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The 2013 Omega-3 Fatty Acid - Prostate Cancer Debacle

Posted by pufa | December 18, 2014
Clinical Conditions, Guest Articles & Invited Opinions
William S. Harris, PhD Senior Research Scientist, Health Diagnostic Laboratory, Inc. (Richmond, VA) Professor, Department of Internal Medicine, Sanford School of Medicine, University of South Dakota President, OmegaQuant Analytics, LLC (Sioux Falls, SD)   On July 11, 2013 a paper was published online by Brasky et al. in the J Natl Cancer Institute entitled, “Plasma Phospholipid Fatty Acids and Prostate Cancer Risk in the SELECT Trial.”(1) This paper was widely publicized across all media platforms, even finding its way onto the network evening news programs. What did the study actually show? In this study, plasma phospholipid omega-3 levels were measured in 834 men who eventually developed prostate cancer (the time between plasma sampling and diagnosis is not available from the abstract), and 1393 men who did not. Using standard statistical methods, they found that men in the highest quartile of omega-3 had a 43% to 71% increased risk for prostate cancer (depending on severity). This is the same conclusion that the same group reached in 2011 in a study in another cohort entitled, “Serum Phospholipid Fatty Acids and Prostate Cancer Risk: Results from the Prostate Cancer Prevention Trial” (2). So with two studies reaching the same conclusion, it is important to seriously consider its findings. Here is the conclusion in the abstract from Brasky et al (1): “This study confirms previous reports of increased prostate cancer risk among men with high blood concentrations of LC ω-3PUFA. The consistency of these findings suggests that these fatty acids are involved in prostate tumorigenesis. Recommendations to increase LCω-3PUFA intake should consider its potential risks.” (italics introduced by the author). What are the problems here? First, blood levels were far from “high.” The reported EPA+DHA level in the plasma phospholipids in this study was 3.62% in the no-cancer control group, 3.67% in the low grade cancer group, and 3.74% in the high-grade group. These differences between cases and controls are very small and would have no meaning clinically as they are within the normal variation. Based on experiments in our lab, the lowest quartile would correspond to an Omega-3 Index of <3.16% and the highest to an Index of >4.77%. These values are obviously low, and virtually none of the subjects were in “danger” of having an Omega-3 Index of >8%. In Framinghama, the mean Omega-3 Index of participants who were not taking fish oil supplements was 5.2% and for those taking supplements, it was 7.5% (3). Both of these numbers are considerably higher than the values reported by Brasky et al., even in their highest quartile. Thus, it is extremely unlikely that these patients were taking fish oil supplements. Indeed, the SELECT study (in which all these patients were participants) was a randomized trial of vitamin E and selenium supplements for the prevention of prostate cancer. In the study protocol, it is stipulated that if the subjects wanted to take a multi-vitamin, the study would provide it; nothing is said about fish oil supplements, but it is hard to imagine their use was widespread in this trial. So to conclude that regular consumption of two oily fish meals a week or taking fish oil supplements (both of which would result in an Index above the observed range) would increase risk for prostate cancer is extrapolating far beyond the data. This study did not test the question of whether giving fish oil supplements (or eating more oily fish) increased prostate cancer risk; it looked only at blood levels of omega-3 which are determined by intake, other dietary factors, metabolism and genetics. The endless repetition of “supplements are dangerous” in the news media is not based on any data from this study. Associations do not imply causation. The second problem with the Brasky conclusion was the use of the word “tumorigenesis” – tumor causation. This is the most basic of logical errors that both scientists and science writers should be well aware of. Even granting that the associations they reported are real, the findings of this study do not mean that EPA and DHA play any role in the development of prostate cancer. For example, it is possible that some