Prebiotic Effect of Eicosapentaenoic Acid Treatment for Colorectal Cancer Liver Metastases

Overview

A significant proportion of patients who undergo liver surgery to remove bowel cancer that has spread to the liver (metastases) develop disease recurrence and die from the disease. The EMT2 study (NCT03428477) is a clinical trial of the omega-3 fatty acid EPA, investigating whether patients who EPA ethyl ester remain free of disease recurrence for longer than those taking placebo. Recent data suggest that the anti-cancer effect of EPA may result from changes to the microbiota (gut bacteria) which lead to an improved anti-cancer response by the immune system. This study will collect biospecimens (stool, urine, blood, tumour tissue) from participants in the EMT2 trial in order to interrogate the microbiome and immune mechanisms associated with EPA treatment, in relation to participant survival. Insights from this study will identify those most likely to benefit from treatment, leading to more targeted, personalised use of EPA.

Despite advance in the diagnosis and treatment of colorectal cancer (CRC), it remains the second most common cause of cancer-related death in the US and the UK. The majority of deaths from CRC are related to distant metastases, predominantly to the liver. There are observational and laboratory data supporting the notion that the omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) has anti-CRC activity. These include a phase 2 'window of opportunity' randomised, placebo-controlled trial of EPA provided before surgery for resection of CRC liver metastasis (called the EMT study). A signal that EPA improved progression-free and overall survival after liver surgery provided the rationale for the EMT2 trial, which is a randomised, double-blind placebo-controlled phase 3 trial of the effect of EPA (started before surgery but continued post-operatively) on CRC recurrence and survival after surgery for resectable liver metastases \[ClinicalTrials.gov NCT03428477 and EudraCT Number: 2016-000628-24\]. The mechanism(s) by which EPA might influence post-operative survival are not well understood. Recent data support the idea that the anti-CRC benefit of EPA may be mediated by modulating the intestinal microbiota and ameliorating tumour-permissive immunosuppressive mechanisms, including inhibition of the activity of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), as well as reduced synthesis of inflammatory mediators such as prostaglandin (PG) E2 and chemokine (C-C motif) ligand 2 (CCL2). Mice fed with a high-EPA-containing diet demonstrate 1) increased abundance of gut bacteria, such as Bifidobacterium and Lactobacillus genera that support the host anti-tumour immune response and improve the efficacy of cancer immunotherapy, and 2) decreased abundance of lipopolysaccharide (LPS)-producing bacteria that trigger chronic inflammation and can promote CRC. These data support a hypothesis that a prebiotic effect of EPA abrogates intra-tumoural immunosuppression and ameliorates systemic inflammation to improve survival of CRCLM patients. EMT2 trial participants are ideally placed to provide biospecimens that can be analysed in order to understand the mechanism(s) of action of EPA given that the laboratory data can eventually be linked to the clinical outcomes from the trial. Biospecimens can be obtained without interference with the EMT2 trial protocol. Stool, urine, and blood samples will be obtained 1) after EMT2 trial randomization, before starting EPA or placebo, 2) just before surgery, and 3) at 6-monthly intervals thereafter, plus liver metastases tumour tissue during surgery. Using these biospecimens, the microbiome and immune pathways altered by EPA will be investigated in relation to participant survival. Mechanistic insights about the anti-CRC activity of EPA from the biospecimen collection project will maximize the knowledge and insights gained from the EMT2 trial and its participants, thereby leading to personalized use of EPA, which will be targeted at those most likely to benefit.