A hotly debated recent study, the SELECT trial, has casted doubt on the well documented health benefits of omega-3 fatty acids. This study found that a higher content of long-chain omega-3 fatty acids (EPA+DPA+DHA) in blood plasma was associated with a with a greater risk of low-grade (44%) and high-grade (71%) prostate cancers over a 5-year follow-up 1. Associations were similar for individual long-chain omega-3 fatty acids. Higher linoleic acid (omega-6) was associated with a 25% reduced risk of low-grade and 23% reduced risk of total prostate cancer 1 .
This has understandably generated confusion among the general public and intense discussions among health professionals and researchers. However, a deeper look at the data and study methodology reveals a different picture…
Will Brink and Dr Lopez have previously commented on the notorious omega-3 / prostate cancer study:
Here is my take on it…
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.
Because of the large number of subjects in the SELECT trial, 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 .
Note that this was not a fish oil supplement study. 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.
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.
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.
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.
About Monica Mollica - www.Trainergize.com
Trainergize.com is an unbiased informational and motivational resource, presenting the latest health, performance and anti-aging related research findings to the public, in an easy to understand way.
While still under development, trainergize.com is committed to providing credible, objective, and reliable health information on a wide range of topics that impact your health and wellness and that of your family. The information is derived from scientific research studies published in top tier medical journals and/or presented at professional medical meetings.
Trainergize was developed by Monica Mollica, who holds a Bachelor and Master degree in Nutrition from the University of Stockholm / Karolinska Institue, Sweden. She has also done PhD level course work at renowned Baylor University, TX.
As a young athlete, Monica realized the importance of nutrition for maximal performance, and went for a major in Nutrition at the University of Stockholm. During her years at the University she was a regular contributor to the Swedish fitness and bodybuilding magazine BODY. She has written a book (in Swedish) for health professionals, “Functional Foods for Health and Energy Control” with over 700 scientific research citations, and authored several book chapters in Swedish popular press publications.
After having earned her Master degree in Nutrition, she completed one semester at the PhD-program “Exercise, Nutrition and Preventive Health” at the Department of Health Human Performance and Recreation, Baylor University in Texas.
Having lost her father in a lifestyle induced heart attack at an age of 49, she is specializing in cardiovascular health, and primordial/primary prevention. She is a strong advocate of early intervention in adolescence and young adulthood, and the importance of lifestyle habits for health promotion at all ages.
Today, Monica is sharing her solid academic knowledge, real-life hands on experience and passion by offering diet/nutrition/exercise/health consultation services, and working as a health journalist and medical writer, specializing in fitness, health promotion and anti-aging.
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. Aug 7 2013;105(15):1132-1141.
2. Cao J, Schwichtenberg KA, Hanson NQ, Tsai MY. Incorporation and clearance of omega-3 fatty acids in erythrocyte membranes and plasma phospholipids. Clinical chemistry. Dec 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). Dec 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, Warnick GR, McConnell JP. 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. September – October 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. Jun 1 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. Nov 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. Aug 1 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. Jan 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, Chen YQ. Mechanisms of omega-3 polyunsaturated fatty acids in prostate cancer prevention. BioMed research international. 2013;2013:824563.
13. Norrish AE, Skeaff CM, Arribas GL, Sharpe SJ, Jackson RT. Prostate cancer risk and consumption of fish oils: a dietary biomarker-based case-control study. British journal of cancer. Dec 1999;81(7):1238-1242.
14. Brinson BE, Miller S. Fish oil: what is the role in cardiovascular health? Journal of pharmacy practice. Feb 2012;25(1):69-74.
15. Calderon Artero P, Champagne C, Garigen S, Mousa S, Block R. Fish oil metabolites: translating promising findings from bench to bedside to reduce cardiovascular disease. Journal of glycomics & lipidomics. Feb 27 2012;2(1).
16. Eslick GD, Howe PR, Smith C, Priest R, Bensoussan A. Benefits of fish oil supplementation in hyperlipidemia: a systematic review and meta-analysis. International journal of cardiology. Jul 24 2009;136(1):4-16.
17. Kromhout D, Yasuda S, Geleijnse JM, Shimokawa H. Fish oil and omega-3 fatty acids in cardiovascular disease: do they really work? European heart journal. Feb 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. Jan 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. May 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. Jan 1 2013;127(1):e6-e245.