggesting approximately 98% of BE/EAC cases may be undetected under current care. Risk factors significantly associated with BE/EAC diagnosis were male sex and age. Using male sex and age, we plotted the probability of a diagnosis of BE/EAC by age and by selecting a ≥3%, ≥5%, and ≥10% probability of BE/EAC diagnosis, we showed that the starting age to screen for BE/EAC at these cut-offs were 50, 55 and 65 for males, and 60, 65 and no screening for females (Table 1). Estimating the change in population-to-screen when going from a ≥3% to ≥5%, and to ≥10% cut-off showed that a 5% probability threshold is likely the optimal strategy as it lowers the population to screen by 45.2% (population of males aged 55-74 and females 65-74) while still diagnosing 71.0% of BE/EAC cases compared to the reference population of screening all males and females from age 50-74. The number needed-to-screen to detect one BE/EAC was 10.7.

Conclusions
A targeted screening strategy has the potential to substantially improve detection rates for BE and stage-1 EAC compared with current care. These findings could inform the optimal age for screening males versus females to maximise the yield of screening according to the resources available.

Judith Offman

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