BEST4: A Platform Trial to determine whether capsule sponge-biomarker technology reduces mortality from oesophageal cancer

This study has joint funding between NIHR HTA and CRUK (total funding is £6m).

Oesophageal cancer (OAC) is a poor prognosis cancer, and the current clinical pathways are ineffective for early diagnosis. Since endoscopic therapy for dysplasia and early cancer occurring in the premalignant condition Barrett’s oesophagus (BO) is now highly effective, the time is ripe for improving methods to identify those patients at high risk of requiring treatment.

We have developed a novel, minimally invasive diagnostic test called Cytosponge, which can be coupled with a molecular biomarker for BO called Trefoil Factor 3 (TFF3). Over the past 18-years, we have rigorously tested the Cytosponge in a series of clinical trials and the results have surpassed expectations. In the recent CRUK-funded BEST3 randomised controlled trial which enrolled >13,000 individuals who were on a repeat prescription for acid-suppressant medications in primary care, we showed that the detection of BO over one year in those offered a Cytosponge test (intervention arm) was ten-fold higher than with usual care.

The Cytosponge also led to the detection of early-stage curable cancers, which are rare in routine practice. However, the BEST3 study was not designed to look at the impact of the Cytosponge on mortality and this information will be crucial before adopting this test into a national population-based targeted screening programme.

Cytosponge-TFF3 screening will lead to the identification of many individuals with previously undiagnosed non-dysplastic BO (NDBO), many of whom may not progress to OAC throughout their lifetime. A further question arises as to how these individuals should be best managed. We have previously shown that the Cytosponge sample can be combined with a biomarker panel, encompassing clinical, molecular, and histological biomarkers, which was able to accurately stratify patients according to their risk of cancer progression. However, our previous study was not validated prospectively.

In this BEST4 platform, we propose a large, randomised trial conducted in the community setting to evaluate the effectiveness of an offer of a Cytosponge to patients on medication for heartburn symptoms and whether it could improve OAC-associated mortality. Additionally, we plan to conduct a prospective cohort study, which will run in parallel to the randomised study to evaluate whether the Cytosponge can be coupled with a multidimensional, but clinically applicable, biomarker panel in the surveillance of patients with NDBO.

We, therefore, envisage that this BEST4 platform could lead to validation of a Cytosponge-based screening and surveillance strategy for BO and OAC that, if successful, would be a step-change for the field. Additionally, we hope to create a platform for basic, clinical, and epidemiological research into BO and OAC. This would include a longitudinal tissue bank of Cytosponge, saliva and blood samples in patients undergoing endoscopy; and the opportunity for trials of lifestyle interventions for patients with GORD and chemoprevention among patients with BO.