Am. J. Epidemiol. (2011) 173 (12): 1429-1439. doi: 10.1093/aje/kwr027
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DISCUSSION
This study found significant associations of inflammation-related phospholipid fatty acids measured in serum with prostate cancer risk, albeit in the directions opposite to those hypothesized. Percent serum DHA above the first quartile was associated with an increased risk of high-grade prostate cancer, and increasing quartiles of TFA 18:1 and 18:2 were inversely associated with risk of high-grade cancer. The remaining fatty acids were not associated with prostate cancer risk. There were some differences in associations stratified by family history of prostate cancer, which are discussed below.
We restrict our review of the previous publications on blood concentrations of fatty acids to those in which blood samples were collected before diagnosis. Several studies examined long-chain ω-3 fatty acids (11–14, 16–18), and 4 have reported results by grade (11, 12, 14, 18). No associations were reported for total prostate cancer (13, 16, 17). Among studies that analyzed by grade, 2 small studies found no associations (14, 18). The most recent report from the Physicians' Health Study (PHS) (ncases = 476) (11) found nonsignificant inverse associations of the percent EPA and DHA, together and separately, with risk of both aggressive and nonaggressive prostate cancers. In the European Prospective Investigation into Cancer and Nutrition (EPIC, ncases = 962) (12), the highest quintile of percent DHA was associated with elevated risks of both low-grade (relative risk (RR) = 1.53, 95% CI: 0.96, 2.44) and high-grade (RR = 1.41, 95% CI: 0.76, 2.62) prostate cancer. They also reported significant positive associations of the percent EPA with high-grade prostate cancer (RR = 2.00, 95% CI: 1.07, 3.76). Given that the Prostate Cancer Prevention Trial and the European Prospective Investigation into Cancer and Nutrition, the 2 largest studies of blood levels of phospholipid fatty acids, reported increased risks of high-grade prostate cancer with high levels of ω-3 fatty acids, it remains a possibility that these fatty acids promote tumorigenesis.
Studies of diet, which we and others judge as less informative than studies based on blood because of their reliance on self-report, have not reported inverse associations between ω-3 fatty acid intake and total prostate cancer risk (27, 28), nor has our recent study of fish oil supplement use (29). However, in a recent meta-analysis of fish consumption and prostate cancer, Szymanski et al. (28) reported a large reduction in late stage (RR = 0.56, 95% CI: 0.37, 0.86; nstudies = 1) or fatal prostate cancer (RR = 0.37, 95% CI: 0.18, 0.74; nstudies = 4) among cohort studies. No reduction was reported for incidence of high-grade prostate cancer (RR = 1.01, 95% CI: 0.82, 1.23; nstudies = 1). These results are not necessarily inconsistent with our findings, which are based on cancers that have not yet metastasized, and the possibility remains that there may be an inverse association of fish consumption with late stage or fatal prostate cancer.
Several studies have examined α-linolenic acid in association with prostate cancer risk; however, in this and most other studies (11, 12, 16–18), there were no significant associations. There is one positive finding from a study of 141 cases that found that high levels of α-linolenic acid were associated with a doubling of prostate cancer risk (OR = 2.0, 95% CI: 1.1, 3.6) (14). A positive finding from the Physicians' Health Study (RR = 2.14, 95% CI: 0.93, 4.93) (13) has been superseded by a more recent analysis with more cases, which found no association with prostate cancer risk (RR = 1.31, 95% CI: 0.89, 1.95) (11). No previous study reported differences in the association by grade. Taken together and in support of our findings, α-linolenic acid does not appear to be associated with prostate cancer risk.
Two studies, the β-Carotene and Retinol Efficacy Trial (CARET), a randomized trial of β-carotene and retinol supplements for lung cancer prevention, and the Physicians' Health Study, examined the association of TFA and prostate cancer risk (10, 15). In the β-Carotene and Retinol Efficacy Trial, high levels of TFAs 18:1 and 18:2 were associated with increased risks of both low-grade and high-grade prostate cancer (15); in the Physicians' Health Study, the highest quintiles of TFAs 18:1 (RR = 1.96, 95% CI: 1.01, 3.80) and 18:2 (RR = 1.97, 95% CI: 1.03, 3.75) were associated with increased risks of nonaggressive prostate cancer but not with the risk of aggressive cancer (10). In contrast, we found an inverse association of TFAs 18:1 and 18:2 with high-grade and no association with low-grade prostate cancer. Similar to our study findings, no study found an association of TFA 16 with prostate cancer (10, 15).
Several smaller studies have investigated the association of the proinflammatory ω-6 fatty acids with prostate cancer risk; similar to our finding, none found an association with arachidonic acid (11–14, 16–18). Two (11, 16) of 7 studies (12–14, 17, 18) reported associations between linoleic acid and prostate cancer risk. One study reported an inverse association that did not differ by grade (tertile 3 vs. tertile 1: RR = 0.28, 95% CI: 0.12, 0.68); howeve, the number of cases was small (ncases = 46) (16). The Physicians' Health Study found that high levels of linoleic acid were associated with significant reductions of aggressive prostate cancer risk (RR = 0.38, 95% CI: 0.17, 0.86) (11). In agreement with the remaining studies (12–14, 17, 18), our study found no association between linoleic acid and prostate cancer risk.
