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Friday, July 12, 2013

Dr. Barry Ritz responds to the Omega-3 Fatty Acid and Prostate Cancer headlines

Literature Watch: Omega-3 Fatty Acids and Prostate Cancer


Author:  Barry W. Ritz, PhD


Observational case-cohort study reports an association between increased blood concentrations of omega-3 fatty acids and risk for prostate cancer among men involved in an intervention study designed to examine prostate cancer risk in subjects supplemented with vitamin E and/or selenium. 

In an analysis of data generated from the SELECT trial (Selenium and Vitamin E Cancer Prevention Trial), Brasky and colleagues have reported that men with the highest quartile of serum long-chain omega-3 polyunsaturated fatty acids were at a 43% increased risk for prostate cancer, including a 44% increased risk of low-grade cancer and a 71% increased risk for clinically-significant, high-grade cancer.  The authors conclude that these data “confirm” the link between omega-3 fatty acid intake and increased risk for prostate cancer and, in both the original paper and subsequent media interviews, specifically emphasize the risks of consuming omega-3 (fish oil) supplements.  The current study effectively adds to a body of inconsistent literature regarding the role of dietary fatty acids and prostate cancer risk, which is an area that does indeed require further study with appropriate, controlled trials.  However, the authors greatly overstate their conclusions, especially in attributing increased risk to fish oil supplementation, such that a more thorough discussion on the study design, a review of the results in context, and illumination of the limitations of their analysis are clearly warranted.

The SELECT trial enrolled 35,533 men between 2001 and 2004 at average risk for developing prostate cancer and assigned them to intervention groups providing selenium, vitamin E, selenium + vitamin E, or placebo.  The trial was discontinued in 2008 due to no observed evidence of a protective effect.  Subsequent analysis, several years after the discontinuation of the intervention, reported a 17% increased risk for prostate cancer among men who had been previously supplemented with vitamin E.  Although the SELECT study was not designed to evaluate an association between fatty acid status and cancer outcome, baseline blood samples were available for the analysis of fatty acid composition, making the current study possible. 

The analysis of blood samples for fatty acid composition was conducted on a sub-sample of the original study population including 1364 subjects who did not develop cancer and 834 total subjects who had developed prostate cancer.  The authors created the case cohort by selecting subjects who had developed prostate cancer during a specific period of time during the study and for which there were baseline blood samples available.  They then created a control subgroup by selecting subjects from the trial that could be matched for the basic demographics of the case cohort but who had not developed prostate cancer.  Fatty acid compositions were then reported for total omega-3, alpha-linolenic, EPA, DHA, DPA, the omega-6 fatty acids linoleic and arachadonic, and a selection of trans-fatty acids as a percentage of total fatty acids, and each group was split up into quartiles from the highest to the lowest percentages.  The authors then analyzed the relative risk of developing prostate cancer by comparing the lowest quartile to the highest for each fatty acid.  It is important to note that these quartiles of fatty acid composition from high to low represented fatty acid composition at BASELINE, not during the course of the study or at the time point at which the subjects were known to develop prostate cancer.  In many cases, the blood sample from which fatty acids were analysis would have been drawn years before the development of cancer.  Although the development of cancer is considered a long-term process, there is absolutely no way to determine whether the baseline fatty acid levels were reflective of typical values for that individual or whether they were reflective of fatty acid intakes or fatty acid status during the time period when cancer was developing or at the time point at which cancer was detected.

The authors report an increase in prostate cancer risk associated with elevations in total omega-3, as well as elevated concentrations of the fatty acids DPA and DHA, specifically.  The omega-3 fatty acids alpha-linolenic and EPA were not associated with increased risk.  The authors also provide a meta-analysis in which they put the current results into the context of previous reports.  According to the meta-analysis of seven studies, EPA was not associated with prostate cancer risk.  An analysis of alpha-linolenic was not provided, but the authors note that results from other studies have consistently demonstrated no relationship.  Results for the fatty acid DHA were mixed.  One trial in the analysis reported a protective effect against total prostate cancer outcomes, three trials reported an increased risk (including both the current study and Brasky 2011), and three studies demonstrated no effects.  The meta-analysis concluded a 16% increased risk for total prostate cancer.  Results for low- and high-grade cancer risks were also mixed, with the overall outcomes being a 20% and 48% increased risk, respectively.  The meta-analysis concluded no association between total omega-3 intake and total or low-grade prostate cancer risk, although high-grade prostate cancer risk was increased by 51%.  This elevated risk came from only one trial, also by Brasky and colleagues (2011), while the other three studies in the meta-analysis yielded null results.  Indeed, much of the data supporting a positive association between omega-3 status and cancer risk have been generated by Brasky and colleagues.  Further, numerous studies appear to be missing from the Brasky meta-analysis (Berquin 2007, Terry 2001, Augustsson 2003, Leitzmann 2004), possibly related to incompatible methodologies, and a previous meta-analysis reporting no association between omega-3 fatty acids intake and prostate cancer risk but a 63% decreased risk of prostate cancer-related mortality with increased omega-3 intake was excluded (Szymanski 2010).  Taken together, the collective literature clearly does not provide definitive evidence associating omega-3 fatty acid status with prostate cancer risk.

