Understanding mechanisms of colorectal cancer chemoprevention using seAFOod polyp prevention trial outcomes and its Biobank: STOP-ADENOMA synopsis

Background The 2 × 2 factorial seAFOod trial demonstrated that aspirin and omega-3 polyunsaturated fatty acid eicosapentaenoic acid reduce colorectal polyp number (a biomarker of colorectal cancer risk) during colonoscopy surveillance in the Bowel Cancer Screening Programme. The lack of a risk and/or therapeutic response biomarker limits a precision medicine approach to maximise efficacy of these chemoprevention agents. The seAFOod trial collected a comprehensive biobank of blood, urine and tissue samples. Objective To use the seAFOod Trial biobank and post-trial Bowel Cancer Screening Programme colonoscopy outcomes to (1) identify a biomarker(s) of colorectal polyp risk and therapeutic response, and (2) investigate the mechanism(s) of colorectal cancer prevention, of aspirin and eicosapentaenoic acid. Design Laboratory analysis of biobank samples and retrospective analysis of colonoscopy outcomes linked to clinical trial data. Setting Randomised, double-blind, placebo-controlled trial and the English Bowel Cancer Screening Programme colonoscopy surveillance programme. Participants seAFOod trial participants, who provided informed consent for use of trial samples and post-trial colonoscopy data. Interventions Aspirin 300 mg and/or eicosapentaenoic acid 2000 mg (or respective placebos) daily for 12 months during the seAFOod trial. Main outcome measures (1) Polyp outcomes from Bowel Cancer Screening Programme colonoscopy performed during and after the seAFOod trial; (2) plasma, red blood cell, urine and rectal mucosal polyunsaturated fatty acid and lipid mediator levels; and (3) genetic polymorphisms relevant to the pharmacology and metabolism of aspirin and eicosapentaenoic acid. Results The post-trial polyp detection rate (the number of individuals with ≥ 1 colorectal polyp) after randomisation to placebo was 71.1% compared with 80.1% for individuals, who had received aspirin (odds ratio 1.13, 95% confidence interval 1.02 to 1.24). Several genetic polymorphisms modified the polyp prevention efficacy of aspirin; for example, polyp risk reduction in aspirin users compared with non-aspirin users was restricted to rs4837960 ( PTGS1 ) common homozygotes (incidence rate ratio 0.69, 95% confidence interval 0.53 to 0.90) and eicosapentaenoic acid [the presence of at least one fatty acid desaturase 2 Indel (rs66698963) insertion allele identified eicosapentaenoic acid users with a reduction in colorectal polyp number (incidence rate ratio 0.50, 95% confidence interval 0.28 to 0.90). A high baseline urinary 11-dehydro-thromboxane B 2 level predicted increased polyp number (incidence rate ratio 2.26, 95% confidence interval 1.11 to 4.58). A low (quartile 1) on-treatment urinary 11-dehydro-thromboxane B 2 level predicted reduced colorectal polyp number compared with placebo (incidence rate ratio 0.34, 95% confidence interval 0.12 to 0.93) for aspirin and eicosapentaenoic acid treatment compared with high on-treatment urinary 11-dehydro-thromboxane B 2 values (incidence rate ratio 0.61, 95% confidence interval 0.34 to 1.11). Limitations The seAFOod trial was relatively small with under-representation according to sex and ethnicity. Conclusions STudy Of Prevention by Aspirin anD EPA; kNowledge Of Mechanism of Action has taken a precision medicine approach to colorectal cancer chemoprevention and has generated novel findings that are applicable to the optimal use of aspirin and eicosapentaenoic acid in a targeted manner. Increased polyp number in trial participants that received aspirin suggests higher neoplastic risk after aspirin cessation. Genetic polymorphisms modify the polyp prevention efficacy of aspirin and EPA. The level of urinary 11-dehydro-thromboxane B 2 predicts polyp risk prior to treatment and polyp risk reduction during aspirin treatment. Future work Validation of risk and therapeutic response biomarkers for eicosapentaenoic acid (e.g. fatty acid desaturase Indel genotype) and aspirin (e.g. urinary 11-dehydro-thromboxane B 2 ) for colorectal cancer prevention (and other non-communicable diseases) is required in other human cohorts. Funding This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme as award number NIHR128210.