Long-chain n-3 polyunsaturated fatty acids (LCPUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have anti-inflammatory properties and may be a potential chemopreventive agent for colorectal cancer. Dietary n-3 LCPUFAs decreases tissue content of arachidonic acid, inhibits prostaglandin-endoperoxide synthase, and reduces prostaglandin E2 (PGE2) production. Eleven alpha-hydroxy-9, 15-dioxo-2, 3, 4, 5-tetranorprostane-1, 20-dioic acid (PGE-M) is a urinary metabolite of prostaglandin E2 that is associated with an increased risk for colorectal adenomas and cancer. Limited data exists investigating the impact of n-3 LCPUFAs on urinary PGE-M production. We conducted a 6-month, randomized, placebo-controlled trial of 1395 mg/day of EPA plus 1125 mg/day of DHA (3 capsules of Lovaza®) versus 3 grams/day oleic acid as a placebo in patients at increased risk for colorectal cancer (NCT01661764). Participants were ages 40 to 80 years and had a past medical history of one or more adenomatous polyps. Exclusion criteria included a known hereditary cancer syndrome, a prior history of any cancer, current use of fish oil supplements, a known fish allergy, and a personal history of inflammatory bowel disease or cardiovascular disease. Red blood cells and urine were collected at baseline, 12-weeks, and 24-weeks while rectal mucosal biopsies were collected at baseline and 24-weeks. The primary outcome of the trial was change in markers of rectal epithelial cell proliferation and apoptosis and these pathological evaluations are ongoing. In this abstract we present results concerning our measurements of urinary PGE-M, a secondary outcome of the study. We determined red blood cell phospholipid membrane fatty acid content using gas chromatography. We measured urinary PGE2 metabolite (PGE-M) using liquid chromatography/tandem-mass spectrometry. A total of 141 subjects were randomized. For this analysis, we included 125 participants (88.7%) who had urine collected at all three time points. Urinary PGE-M results were significantly skewed and we present geometric means. We calculated P-values using repeated measures ANOVA with log-transformed urinary PGE-M values. Regression models were adjusted for age, sex, tobacco use, aspirin use, and baseline red blood cell phospholipid membrane n-3 LCPUFA percentages. All analyses were conducted as intention-to-treat. The median age of participants was 58 years (interquartile range [IQR] 54, 64), with 49.6% female (n = 62), 9.6% reporting tobacco use (n = 12) and 31.2% reporting regular aspirin use (n = 39). Over the 24-week study, red blood cell phospholipid membrane total n-3 LCPUFA concentrations (EPA + DHA) increased by 105% from a median of 3.57 (IQR 2.95, 5.19) to 7.32 (IQR 5.42, 9.07) in participants allocated to fish oil supplementation compared to a 5% increase in the placebo group (median at baseline 3.97 (IQR 2.91, 4.87) to 4.15 (IQR 3.28, 5.09). This difference was statistically significant (P =< 0.0001) and indicated good compliance with the study medication. Individuals allocated to fish oil supplements (n = 61) had a urinary PGE-M measurement of 8.45 ± 9.01 [geometric mean and standard deviation] at baseline, 5.85 ± 4.49 at 12-weeks and 7.21 ± 6.26 at 24-weeks. Participants allocated to the placebo arm (n = 64) had a baseline urinary PGE-M of 10.6 ± 11.0, a 12-week measurement of 10.4 ± 11.5, and a 24-week measurement of 9.89 ± 11.0. Supplemental n-3 LCPUFAs were associated with a statistically significant decrease in urinary PGE-M measurements (P = 0.05). In conclusion, n-3 LCPUFA supplementation appears to reduce urinary PGE-M levels compared to placebo; however, this effect seemed to be more pronounced at 12-weeks than 24-weeks. The reduction of urinary PGE-M seen with fish oil supplementation suggests these agents might have use as a colorectal cancer chemopreventive agent.

Citation Format: Harvey J. Murff, Martha J. Shrubsole, Qiuyin Cai, Timothy Su, Stephanie M. Martin, Sandra Motley, Ginger Milne, Wei Zheng, Qi Dai. A randomized, controlled trial of fish oil supplementation on eicosanoid production in patients at risk for colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr A32.