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 Epidem. 2011 April 24. Epub ahead of print.
A 7-year, randomized, placebo-controlled trial that tested whether the 5 alpha-reductase inhibitor, finasteride, reduces prostate cancer (PCa) risk. During the course of the study, men underwent annual prostate-specific antigen (PSA) and digital rectal examination (DRE) testing. Men who had an abnormal DRE or PSA >/= 4.0 ng/mL were recommended for prostate biopsy. At the end of the study, all men who had not been diagnosed with PCa were requested to undergo a prostate biopsy.
A case-control study was nested within the Prostate Cancer Prevention Trial. Serum phospholipid levels were compared from 1,809 men with biopsy-confirmed invasive prostate cancer and 1,809 men (controls) who were disease-free at the end-of-study biopsy. Controls were frequency-matched to cases on distributions of age (+/- 5 years), treatment group (finasteride/placebo), and a first-degree relative with PCa, and they were oversampled for nonwhites.
18,882 men age 55 or older were randomized to receive finasteride or placebo.
Subjects received finasteride 5 mg/day.
Serum samples were collected at years 1 and 4 and pooled to reduce intraindividual variability of the phospholipid fatty acid assay. Calculations were made of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) as a measure of total long-chain omega-3 fatty acids; linoleic + arachidonic acids as a measure of total omega-6 fatty acids; total trans-fatty acids (TFA) 18:1; total TFA 16; and total TFA 18:2.
The primary outcome measure was the distribution of serum phospholipid fatty acids by percent of total among PCa cases and controls, stratified by prostate cancer grade.
Levels of DHA were higher among high-grade cases compared with controls. Levels of TFA 18:1 and 18:2 were significantly lower among high-grade cases compared with controls. There were no other significant differences in the remaining phospholipids between control and cancer groups. EPA was not associated with risk of high-grade PCa, and associations were similar for EPA+DHA to that of DHA alone.
Epidemiologic, animal model, and in vitro studies indicate that omega-3 fatty acids, lycopene, and selenium are chemopreventive for PCa.1 The findings of this study run counter to what the investigators hypothesized, which was that omega-6 and TFAs would be positively and omega-3 fatty acids inversely associated with PCa risk. Although unexpected, the authors cite several other studies that are consistent with their results, and the possibility exists that there may be an inverse association of fish consumption with late-stage or fatal prostate cancer. It is important to keep in mind, however, that it was only with DHA, and only with high-grade prostate cancer, where an increased risk of PCa risk was found. Replication in more studies is needed before any conclusive recommendations can be made.
The findings of this study run counter to what the investigators hypothesized, which was that omega-6 and TFAs would be positively and omega-3 fatty acids inversely associated with PCa risk.
A major limitation of this sero-epidemiological study is the fact that fatal prostate cancer takes many years from formation until death. The question is whether the fatty acid content of a man’s blood on 2 days out of the thousands of days over those years is a reliable measure of his average fatty acid status. Another limitation is that the researchers did not take into account the impact of vitamin E, selenium, lycopene, cruciferous vegetables, meat, and dairy intake.
EPA and DHA are thought to reduce cancer risk in general through their anti-inflammatory and immunomodulatory properties and by affected cell permeability, gene expression, and signal transduction. The effects of omega-3s on these pathways in prostate carcinogenesis are not fully understood. There is no known mechanism by which EPA or DHA would be procarcinogenic, nor is there any evidence suggesting anticancer properties of trans-fats.
Genetic and molecular studies of high-grade prostate intraepithelial neoplasia have indicated that loss of heterozygosity is prominent and that certain oncogenes are expressed.2 What causes the expression of these oncogenes? What down-regulates their expression?
Androgenic hormones are necessary for prostate growth and development. It is not surprising that polymorphic variants of genes involved in androgen action may affect PCa risk. African Americans, who have higher PCa risks than Asians, have androgen-receptor polymorphisms that cause their increased predisposition. 5-alpha reductase variants also may respond differently to inhibition by finasteride.
Accumulated epidemiologic evidence implicates the environment as the major contributor to the development of most prostate cancers. PCa incidence has wide geographic variation, with high rates in the United States and western Europe and low rates in Asia. African Americans have very high PCa risks. The geographic variation can be explained best by lifestyle, as Asian immigrants to North America have higher PCa risks. The key lifestyle factor in the United States most likely responsible for high PCa incidence is the diet, generally rich in animal fats and meats and poor in fruits and vegetables. Total fat intake, animal fat intake, and consumption of red meats are associated with increased PCa risk.3 Ingestion of 2-amino-1-methyl-6-phenylimidazopyridine, one of the heterocyclic amine carcinogens that appear in “well-done” red meats, leads to PCa in rats.4 Consumption of dairy products also increases PCa risk.5 Consumption of lycopene, cruciferous vegetables, vitamin E, and selenium reduces PCa risk.6,7,8
The understanding about role of genetics in identifying individuals at high risk for prostate cancer is in its infancy, but epidemiologic studies support the concept that genetic risk plays a role, and clinical studies support the observation that early prostate cancer in some individuals is highly aggressive, while in the majority it is indolent. Linking these 2 factors should identify a population of men in whom screening, early detection, and chemoprevention agents can be intensively directed. In the meantime, the take-home message of this study was expressed by the chief author: "Overall, the beneficial effects of eating fish to prevent heart disease outweigh any harm related to prostate cancer risk."
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8. Hoque A, Albanes D, Lippman SM, et al. Molecular epidemiologic studies within the Selenium and Vitamin E Cancer Prevention Trial (SELECT). Cancer Causes Control. 2001;12:627-633.