Something's Fishy – DHA and Prostate Cancer
Abstract & Commentary
By Russell H. Greenfield, MD
Synopsis: In a shocking series of findings, this well-done prospective study showed that in men older than age 55 years a higher proportion of serum omega-3 fatty acids, specifically DHA, actually may increase the risk for high-grade prostate cancer.
Source: Brasky TM, et al. Serum phospholipid fatty acids and prostate cancer risk: Results from the Prostate Cancer Prevention Trial. Am J Epidemiol 2011;173:1429-1439.
Data suggest that the omega-3 fatty acids found in fish oils may help prevent a variety of cancers, including prostate cancer, with the most likely mechanism being modulation of inflammation. The researchers behind this prospective, nested case-control trial were interested in furthering investigation in this area, working from the hypothesis that higher serum omega-3 fats would be associated with a lessened incidence of prostate cancer, and that high serum concentrations of omega-6 and trans fatty acids would be tied to an increased risk.
The study comes out of the Prostate Cancer Prevention Trial, a randomized, placebo-controlled trial that evaluated the effect of finasteride on prostate cancer risk (of note, results suggested that finasteride reduced the risk of prostate cancer; however, cancers that developed in those on the medication were more aggressive). Subjects were men older than 55 years with no history of antecedent cancer (save for non-melanoma skin cancer) or severe benign prostatic hyperplasia; prostate-specific antigen concentrations of ≤ 3.0 ng/mL; and normal digital rectal examination. Nearly 19,000 men receiving care out of 221 U.S. medical centers were randomized to receive either finasteride or placebo. Over the course of the 7-year study, men underwent annual prostate-specific antigen and digital rectal examination testing. Men who had an abnormal digital rectal examination or finasteride-adjusted prostate-specific antigen result ≥ 4.0 ng/mL were recommended for prostate biopsy. At the final study visit, all men who had not been diagnosed with prostate cancer also were requested to undergo prostate biopsy. Pathology specimens were reviewed for adenocarcinoma by both the pathologist at the local study site and at a central pathology laboratory, with concordance achieved in all cases. Clinical stage was assigned locally, and grade was assigned by a single pathologist at the central laboratory. Non-fasting blood was collected 3 months prior to randomization and then annually until either the end of the study or a diagnosis of prostate cancer was made. Total lipids were extracted from serum, and phospholipids were separated from other lipids by one-dimensional thin-layer chromatography. Proportions of fatty acids were categorized into quartiles on the basis of the distribution in the controls.
Excluding men without baseline serum available for analysis, cases (n = 1809) were men with biopsy- confirmed invasive prostate cancer identified before the study was unblinded, and controls (n = 1809) were selected from subjects who had no cancer detectable at the end-of-study biopsy. Controls were frequency matched to cases on distributions of age (± 5 years), treatment group (finasteride or placebo), and other factors. All models were adjusted for the matching variables of age, family history of prostate cancer, and race, and additionally adjusted for risk factors including history of diabetes, alcohol consumption, and body mass index.
Results were sobering proportions of DHA were higher among high-grade cases of prostate cancer (Gleason score 8-10) compared with controls, whereas trans fatty acid levels were significantly lower among high-grade cases compared with controls. Higher quartile levels of percent serum DHA were associated with an almost doubling of the risk for high-grade disease compared with the lowest quartile; on the other hand, a significant inverse relationship was found between the percent serum trans fatty acid level and risk of high-grade prostate cancer. Associations for DHA + EPA were similar to those for DHA alone. There were no other significant findings for the remaining phospholipids between control and cancer groups, including for EPA alone or linoleic acid, and no association identified for any fatty acid with low-grade disease (Gleason score 2-7).
The researchers concluded that, in this large prospective investigation of inflammation-associated phospholipid fatty acids and prostate cancer risk, omega-3 fatty acids do not reduce prostate cancer risk, and trans fatty acids do not increase prostate cancer risk in fact, just the opposite. The authors are frank about being "disconcerted" by their findings, noting that the results illustrate the complexity of research on nutrition and chronic disease risk.
Good research has a way of turning things topsy-turvy and making us revisit long-held assumptions previously deemed fact. This paper represents good research. The study authors entered into their protocol fully expecting to find that higher serum levels of omega-3 fats would be protective against prostate cancer, and that the presence of those evil trans fats in high concentrations would be shown yet again to be harbingers of ill health. Oops...
A wealth of research strongly suggests that inappropriate inflammation may contribute to the development of carcinogenesis, and studies that examine dietary omega-3 fatty acid intakes have supported the general inflammation–cancer hypothesis. Simply put, omega-3s are anti-inflammatory or at least less pro-inflammatory (good), while omega-6s and trans fatty acids are more pro- inflammatory (bad). It's been pretty easy, pretty linear, but like few studies before, these investigators looked at things differently actual serum levels of phospholipid fatty acids. And they found the opposite of what was anticipated increased risk with higher proportions of DHA, lowered risk with increased proportions of trans fats, and no identifiable association with omega-6s or EPA. These findings, when taken together with those from the large EPIC trial that suggested an increased risk of both high- and low-grade prostate cancer in the highest quintile of DHA blood levels, as well as an increased risk of prostate cancer with increasing blood levels of EPA (unlike what is reported in the current study),1 must give us pause when considering the overall benefits, and risks, associated with omega-3 fatty acids. The authors themselves state it is possible that omega-3 fatty acids promote tumorigenesis.
This was an extremely well-done bit of research, which makes the conclusions all the more concerning. The researchers even analyzed the results on the basis of whether subjects received finasteride or not (cases of high-grade prostate cancer were more likely to have been randomized to treatment with finasteride). Yes, there was over-sampling with respect to the frequency of prostate biopsy, as evidenced by the fact that almost all cases of prostate cancer detected were local stage (although high-grade disease was detected). In addition, the study authors point out that they looked at fatty acid as a proportion (%) rather than by concentrations. Regardless, across an array of statistical analyses the findings held true.
Now what? DHA is often thought of as the "eye and memory fatty acid" with its cousin, EPA, typically considered the "heart and joint fatty acid." Practitioners should discuss the risks and benefits of fish oils with individual patients based upon their unique clinical circumstances. For those using fish oil supplements for general health purposes, especially men, it may be worthwhile taking products that contain a significantly higher percentage of EPA compared to DHA. Clarity on this topic demands further data. Considering how many people make a habit of eating fatty, cold water fish for health reasons or who take fish oil supplements, here's hoping those data come soon.
1. Crowe FL, et al. Fatty acid composition of plasma phospholipids and risk of prostate cancer in a case-control analysis nested within the European Prospective Investigation into Cancer and Nutrition. Am J Clin Nutr 2008;88:1353-1363.