Title: BEST4: A Platform Trial to determine whether Cytosponge-biomarker technology reduces mortality from oesophageal cancer
Funder: Department of Health and Social Care

Abstract: This study has joint funding between NIHR HTA and CRUK (total funding is £6m). _x000D_ _x000D_ The overall aim of this project is to determine whether a test called the Cytosponge can be used to reduce the number of deaths due to oesophageal cancer (OAC). The Cytosponge is a test that can detect signs of a health condition called Barrett’s oesophagus (BO). In BO, there are problems in the cells in the oesophagus (the pipe that connects the mouth and the stomach), and these abnormal cells are a sign that a person is at risk of later developing OAC. If we want to prevent people from dying from OAC, we need a test that can tell whether a person has these abnormal cells so that the person can be monitored to make sure the abnormal cells do not progress to cancer, or so they can receive treatment to remove the abnormal cells. The Cytosponge test enables us to do this._x000D_ _x000D_ The Cytosponge is an easier, more convenient, and affordable alternative to endoscopy that can be done at a GP clinic or in a mobile unit by trained staff. The procedure itself takes less than 10 minutes and involves swallowing a capsule that contains a sponge tied to a long string. The patient swallows the capsule, waits for the capsule to dissolve in their stomach so the sponge can expand, then a nurse or GP pulls on the string to bring the sponge back up the oesophagus and out the mouth. As the sponge comes up, it collects cells that can then be tested to see if they have abnormalities that suggest the person has BO. In some cases, it even detects cells that suggest early-stage cancer, which enables a person to receive the treatment they need. Without the Cytosponge, those cancers might not have been detected until they were more advanced and causing more obvious symptoms. _x000D_ _x000D_ The previous studies of the Cytosponge have shown that patients generally find it an acceptable procedure. Some people find it a bit uncomfortable when the sponge is pulled out, but they still consider it tolerable, and some people would much prefer the Cytosponge procedure to an endoscopy. Overall, the previous studies have demonstrated that the Cytosponge is an effective and easy way of detecting BO. However, what the previous studies have not specifically looked at is how effective the Cytosponge is at saving people’s lives. We know that it successfully detects BO, but to be able to understand how many lives it can potentially save, we need to run a study over a longer period. That is what this BEST4 project proposes to do. It is comprised of two related studies._x000D_ _x000D_ 1) A targeted screening study to determine the extent to which the Cytosponge can prevent people from dying from OAC._x000D_ _x000D_ 2) A surveillance study looking at whether the Cytosponge can be used to tell whether a person is at low or high risk of developing cancerous cells in the oesophagus

Lay abstract: This study has joint funding between NIHR HTA and CRUK (total funding is £6m). _x000D_ _x000D_ 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. _x000D_ _x000D_ 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. _x000D_ _x000D_ 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. _x000D_ _x000D_ 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. _x000D_ _x000D_ 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.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS;ORAL AND GASTROINTESTINAL