Title: STudy Of Prevention by Aspirin anD EPA; kNowledge Of Mechanism of Action (STOP-ADENOMA)
Funder: Medical Research Council

Abstract: Despite advances in diagnosis and treatment of bowel (also known as colorectal) cancer, it remains a major cause of death. More attention needs to be focussed on ways to prevent bowel cancer, including the use of medicines and nutrients - an approach called chemoprevention. Colorectal cancer (CRC) develops over a number of years from a benign fleshy growth in the bowel called a polyp. Polyps are found and removed during a lower bowel camera test called a colonoscopy. The higher the number of polyps that anyone has, the higher that person’s risk of CRC in the future._x000D_ _x000D_ This research team has recently completed a research study called the seAFOod Trial. That trial showed that the medicine aspirin (already used as an anti-inflammatory, as well as for prevention of heart attack and stroke), and a naturally-occurring oil found in fish called EPA, reduce the number of polyps detected in individuals at check-up who already had several polyps removed during a colonoscopy in the National Bowel Cancer Screening Programme. Aspirin and EPA reduced polyp number in different ways, depending on the type of polyp, and where in the bowel the polyp was situated. The trial also suggested that aspirin and EPA might work even better together._x000D_ _x000D_ Despite aspirin use for over a century, and widespread use of omega-3 fish oil as a health supplement, it is still not understood how they work against polyps and CRC. So, knowledge of how they work is needed in order to use them as chemoprevention most effectively in the clinic._x000D_ _x000D_ A major legacy of the seAFOod Trial is a collection of blood, urine and tissue samples, which were collected from over 90% of the 709 people in the trial. We also have individual consent for research use of the samples and for access to future colonoscopy results after the trial. Laboratory results can be linked with the trial colonoscopy results for each participant in a secure, confidential database._x000D_ _x000D_ This means that the seAFOod Trial team are now in a unique position to ask questions about how aspirin and EPA work, each relevant to future best use of chemoprevention in people at increased risk of bowel cancer. We want to;_x000D_ _x000D_ 1) See whether the reduction in bowel polyp recurrence persists at future check-up colonoscopies (or perhaps increases) after the trial has ended, which will tell us whether long-term treatment is needed, or not._x000D_ 2) In the laboratory, measure the levels of several products of EPA and aspirin that are produced by the body, which will tell us whether combination aspirin plus EPA treatment is likely to give added benefit and which may identify patient (blood test) markers that tell us in advance whether aspirin and/or EPA is likely to work for prevention._x000D_ 3) Address whether an EPA supplement, one’s genetic profile and/or omega-3 intake in the diet is important on an individual level for whether aspirin prevents polyps and for whether EPA supplement use will be worthwhile. These results have the potential to lead to dietary guidance for individuals at higher risk of bowel cancer and to identify markers that could be used in the clinic to match the best chemoprevention, at the right dose, with the right person._x000D_ _x000D_ Any marker that we identify as predicting benefit of aspirin and/or EPA on a personal level will need confirming ‘in real life’ in future clinical studies such as a planned trial including combination aspirin and EPA called COLO-PREVENT.

Lay abstract: The EME-funded seAFOod polyp prevention trial demonstrated that aspirin and the omega-3 polyunsaturated fatty acid (PUFA) eicosapentaenoic acid (EPA) both display colorectal cancer (CRC) chemopreventive activity, based on reduction in colorectal adenoma number, in a manner dependent on the type and location of colorectal neoplasia (Lancet 2018;392:2583-94). It also suggested that the combination of aspirin plus EPA had greater efficacy than either agent alone, particularly for distal (left) colorectal lesions. Therefore, a precision medicine approach is needed in order to maximise efficacy of these chemoprevention agents. However, lack of understanding of mechanism(s) of action of both aspirin and EPA currently limits such an approach to CRC chemoprevention, which requires identification of biomarkers for risk stratification and therapeutic response prediction. Understanding the mechanistic basis of an interaction between aspirin and EPA also strengthens the justification for a clinical trial of combination aspirin and EPA treatment._x000D_ _x000D_ During the seAFOod polyp prevention trial, we amassed a comprehensive (>95% coverage), high quality-assured Biobank of blood (plasma, leukocytes, and red blood cells), urine and rectal mucosa samples, aligned to detailed clinical (colonoscopy) trial outcomes. We have individual consent for laboratory analysis of samples and collection of post-trial clinical outcomes from all trial participants at randomisation. Therefore, we now have an unparalleled opportunity to utilise this resource in order to test hypotheses about mechanism(s) of action of aspirin and EPA, which are relevant to identification of biomarkers for risk stratification and response prediction, using a tissue collection unique in chemoprevention trials, thus maximising the impact of investment by the NIHR in cancer prevention research. _x000D_ _x000D_ We will use a combination of laboratory techniques (mass spectrometry for lipid mediators, SNP genotype analysis, tissue gene expression [qPCR, immunohistochemistry]) and database interrogation (Bowel Cancer Screening [colonoscopy] outcomes, National Cancer Registration and Analysis Service [cancer] outcomes) in order to answer pre-specified questions regarding the molecular and clinical pharmacology of aspirin and EPA (particularly related to cyclooxygenase activity and lipid mediator signalling), as well as about endogenous factors controlling omega-3 PUFA levels and aspirin efficacy (genotype and diet)._x000D_ _x000D_ Laboratory data will be linked to the existing seAFOod polyp prevention trial database in a secure virtual research environment in the Leeds Institute of Data Analytics (LIDA; ISO27001 and NHS IG Toolkit compliant). Proof-of-principle for this approach has been gained from the analysis of red blood cell fatty acid levels described in the primary seAFOod trial paper. Individual-level data from other sources (eg. Bowel Cancer Screening System) will be linked through the Cancer Research UK-funded CORECT-R CRC data repository that sits within Public Health England._x000D_ _x000D_ Putative biomarkers identified by the mechanistic studies in STOP-ADENOMA will be validated using existing trial datasets (eg. ASPIRED) and currently planned polyp prevention trials, which will include aspirin alone and combination treatment arms (eg. COLO-PREVENT). Collectively, these studies will drive forward a precision medicine approach to CRC chemoprevention highlighted by the seAFOod polyp prevention trial

Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: CANCER AND NEOPLASMS