Insufficient omega-3 levels in all groups

On aspect of this study that immediately jumps off the page is that subjects in even the highest category of plasma long-chain omega-3 fatty acids were insufficiency. The omega-3 levels in this study were even lower than the levels seen with a typical non-fish and non-supplemented diet [2], and were only 40-50% of what would be expected in health conscious people taking the typical health promoting dose of fish oil (providing about 1300 mg EPA + 860 mg DHA/day) [2]. The very low levels of omega-3s was even acknowledged by the study authors in the research paper, but was overlooked by the media. Note that this was not a fish oil supplement study.

Because of the large number of subjects in this study, the differences in long-chain omega-3 levels (expressed as percentages of total blood fatty acids) among the low level category without prostate cancer (4.48%) and "high" level category with prostate cancer (4.88%) did reach statistical significance. However, statistical significance and clinical (i.e. real life) significance are two different things. In studies, statistical significance (meaning that results are not caused by change) can be achieved despite minor differences in dependent variables thanks to having a large number of subjects. But when taking the subjects of out the study, the statistical significance does not translate into clinical significance when differences are small, like they were in this study [1].

Therefore, these results have no relevance for people who eat fatty fish and/or take fish oil supplements. This is underscored by another study where supplementing a low fat diet with 5 g fish oil/day (providing a daily dose of 1000 mg EPA and 1835 mg DHA) was found to decrease prostate cancer proliferation and lower the prostate tissue omega-6:omega-3 ratio [3]. A recent review paper outlining the current evidence linking polyunsaturated fatty acids with cancer risk and progression also points out that larger intakes of omega-3s may be required in order to achieve the anti-carcinogenic benefits [4].

Blood Plasma vs. Red Blood Cell Omega-3s

Another important methodological issue with this study is that it measured long-chain omega-3 fatty acids in the blood plasma fraction, as opposed to the more reliable red blood cell (RBC) fraction [5]. Plasma omega-3 changes rapidly with food intake, and does not reflect long-term incorporation of omega-3 into cells and tissues. The potential measurement error can be envisioned by the fact that 24 hours after ingesting a typical fish oil dose (3.6 g), the elevation in plasma long-chain omega-3 fatty acids EPA and DHA is 10-fold greater in than that in RBCs [5]. Thus, the blood plasma measurement in the SELECT trial doesn't reflect long-term omega-3 intakes, and therefore relating such a highly fluctuating measurement to a chronic outcome like prostate cancer is absurd. It also means that an incidental fatty fish meal the previous day before the blood draw easily could have placed in the highest omega-3 level category.

Results confounded by other prostate cancer risk factors

Despite collecting data on other prostate cancer risk factors, no adjustment was made for these in the statistical models [1]. For example, baseline PSA (prostate specific antigen, a blood marker of prostate disease) was higher in those who contracted prostate cancer, indicating pre-existing prostate disease.

Further, more subjects in the prostate cancer group also had first-degree relative with prostate cancer, indicating a genetic influence. This is supported by the identified strong genetic impact on the fatty acid composition in blood phospholipids [6].

Finally, blood fatty acid composition might not be the best indicator of prostate cancer risk. Another recent study showed that the omega-3 fatty acid alpha-linolenic acid (ALA)in prostate tissue, regardless of intake (and blood level), is positively associated with aggressive prostate cancer, and that this relationship may depend on genetic variation in ALA metabolism [7]. This counters the finding in the notorious "long-chain omega-3 fatty acids - prostate cancer risk" study which found blood levels of ALA not to be associated with prostate cancer risk.

Evidence to the contrary

In contrast to the findings in the SELECT trial, numerous other prior studies have found higher intakes of fish oil to be associated with reduced prostate cancer incidence and deaths [8-13].

The SELECT trial is also found higher linoleic acid (omega-6) to be associated with a 25% reduced risk of low-grade and 23% reduced risk of total prostate cancer [1]. This also counters previous findings that a high ratio of oomega-6 to omega-3 fat intake may increase the risk of overall prostate cancer [10].

These contradictory results in the SELECT trial, compared to many other controlled studies, further strengthen the suspicions on its methodological issues. 

Bottom Line

Long-chain omega-3 fatty acids, like those found in fish oil, have well documented health promoting effects on the cardiovascular system and significantly protect against cardiovascular diseases [14-19], which remain the leading cause of morbidity and mortality in modern societies [20, 21].  Even if there is a slim chance of an increased prostate cancer risk, when looking at the whole picture, for majority of men the benefits far outweigh the potential risk. Thus, daily intake of long-chain omega-3 fatty acids is still recommended for health promotion and disease prevention, even for men.