To our knowledge, no previous studies have examined effect modification of fatty acids stratified by family history of prostate cancer. The differences in associations that we observed for linoleic acid and TFA 18:1 by family history are nevertheless intriguing. It is possible that genetic characteristics associated with a family history of prostate cancer modify the associations of these fatty acids with prostate cancer risk; however, we had no strong a priori hypothesis when completing this analysis, and the finding may be due to chance. As with any exploratory results, replication in other studies is needed.
The most striking aspect of our findings is that they were not in the directions hypothesized. We hypothesized that the ω-3 fatty acids would be associated with reductions in prostate cancer risk, while the ω-6 fatty acids would increase risk. EPA and DHA, found in fatty fish and in fish oil supplements, are hypothesized to reduce cancer risk through their antiinflammatory and immunomodulatory properties (8, 30). They have also been shown to affect cell permeability, gene expression, and signal transduction (31). The effects of these pathways on prostate carcinogenesis are not fully understood. Although we are unaware of a proposed mechanism by which EPA or DHA would be procarcinogenic, in a previous analysis of dietary ω-3 fatty acids in the Prostate Cancer Prevention Trial, we also observed elevated risks of high-grade prostate cancer (quartile 4 vs. quartile 1: OR = 1.52, 95% CI: 0.89, 2.58) (32). trans-Fats, found in food products which contain hydrogenated vegetable oils and in ruminant animals (33), have been associated with increased risk of cardiovascular disease (34). There is some evidence that TFAs exhibit proinflammatory effects and therefore may promote carcinogenesis (9). With the exception of results in men with a family history of prostate cancer, high levels of TFA 18:1 were associated with reductions in high-grade prostate cancer and were not associated with low-grade cancer. We know of no evidence suggesting anticancer properties of trans-fats.
We considered the possibility that the unexpected directions of our findings reflected the unique nature of the Prostate Cancer Prevention Trial design and cancer endpoints. The Prostate Cancer Prevention Trial did not use biopsy-determined absence of prostate cancer as an eligibility criterion, and thus cancers may have been prevalent at baseline. If DHA decreased the development of metastases, then men with high DHA levels would have more prevalent disease. However, all participants had a prostate-specific antigen of <3.0 ng/mL at baseline, among whom prevalent high-grade cancer is rare (35). Further, there were no associations of baseline prostate-specific antigen with DHA (r = 0.04), TFA 18:1 (r = −0.00), or TFA 18:2 (r = −0.03). It seems unlikely that a higher prevalence of high-grade disease at baseline among men with high levels of DHA, or a lower prevalence among men with high levels of TFAs, could explain our findings.
This study has several strengths. It is the largest prospective study to examine the association of circulating fatty acids and prostate cancer risk. The absence or presence of cancer was determined by prostate biopsy, which reduced the probability of disease misclassification. Measurement error due to intraindividual variability in fatty acid concentration was further reduced by pooling 2 blood draws.
The primary limitation of the Prostate Cancer Prevention Trial is that almost all cases were local stage, and many would likely have never been diagnosed by standard clinical practice. It is important to note that most significant associations were for risk of clinically relevant, high-grade cancer only, which was defined very conservatively as a Gleason score of 8–10. In a sensitivity analysis, we examined associations by using other definitions for prostate cancer grade. Despite smaller sample sizes, associations with high-grade tumors were stronger when they were defined as Gleason scores 8–10, compared with Gleason scores 7–10 or Gleason (4 + 3) plus 8–10. Thus, our findings for high-grade cancer are specific to the most clinically relevant, localized disease. An additional limitation is that fatty acids were parameterized as a proportion rather than a concentration. When expressed as a proportion, a positive association with one fatty acid could lead to a falsely inverse association with another (36). However, when all the fatty acids examined were included in a single model, the results did not change.
In conclusion, this large prospective investigation of inflammation-associated phospholipid fatty acids and prostate cancer risk found no support that ω-3 fatty acids reduce or trans-fatty acids increase prostate cancer risk. Indeed, our findings are disconcerting as they suggest that ω-3 fatty acids, considered beneficial for coronary artery disease prevention, may increase high-grade prostate cancer risk, whereas trans-fatty acids, considered harmful, may reduce high-grade prostate cancer risk. These findings illustrate the complexity of research on nutrition and chronic disease risk, in which the effects of nutrients may differ across multiple diseases. A comprehensive understanding of the effects of nutrients on a broad range of diseases will be necessary before making recommendations for dietary changes or use of individual dietary supplements for disease prevention.
- Abbreviations
- CI
- confidence interval
- DHA
- docosahexaenoic acid
- EPA
- eicosapentaenoic acid
- OR
- odds ratio
- RR
- relative risk
- TFA
- trans-fatty acid
