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reference
Brasky TM, Till C, White E, et al. Serum phospholipid fatty acids and prostate cancer risk: results of the prostate cancer prevention trial.Am J Epidemic.April 24, 2011. Epub ahead of print.
design
A 7-year, randomized, placebo-controlled trial testing whether the 5-alpha-reductase inhibitor finasteride reduces the risk of prostate cancer (PCa). During the course of the study, men underwent prostate-specific antigen (PSA) testing and a digital rectal examination (DRE) annually. Prostate biopsy was recommended for men with an abnormal DRE or PSA level >/= 4.0 ng/mL. At the end of the study, all men who had not been diagnosed with PCa were asked to undergo a prostate biopsy.
A case-control study was conducted as part of the prostate cancer prevention study. Serum phospholipid levels were compared in 1,809 men with biopsy-confirmed invasive prostate cancer and 1,809 men (controls) who were disease-free at end-of-study biopsy. Frequency of controls was matched to cases based on age distribution (+/- 5 years), treatment group (finasteride/placebo), and first-degree relative with PCa, and was overestimated for non-whites.
Participant
18,882 men aged 55 years or older were randomized to receive finasteride or placebo.
Study medications
The subjects received 5 mg finasteride/day.
Target parameters
Serum samples were collected at years 1 and 4 and pooled to reduce intra-individual variability of the phospholipid fatty acid assay. Calculations were performed for eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) as a measure of total long-chain omega-3 fatty acids; Linoleic and arachidonic acid as a measure of total omega-6 fatty acids; total trans fatty acids (TFA) 18:1; total TFA 16; and overall TFA 18:2.
The primary outcome measure was the distribution of serum phospholipid fatty acids as a percentage of total among PCa cases and controls stratified by prostate cancer grade.
Key findings
DHA levels were higher in high-grade cases than controls. TFA levels 18:1 and 18:2 were significantly lower in high-grade cases compared to controls. There were no other significant differences in remaining phospholipids between the control and cancer groups. EPA was not associated with risk of high-grade PCa, and the associations were similar for EPA+DHA than for DHA alone.
Effects on practice
Epidemiological, animal model andin vitroStudies indicate that omega-3 fatty acids, lycopene and selenium have chemopreventive effects on PCa.1The results of this study contradict the researchers' hypothesis that omega-6 and TFAs would be positively associated and omega-3 fatty acids would be inversely associated with PCa risk. Although unexpected, the authors cite several other studies that are consistent with their findings, and there is a possibility that an inverse association exists between fish consumption and advanced or fatal prostate cancer. However, it is important to remember that only DHA and only high-grade prostate cancer have been found to increase the risk of PCa. Replication in further studies is required before conclusive recommendations can be made.
The results of this study contradict the researchers' hypothesis that omega-6 and TFAs would be positively associated and omega-3 fatty acids would be inversely associated with PCa risk.
A major limitation of this seroepidemiological study is the fact that fatal prostate cancer takes many years from development to death. The question is whether the fatty acid content of a man's blood on two days out of thousands of these years is a reliable measure of his average fatty acid status. Another limitation is that researchers did not take into account the effects of vitamin E, selenium, lycopene, cruciferous vegetables, meat and dairy intake.
EPA and DHA are believed to reduce cancer risk in general through their anti-inflammatory and immunomodulatory properties, as well as by interfering with cell permeability, gene expression and signal transduction. The effects of omega-3 fatty acids on these pathways in prostate carcinogenesis are not fully understood. There is no known mechanism by which EPA or DHA could be procarcinogenic, nor is there any evidence of anticancer properties of trans fats.
Genetic and molecular studies of high-grade prostate intraepithelial neoplasia have shown that loss of heterozygosity is prominent and that certain oncogenes are expressed.2What causes the expression of these oncogenes? What downregulates their expression?
Androgenic hormones are necessary for the growth and development of the prostate. Not surprisingly, polymorphic variants of genes involved in androgen action may influence PCa risk. African Americans, who are at higher risk of PCa than Asians, have androgen receptor polymorphisms that lead to their increased predisposition. 5-alpha-reductase variants may also respond differently to inhibition by finasteride.
Accumulated epidemiological evidence suggests that the environment is the primary contributor to the development of most prostate cancers. PCa incidence varies greatly geographically, with high rates in the United States and Western Europe and low rates in Asia. African Americans have a very high risk of PCa. The geographic differences are best explained by lifestyle, as Asian immigrants to North America are at higher risk of PCa. The most important lifestyle factor in the United States most likely responsible for high PCa incidence is diet, which is generally high in animal fats and meat and low in fruits and vegetables. Total fat intake, animal fat intake, and red meat consumption are associated with an increased risk of PCa.3Ingestion of 2-amino-1-methyl-6-phenylimidazopyridine, one of the heterocyclic amine carcinogens found in “well-done” red meat, causes PCa in rats.4Eating dairy products also increases the risk of PCa.5Consuming lycopene, cruciferous vegetables, vitamin E and selenium reduces the risk of PCa.6,7,8
Understanding of the role of genetics in identifying individuals at high risk for prostate cancer is still in its infancy, but epidemiological studies support the concept that genetic risk plays a role and clinical studies support the observation that early-stage prostate cancer is extremely aggressive in some individuals. while in the majority it is sluggish. By combining these two factors, a population of men in whom screening, early detection and chemoprevention can be intensively used should be identified. Meanwhile, the lead author expressed the take-home message of this study: “Overall, the positive effects of eating fish to prevent heart disease outweigh any harm associated with prostate cancer risk.”
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