component of whatever fish these patients were consuming was carcinogenic, in which case the serum omega-3 levels were just a marker of fish (i.e., carcinogen) intake. They also failed to consider another potential explanation for their observed association, i.e., reverse causation, which is always a possibility in studies with this design. A much larger proportion of men who ultimately developed cancer (30-40%) had PSA levels >3 at baseline (compared to 7% of the controls). Thus, it is possible that sub-clinical prostate cancer was already developing in the higher risk men. He et al. (4) and Azordegan et al. (5) both provide evidence that, in pre-cancerous tissues, early changes in fatty acid metabolism (e.g., increases in the activity of delta-6-desaturase which is the rate limiting enzyme in the generation of long-chain from short-chain omega-3 fatty acids) could increase tissue (and possibly plasma?) levels of long-chain n-3 fatty acids. Hence, it is possible that metabolic changes (e.g., desaturase upregulation) associated with the carcinogenic process could have raised omega-3 levels. Differences in fish intake (unmeasured in this study) or in fish oil supplement use (prohibited in this study) may have had nothing to do with the microscopically higher plasma levels. A Wider Perspective The authors also failed to present the fuller story taught by the literature. The same team reported in 2010 that the use of fish oil supplements was not associated with any increased risk for prostate cancer (6). A 2010 meta-analysis of fish consumption and prostate cancer reported a reduction in late stage or fatal cancer among cohort studies, but no overall relationship between prostate cancer and fish intake (7). Terry et al. in 2001 (8) reported higher fish intake was associated with lower risk for prostate cancer incidence and death, and Leitzmann et al. in 2004 (9) reported similar findings. Higher intakes of canned, preserved fish were reported to be associated with reduced risk for prostate cancer (10). Epstein et al. found that a higher omega-3 fatty acid intake predicted better survival for men who already had prostate cancer (11), and increased fish intake was associated with a 63% reduction in risk for aggressive prostate cancer in a case-control study by Fradet et al (12). The incidence of prostate cancer is much higher than mortality from prostate cancer, and LC n-3 PUFA may play a role in limiting the transition from sub-clinical prostate cancer stages to aggressive forms that are responsible for death from prostate cancer (13). So there is considerable evidence actually FAVORING an increase in fish intake for prostate cancer risk reduction. Another piece of the picture is to compare prostate cancer rates in Japan vs the US. Here is a quote from the World Foundation of Urology*: “[Prostate cancer] incidence is really high in North America and Northern Europe (e.g., 63 X 100,000 white men and 102 X 100,000 Afro-Americans in the United States), but very low in Asia (e.g., 10 X 100,000 men in Japan).” http://www.prostatecancerprevention.net/index.php?p=prostate-cancer Since the Japanese typically eat about 8x more omega-3 fatty acids than Americans do and their blood levels are twice as high, you’d think their prostate cancer risk would be much higher… but the opposite is the case.   There is also a wealth of evidence from randomized clinical trials (RCT) with fish oils and omega-3 concentrates in which the incidence of cancer (rarely sub-setted) is always tracked as a possible adverse event. The table below shows the findings for the eight major studies reported to date, which included over 78,000 patients. In none of these studies was cancer incidence significantly increased by omega-3 fatty acid supplementation.   Table: Reported incident cancer diagnosis (or cancer deaths)
Trial n Duration (yrs) Placebo N-3
Alpha-Omega (14) (prostate cancer) 4837 3.4 0.8% 1.4%
GISSI-Heart Failure (15) (cancer death) 6975 3.9 3.2% 3.1%
GISSI-Prevenzione (16) 11,320 3.5 2.25% 2.65%
JELIS (17) 18,645 4.6 2.4% 2.6%
SUFOLOM3 (18) (cancer death) 2501 4.2 6.5% 7%
Origin (19) 12,536 6.2 “no difference in the rate of cancer”
Risk and Prevention (20) 12,513 5 7.2% 7.9%
Omega (21) 3851 1 1.4% 1.7%
