AUGMENTED RESPONSE OF VOLATILE BIOMARKERS IN THE ASSESSMENT OF OESOPHAGOGASTRIC CANCER (AROMA2)

Oesophagogastric Cancer Early Detection: A Clinical Challenge

The detection of oesophagogastric cancer at an early stage remains an unmet clinical need. It's incidence in the UK and many other western countries has risen dramatically in recent years. Challenges in diagnosis are attributable to the largely non-specific nature of its early symptoms, which overlap with benign gastrointestinal conditions, alongside the resource intense and invasive nature of the current diagnostic pathways such as endoscopy. The so called 'red flag' symptoms that prompt more urgent investigation are often associated with advanced disease where curative treatments are limited. As a result, the five-year survival rate for oesophagogastric cancer in the UK remains distressingly low at 15-20%, one of the poorest in Europe. Early detection offers the best chance for effective intervention, where minimally invasive treatments and surgical procedures can lead to survival rates of over 85%.

There is a growing body of evidence that volatile organic compounds (VOCs), which are small molecules exhaled in breath, hold promise as non-invasive biomarkers for cancer detection in the form of a breath test. Our work suggests that VOCs are produced by both cancer cells and the tumour-associated microbiome. Our understanding of the pathways leading to VOC production allow us to propose augmentation of the breath test using certain nutrients to increase the production of volatile markers and improve the tests accuracy.

We have developed a breath test for diagnosing oesophagogastric cancer, starting with volatile biomarker discovery and progressing to a multi-centre NIHR-funded clinical study which demonstrated a sensitivity of 80% and specificity of 81%. To explore the origin of VOCs in oesophagogastric cancer, we developed an in-vivo human model that allowed for the compartmental measurement of VOCs from the gastrointestinal tract, airways, and mixed breath during general anaesthesia. The comparable levels of volatile fatty acids in both mixed and bronchial breath from cancer patients suggest that the primary source of these VOCs is the lungs, likely entering the breath through the systemic circulation.

Alongside this we have developed standardised operating procedures for VOC analysis with a platform for high-throughput breath analysis adherent to ISO accreditation standards. Our validated methodology has a VOC quantitation limit of 1.25 ng/L with established quality assurance and control procedures.