Inclusion criteria, exclusion criteria and study summary
The mechanism(s) by which the omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) has anti-colorectal cancer (CRC) activity is not understood. Recent experimental data support the idea that the anti-CRC benefit of EPA may be mediated by modulating the intestinal microbiota (gut bacteria), thereby reducing immunosuppressive mechanisms that allow CRC cells to ‘hide’ from the host anti-tumour immune response. The EMT2 trial is an ongoing randomized, double-blind, placebo-controlled phase 3 trial of the effect of EPA ethyl ester 4 g daily on CRC recurrence and survival after surgery for resectable CRC liver metastases (ClinicalTrials.gov NCT03428477). There is a unique opportunity to collect samples from participants in the trial in order to characterise the intestinal microbiota and immune response to CRC. We will collect biospecimens (faecal [stool] samples, CRC liver metastasis tissue, blood and urine) from EMT2 trial participants in a way that does not interfere with participation in the EMT2 trial. Using stool, blood and urine samples collected 1) after EMT2 trial randomisation, before starting active EPA or placebo, 2) just before surgery, and 3) at 6-monthly intervals thereafter, we will interrogate immune and microbiome pathways in relation to survival in EMT2 trial participants. We will address causality and characterize the mechanisms by which EPA potentiates host anti-tumour immunity and suppresses CRCLM using a novel ‘avatar’ germ-free CRCLM mouse model humanized with faecal material from EMT2 trial participants. Mechanistic insights about the anti-CRC activity of EPA from the biospecimen collection project will maximise the knowledge and insights gained from the EMT2 trial and its participants, thereby leading to personalised use of EPA, which will be targeted at those most likely to benefit.