  There will always be mixed findings in studies of “diet” and “disease” since both predictor and outcome entail so many variables, known and unknown. Higher omega-3 levels are associated with lower rates of death from any cause (22, 23), from sudden cardiac arrest (24), and with slower rates of cellular aging (25). It is therefore important to put these findings into perspective (which the authors failed to do). First consider the risk of dying from prostate cancer vs ischemic heart disease (IHD). Based on the National Vital Statistics Report for deaths in the US in males in 2010, (http://www.cdc.gov/nchs/data/dvs/deaths_2010_release.pdf), there were about 28,500 deaths from prostate cancer and 207,500 deaths from IHD: a 7.3x higher rate of death for heart disease. If one assumes (conservatively) that higher fish intake reduces risk for death from heart disease by only 10%, and (liberally) increases risk for death from prostate cancer by 50%, then the chances of dying from CHD are still 4.4x higher than from prostate cancer. This very crude analysis suggests that even in the worst case scenario, the benefit of higher omega-3 intakes/levels still far outweighs the risk.   In summary, the work of Brasky et al. does add to the evidence-base for omega-3 fatty acids and prostate cancer, which taken as a whole (not even getting into animal studies, which are typically positive) support a neutral, if not beneficial, effect of fish oil in prostate cancer. The RCT data do not support an effect of omega-3 on cancer risk in general, and a 2012 review of omega-3 and prostate cancer concluded, “Thus, epidemiological studies provide inconsistent results, suggesting an inverse association of LC n-3 PUFA” (26). A recent report from the European Food Safety Authority’s Panel on Dietetic Products, Nutrition and Allergy (27) examined the fish oil – prostate cancer question and concluded after extensive review that “there is no evidence for a role of EPA and/or DHA intake in the development of prostate cancer.” Another comprehensive meta-analysis of this question by Crowe et al. (28) (on which Brasky was a co-author) concluded more appropriately, “There was no strong evidence that circulating fatty acids are important predictors of prostate cancer risk. It is not clear whether the modest associations of stearic, eicosapentaenoic, and docosapentaenoic acid are causal”. This is a far more appropriate conclusion than that expressed in Brasky et al. (1), which is tempered by the limitations of observational cohort designs. Unfortunately, none of these later findings have found their way into the evening news.  
  1. Brasky TM, Darke AK, Song X, Tangen CM, Goodman PJ, Thompson IM, Meyskens FL, Jr., Goodman GE, Minasian LM, Parnes HL, et al. Plasma phospholipid fatty acids and prostate cancer risk in the SELECT trial. J. Nat. Cancer Inst. 2013;105(15):1132-1141.
  2. He K, Xun P, Brasky TM, Gammon MD, Stevens J, White E. Types of fish consumed and fish preparation methods in relation to pancreatic cancer incidence: the VITAL Cohort Study. Am. J. Epidemiol. 2013;177(2):152-160.
  3. Harris WS, Pottala JV, Vasan RS, Larson MG, Robins SJ. Changes in Erythrocyte Membrane Trans and Marine Fatty Acids between 1999 and 2006 in Older Americans. J. Nutr. 2012;142:1297-1303.
  4. He C, Qu X, Wan J, Rong R, Huang L, Cai C, Zhou K, Gu Y, Qian SY, Kang JX. Inhibiting delta-6 desaturase activity suppresses tumor growth in mice. PloS one 2012;7(10):e47567.
  5. Azordegan N, Fraser V, Le K, Hillyer LM, Ma DW, Fischer G, Moghadasian MH. Carcinogenesis alters fatty acid profile in breast tissue. Mol. Cell. Biochem. 2013;374(1-2):223-232.
  6. Brasky TM, Kristal AR, Navarro SL, Lampe JW, Peters U, Patterson RE, White E. Specialty supplements and prostate cancer risk in the VITamins and Lifestyle (VITAL) cohort. Nutr. Cancer 2011;63(4):573-582.
  7. Szymanski KM, Wheeler DC, Mucci LA. Fish consumption and prostate cancer risk: a review and meta-analysis. Am. J. Clin. Nutr. 2010;92(5):1223-1233.
  8. Terry P, Lichtenstein P, Feychting M, Ahlbom A, Wolk A. Fatty fish consumption and risk of prostate cancer. Lancet 2001;357:1764-1766.
  9. Leitzmann MF, Stampfer MJ, Michaud DS, Augustsson K, Colditz GC, Willett WC, Giovannucci EL. Dietary intake of n-3 and n-6 fatty acids and the risk of prostate cancer. Am. J. Clin. Nutr. 2004;80(1):204-216.
  10. Mina K, Fritschi L, Johnson KC. An inverse association between preserved fish and prostate cancer: results from a population-based case-control study in Canada. Nutr. Cancer 2008;60(2):222-226.