In addition to reporting an increased risk for prostate cancer associated with increased omega-3s, the authors reported a decreased risk of prostate cancer of about 25-30% associated with an increase in the omega-6 fatty acid linoleic acid.  Arachadonic acid was not associated with an increased or decreased risk.  In addition, in a previous study using data in a similar manner but obtained from the Prostate Prevention Trial, the same authors reported a decreased risk for prostate cancer associated with increased trans-fats.  It is unknown why generally recognized pro-inflammatory omega-6 and trans-fatty acids might be associated with a protective effect against prostate cancer.  Given this unknown and the inconsistency in results, the authors conclude that it is unlikely that omega-6 or trans-fats are associated either positively or negatively with prostate cancer risk.  However, while the authors concede that a coherent mechanism is also missing for why anti-inflammatory omega-3s would be associated with increased prostate cancer risk, they conclude that their data are definitive in establishing a relationship between increased omega-3 fatty acids and increased prostate cancer risk.  This conclusion is clearly overstated.

Importantly, the authors go on to explain their results in the context of “other” clinical trials in which nutritional supplements have reported increases in cancer risk despite a complex association between nutrients and chronic disease.  This is the salient error in the authors’ analysis and conclusion—they implicate supplemental omega-3 fats without any data related to supplemental intake.  The study was not designed to look at omega-3 intake.  Remember, outcomes were compared to the subjects’ fatty acid status at baseline, possibly years before cancer was detected.  Further, no data on dietary or supplemental nutrient intakes was provided.  In the original study design, an intervention trial looking at selenium and vitamin E, subjects were asked to avoid consumption of any multivitamin or supplemental selenium or E.  Instead, a special multi-vitamin was provided for free to account for subjects who might wish to consume a multi and would otherwise confound the results.  There were apparently no restrictions or recommendations on diet or supplements related to omega-3 fatty acids (fish intake or fish oils).  As a result of the lack of any intervention related to fish or fish oil intake, the resultant quartiles of fatty acid status were quite close together.  As noted by the senior author on the study Dr. Alan Kristal and reported in Science Daily, the difference in blood concentrations between the lowest and highest quartiles for total omega-3 was quite small and reflects a difference of about 2 fish meals per week.  The range in total omega-3 as a percentage of total fatty acids was only about 1.6%, from 3.7% in the lowest group to 5.3% in the highest quartile.  (Note: the percentages and range reported in Science Daily and commented on by Dr. Kristal are incorrect.)  While methodologies differ, the literature suggests that a fatty acid percentage of approximately 4% is indicative of a normal, unsupplemented population (Skulas-Ray 2011, Carney 2009).  Therefore, the current study even at the highest quartile is probably not reflective of a generally supplemented population.  According to Atrium’s our own data (unpublished, in press), we have observed a baseline fatty acid status of 6% in a healthy population regularly consuming fish oil supplements.  This exceeds the highest fatty acid quartile in the current study.  In conclusion, any association between fatty acid status and prostate cancer cannot be attributed to supplementation.  Notably, the authors appear to be eager to recommend against the use of fish oil supplements, despite their established health benefits, but stop short of calling for a reduction in dietary fish intake.

Despite these limitations and the gross overextension of the results by the study authors and media, the current study does make an important contribution to the overall body of literature investigating the potential association between fatty acid status and prostate cancer risk.  As currently available data are inconsistent and a plausible mechanism remains unknown, further studies are warranted.  These should be of proper design and account for omega-3 intake from dietary and supplemental sources. 


Brasky TM, Darke AK, Song X, et al. Plasma phospholipid fatty acids and prostate cancer risk in the SELECT trial. J Nat Cancer Inst. 2013

Additional references:

Brasky TM, Till C, White E, et al. Serum phospholipid fatty acids and prostate cancer risk: results from the prostate cancer prevention trial. Am J Epidemiol. 2011;173(12):1429-39.

Berquin IM, Min Y, Wu R, et al. Modulation of prostate cancer genetic risk by omega-3 and omega-6 fatty acids. J Clin Invest. 2007;117:1866-75.

Terry P, Lichtenstein P, Feychting M, Ahlbom A, Wolk A. Fatty fish consumption and risk of prostate cancer. Lancet. 2001;357:1764-6.

Augustsson K, et al. A prospective study of intake of fish and marine fatty acids and prostate cancer. Cancer Epidemiol Biomarkers Prev. 2003;12(1):64-7.

Leitzmann MF, Stampfer MJ, Michaud DS, et al. Dietary intake of n-3 and n-6 fatty acids and the risk of prostate cancer. Am J Clin Nutr. 2004;80(1):204-16.

Szymanski KM, Wheeler DC, Mucci LA. Fish consumption and prostate cancer risk: a review and meta-analysis. Am J Clin Nutr. 2010;92(5):1223-33.

Skulas-Ray AC, Kris-Etherton PM, Harris WS, et al. Dose-response effects of omega-3 fatty acids on triglycerides, inflammation, and endothelial function in healthy persons with moderate hypertriglyceridemia. Am J Clin Nutr. 2011;93:243-52.

Carney RM, Freedland KE, Rubin EH, et al. Omega-3 augmentation of sertraline in the treatment of depression in patients with coronary heart disease: a randomized controlled trial. JAMA. 2009;302(15):1651-7.

Science Daily: Link between Omega-3 fatty acids and increased prostate cancer risk confirmed, www.sciencedaily.com, July 10, 2013.

NutraIngredients: Omega-3 “confirmed” to increase prostate cancer risk: study, by Nathan Gray, www.nutraingredients-usa.com, July 11, 2013.


Literature Watch

Dr. Barry Ritz

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