Title: Profiling of Dysplastic Changes in Barrett's Oesophagus and Early Oesophageal Cancer Using Non-Invasive Volatile Organic Compound Analysis of Exhaled Breath
Funder: Guts UK

Abstract: Background The incidence of oesophageal adenocarcinoma has been rising over the last decade. Despite improvements in oncological and surgical therapies the associated survival remains poor, mainly due to delays in diagnosis and advanced stage at presentation. Identifying patients at earlier stages as well as those at risk of cancer may lead to survival benefit. Barrett’s oesophagus is an established risk factor for the development of oesophageal adenocarcinoma. It has an established histopathologic progression from low-grade, through high-grade dysplasia (HGD) to oesophageal adenocarcinoma (OAC). Barrett’s oesophagus patients currently undergo regular endoscopic surveillance to allow earlier detection of oesophageal cancer. The UK national Oesophago-Gastric Cancer Audit (2017) suggested that roughly half of patients were diagnosed with high grade dysplasia through surveillance route while other half being through primary care referrals after experiencing symptoms. Furthermore, those patients tended to have regular series of endoscopic procedures with about one third being diagnosed with cancer during their lifetime. The average cost of endoscopy with biopsies is £1500 per endoscopy. This represents a significant source of inefficient financial expenditure to the NHS, adding to the already financially burdened health system. Hypothesis and objectives The hypothesis of this work is volatile organic compounds in exhaled breath can accurately profile dysplastic changes in Barrett’s oesophagus and early stage oesophageal cancer. The primary objective is to evaluate the diagnostic accuracy and clinical utility of the volatile organic compounds (VOC) in exhaled breath to detect high-grade dysplastic Barrett’s oesophagus and early stage oesophageal adenocarcinoma. Design and methods This is a multi-centre study across four hospital sites. Patients will be recruited on attendance to endoscopy and breath samples will be collected via ReCIVA device prior to investigation. Upper gastro-intestinal endoscopy and histological confirmation will form the gold standard for classification of patients within the study groups. The breath profile will be compared to the endoscopy and biopsy findings. Critical quality assurance measures will be included such as sampling room air, dedicated training to all researchers in breath sampling to avoid contamination and regular instrument calibration. The breath samples will be returned to a central laboratory for Gas Chromatography- Mass Spectrometry (GC-MS) and Proton Transfer Reaction Time-of-Flight Mass Spectrometric (PTR-TOF-MS) analytical method. Plan of investigation The following studies will be conducted, (i) Model development of VOCs from exhaled breath analysis in high-grade dysplasia and early oesophageal adenocarcinoma. (ii) Exhaled breath VOC risk prediction model in HGD/ early oesophageal adenocarcinoma. (iii) Clinical validation study for VOC profile changes following Endoscopic interventions for high grade dysplasia (HGD) and early oesophageal adenocarcinoma. Clinical and scientific impact The deliverable of this study is a breath test based upon dysregulation of VOCs, that can identify Barrett’s oesophagus with high-grade dysplasia and early stage oesophageal adenocarcinoma. This will allow appropriate allocation of diagnostic endoscopy and introduce a non-invasive diagnostic tool improving patient satisfaction. Therefore, this project will address the current challenge in early oesophageal adenocarcinoma diagnosis and risk stratification of patients with Barrett’s oesophagus and those on dedicated surveillance.

Lay abstract: Background Oesophageal cancer (cancer of the food pipe) is the fourth commonest cause of cancer death in the United Kingdom. Often this is because people don’t notice symptoms until the disease is at a late stage. Barrett’s oesophagus is a well-known condition that increases the risk of developing oesophageal cancer. In Barrett’s oesophagus, the cells lining the inside of the oesophagus change and can transform to early cancerous cells. This is called dysplasia. Between one to five out of a hundred people with Barrett’s oesophagus will go on to develop oesophageal cancer. Currently, people with Barrett’s oesophagus have a routine endoscopy test where a small camera on a thin flexible tube looks at the lining of the oesophagus. Small samples of the lining (biopsies) can be taken to ensure that there are no signs of dysplasia or cancer. This means that any dysplasia or cancer can be found early allowing more patients to be treated at early stage. Questions and objectives The main research question is whether the cell changes in Barrett’s oesophagus can be detected by testing the breath of people with the condition. This will provide an easy and cheaper way to identify people at high risk of having dysplasia who should then have close monitoring to detect any signs of early cancer. How it will be done A clinical study will be carried out in four hospital sites with dedicated Barrett’s oesophagus services. Participants will be recruited when they attend the hospital for their routine endoscopy. Before their endoscopy they will be asked to undergo a breath test. The breath test is a quick method that is non-invasive and has no associated discomfort. It involves breathing out normally through a mask, to allow the breath to be collected into small tubes located within the mask. The breath samples will be analysed in a laboratory for gases emitted from cells, known as Volatile Organic Compounds (VOCs). The gases present in participants with and without dysplasia and cancer will be compared to identify the differences that could be used to test for the condition. We aim to recruit 463 participants across the 4 sites. Potential impact Endoscopy used for Barrett’s surveillance costs roughly £1500. The proportion of people with Barrett’s disease that will progress to early cancer is 0.9% to 1.0%. This places a big financial burden on the National Health Service. Therefore, it is important to identify patients at risk, with the ultimate goal of targeting endoscopy towards the people at high risk of developing cancer. This study will look to introduce a new non-invasive and cost-effective test to monitor people with Barrett’s through means of breath testing. This will provide a more comfortable investigation for patients who are already anxious about the outcomes, enabling earlier diagnosis of those at risk and improving treatment success rates.

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