  11. Epstein MM, Kasperzyk JL, Mucci LA, Giovannucci E, Price A, Wolk A, Hakansson N, Fall K, Andersson SO, Andren O. Dietary fatty acid intake and prostate cancer survival in Örebro County, Sweden. Am. J. Epidemiol. 2012;176(3):240-252.
  12. Fradet V, Cheng I, Casey G, Witte JS. Dietary omega-3 fatty acids, cyclooxygenase-2 genetic variation, and aggressive prostate cancer risk. Clin. Cancer Res. 2009;15(7):2559-2566.
  13. Chavarro JE, Stampfer MJ, Hall MN, Sesso HD, Ma J. A 22-y prospective study of fish intake in relation to prostate cancer incidence and mortality. Am. J. Clin. Nutr. 2008;88(5):1297-1303.
  14. Kromhout D, Giltay EJ, Geleijnse JM. n-3 fatty acids and cardiovascular events after myocardial infarction. N. Engl. J. Med. 2010;363:2015-2026.
  15. Investigators G-H. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008;372:1223-1230.
  16. Investigators G-P. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E in 11,324 patients with myocardial infarction: Results of the GISSI-Prevenzione trial. Lancet 1999;354:447-455.
  17. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007;369:1090-1098.
  18. Galan P, Kesse-Guyot E, Czernichow S, Briancon S, Blacher J, Hercberg S. Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial. B.M.J. 2010;341:c6273.
  19. Origin Trial Investigators. N-3 Fatty Acids and Cardiovascular Outcomes in Patients with Dysglycemia. N. Engl. J. Med. 2012;367(4):309-318.
  20. Roncaglioni MC, Tombesi M, Avanzini F, Barlera S, Caimi V, Longoni P, Marzona I, Milani V, Silletta MG, Tognoni G, et al. n-3 fatty acids in patients with multiple cardiovascular risk factors. N. Engl. J. Med. 2013;368(19):1800-1808.
  21. Rauch B, Schiele R, Schneider S, Diller F, Victor N, Gohlke H, Gottwik M, Steinbeck G, Del CU, Sack R, et al. OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction. Circulation 2010;122:2152-2159.
  22. Mozaffarian D, Lemaitre RN, King IB, Song X, Huang H, Sacks FM, Rimm EB, Wang M, Siscovick DS. Plasma phospholipid long-chain omega-3 fatty acids and total and cause-specific mortality in older adults: a cohort study. Ann. Intern. Med. 2013;158(7):515-525.
  23. Pottala JV, Garg S, Cohen BE, Whooley MA, Harris WS. Blood eicosapentaenoic and docosahexaenoic acids predict all-cause mortality in patients with stable coronary heart disease: The Heart and Soul Study. Circ. Cardiovasc. Qual. Outcomes 2010;3:406-12.
  24. Albert CM, Campos H, Stampfer MJ, Ridker PM, Manson JE, Willett WC, Ma J. Blood levels of long-chain n-3 fatty acids and the risk of sudden death. N. Engl. J. Med. 2002;346:1113-8.
  25. Farzaneh-Far R, Lin J, Epel ES, Harris WS, Blackburn EH, Whooley MA. Association of marine omega-3 fatty acid levels with telomeric aging in patients with coronary heart disease. JAMA 2010;303:250-257.
  26. Gerber M. Omega-3 fatty acids and cancers: a systematic update review of epidemiological studies. Br. J. Nutr. 2012;107 Suppl 2:S228-S239.
  27. EFSA Panel on Dietetic Products NaA. Scientific Opinion on the extension of use for DHA and EPA-rich algal oil from Schizochytrium sp. as a Novel Food ingredient. EFSA Journal 2014;12 (10):3843.
  28. Crowe FL, Appleby PN, Travis RC, Barnett M, Brasky TM, Bueno-de-Mesquita HB, Chajes V, Chavarro JE, Chirlaque MD, English DR, et al. Circulating fatty acids and prostate cancer risk: individual participant meta-analysis of prospective studies. J. Natl. Cancer Inst. 2014;106(9).
   a Framingham refers to Framingham, Massachusetts, where a group of residents is extremely well characterized with respect to their blood lipid composition and cardiovascular health, as part of longitudinal studies carried out within the Framingham Heart Study.