  1. Brasky TM, Darke AK, Song X, et al. Plasma Phospholipid Fatty Acids and Prostate Cancer Risk in the SELECT Trial. Journal of the National Cancer Institute. 2013;105(15):1132-1141.
  2. Cao J, Schwichtenberg KA, Hanson NQ, et al. Incorporation and clearance of omega-3 fatty acids in erythrocyte membranes and plasma phospholipids. Clinical chemistry. 2006;52(12):2265-2272.
  3. Aronson WJ, Kobayashi N, Barnard RJ, et al. Phase II prospective randomized trial of a low-fat diet with fish oil supplementation in men undergoing radical prostatectomy. Cancer Prev Res (Phila). 2011;4(12):2062-2071.
  4. Azrad M, Turgeon C, Demark-Wahnefried W. Current Evidence Linking Polyunsaturated Fatty Acids with Cancer Risk and Progression. Frontiers in oncology. 2013;3:224.
  5. Harris WS, Varvel SA, Pottala JV, et al. Comparative effects of an acute dose of fish oil on omega-3 fatty acid levels in red blood cells versus plasma: Implications for clinical utility. Journal of clinical lipidology. 2013;7(5):433-440.
  6. Schaeffer L, Gohlke H, Muller M, et al. Common genetic variants of the FADS1 FADS2 gene cluster and their reconstructed haplotypes are associated with the fatty acid composition in phospholipids. Human molecular genetics. 2006;15(11):1745-1756.
  7. Azrad M, Zhang K, Vollmer RT, et al. Prostatic alpha-linolenic acid (ALA) is positively associated with aggressive prostate cancer: a relationship which may depend on genetic variation in ALA metabolism. PloS one. 2012;7(12):e53104.
  8. Szymanski KM, Wheeler DC, Mucci LA. Fish consumption and prostate cancer risk: a review and meta-analysis. The American journal of clinical nutrition. 2010;92(5):1223-1233.
  9. Epstein MM, Kasperzyk JL, Mucci LA, et al. Dietary fatty acid intake and prostate cancer survival in Orebro County, Sweden. American journal of epidemiology. 2012;176(3):240-252.
  10. Williams CD, Whitley BM, Hoyo C, et al. A high ratio of dietary n-6/n-3 polyunsaturated fatty acids is associated with increased risk of prostate cancer. Nutr Res. 2011;31(1):1-8.
  11. Torfadottir JE, Valdimarsdottir UA, Mucci LA, et al. Consumption of fish products across the lifespan and prostate cancer risk. PloS one. 2013;8(4):e59799.
  12. Gu Z, Suburu J, Chen H, et al. Mechanisms of omega-3 polyunsaturated fatty acids in prostate cancer prevention. BioMed research international. 2013;2013:824563.
  13. Norrish AE, Skeaff CM, Arribas GL, et al. Prostate cancer risk and consumption of fish oils: a dietary biomarker-based case-control study. British journal of cancer. 1999;81(7):1238-1242.
  14. Brinson BE, Miller S. Fish oil: what is the role in cardiovascular health? Journal of pharmacy practice. 2012;25(1):69-74.
  15. Calderon Artero P, Champagne C, Garigen S, et al. Fish oil metabolites: translating promising findings from bench to bedside to reduce cardiovascular disease. Journal of glycomics & lipidomics. 2012;2(1).
  16. Eslick GD, Howe PR, Smith C, et al. Benefits of fish oil supplementation in hyperlipidemia: a systematic review and meta-analysis. International journal of cardiology. 2009;136(1):4-16.
  17. Kromhout D, Yasuda S, Geleijnse JM, et al. Fish oil and omega-3 fatty acids in cardiovascular disease: do they really work? European heart journal. 2012;33(4):436-443.
  18. Swanson D, Block R, Mousa SA. Omega-3 fatty acids EPA and DHA: health benefits throughout life. Adv Nutr. 2012;3(1):1-7.
  19. Peter S, Chopra S, Jacob JJ. A fish a day, keeps the cardiologist away! - A review of the effect of omega-3 fatty acids in the cardiovascular system. Indian journal of endocrinology and metabolism. 2013;17(3):422-429.
  20. Murphy SL, Xu JQ, Kochanek KD. Deaths: final data for 2010. 2010.
  21. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics--2013 update: a report from the American Heart Association. Circulation. 2013;127(1):e6-e245.