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Link Between Omega-3 Fatty Acids & Increased Prostate Cancer Risk
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Experts slam omega-3 link to prostate cancer as overblown 'scaremongering'
A raft of industry and academic experts have slammed the publication of a recent study claiming to 'confirm' a link between long-chain omega-3s and an increased risk of prostate cancer - arguing that the authors conclusions are overblown and have caused widespread scaremongering.
Jnl NCI original article full text/pdf below
Link Between Omega-3 Fatty Acids and Increased Prostate Cancer Risk Confirmed
http://www.sciencedaily.com
July 10, 2013 - A second large, prospective study by scientists at Fred Hutchinson Cancer Research Center has confirmed the link between high blood concentrations of omega-3 fatty acids and an increased risk of prostate cancer.
Published July 11 in the online edition of the Journal of the National Cancer Institute, the latest findings indicate that high concentrations of EPA, DPA and DHA -- the three anti-inflammatory and metabolically related fatty acids derived from fatty fish and fish-oil supplements -- are associated with a 71 percent increased risk of high-grade prostate cancer. The study also found a 44 percent increase in the risk of low-grade prostate cancer and an overall 43 percent increase in risk for all prostate cancers.
The increase in risk for high-grade prostate cancer is important because those tumors are more likely to be fatal.
The findings confirm a 2011 study published by the same Fred Hutch scientific team that reported a similar link between high blood concentrations of DHA and a more than doubling of the risk for developing high-grade prostate cancer. The latest study also confirms results from a large European study.
"The consistency of these findings suggests that these fatty acids are involved in prostate tumorigenesis and recommendations to increase long-chain omega-3 fatty acid intake, in particular through supplementation, should consider its potential risks," the authors wrote.
"We've shown once again that use of nutritional supplements may be harmful," said Alan Kristal, Dr.P.H., the paper's senior author and member of the Fred Hutch Public Health Sciences Division. Kristal also noted a recent analysis published in the Journal of the American Medical Association that questioned the benefit of omega-3 supplementation for cardiovascular diseases. The analysis, which combined the data from 20 studies, found no reduction in all-cause mortality, heart attacks or strokes.
"What's important is that we have been able to replicate our findings from 2011 and we have confirmed that marine omega-3 fatty acids play a role in prostate cancer occurrence," said corresponding author Theodore Brasky, Ph.D., a research assistant professor at The Ohio State University Comprehensive Cancer Center who was a postdoctoral trainee at Fred Hutch when the research was conducted. "It's important to note, however, that these results do not address the question of whether omega-3's play a detrimental role in prostate cancer prognosis," he said.
Kristal said the findings in both Fred Hutch studies were surprising because omega-3 fatty acids are believed to have a host of positive health effects based on their anti-inflammatory properties. Inflammation plays a role in the development and growth of many cancers.
It is unclear from this study why high levels of omega-3 fatty acids would increase prostate cancer risk, according to the authors, however the replication of this finding in two large studies indicates the need for further research into possible mechanisms. One potentially harmful effect of omega-3 fatty acids is their conversion into compounds that can cause damage to cells and DNA, and their role in immunosuppression. Whether these effects impact cancer risk is not known.
The difference in blood concentrations of omega-3 fatty acids between the lowest and highest risk groups was about 2.5 percentage points (3.2 percent vs. 5.7 percent), which is somewhat larger than the effect of eating salmon twice a week, Kristal said. The current study analyzed data and specimens collected from men who participated in the Selenium and Vitamin E Cancer Prevention Trial (SELECT), a large randomized, placebo-controlled trial to test whether selenium and vitamin E, either alone or combined, reduced prostate cancer risk. That study showed no benefit from selenium intake and an increase in prostate cancers in men who took vitamin E.
The group included in the this analysis consisted of 834 men who had been diagnosed with incident, primary prostate cancers (156 were high-grade cancer) along with a comparison group of 1,393 men selected randomly from the 35,500 participants in SELECT. The National Cancer Institute and the National Center for Complementary and Alternative Medicine funded the research.
Also participating in the study were additional Fred Hutch scientists and researchers from the University of Texas, University of California, University of Washington, National Cancer Institute and the Cleveland Clinic.
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Omega-3 fatty acids may raise prostate cancer risk
http://www.cbsnews.com
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Though many laud the health benefits omega-3 fatty acids, one study is showing that eating the fatty acids found in fish oils may increase the risk of prostate cancer for men.
The study showed that men who consume a lot of EPA, DPA and DHA -- three anti-inflammatory, metabolically-related fatty acids that come from fatty fish and fish-oil supplements -- have a 43 percent increased chance of developing prostate cancer. Men with diets high in fatty acids were also shown to have a 71 percent increased risk of developing high-grade prostate cancer, and a 44 percent higher chance of having low-grade prostate cancer.
"We've shown once again that use of nutritional supplements may be harmful," author Dr. Alan Kristal, member of the Fred Hutch Public Health Sciences Division in Seattle, Wash., said in a press release.
Prostate cancer will affect an estimated 238,590 new patients in 2013, according to the National Cancer Institute. About 29,720 prostate cancer patients will die from the disease this year.
The study involved 834 men who had been diagnosed with prostate cancer, with 156 having high-grade type. They were compared to 1,393 randomly selected cancer-free men. The group that ate the highest amount of omega-3 fatty acids had about 2.5 percent more of the compounds in their blood compared to the group that ate the lowest amount. The difference corresponded to a little larger than eating two extra servings of salmon weekly, Kristal noted.
The new research echoes an earlier 2011 study completed by the same team that showed high blood concentrations of DHA were linked to a more than double risk for developing high-grade prostate cancer, as well as a large European study that came to the same conclusion.
"What's important is that we have been able to replicate our findings from 2011 and we have confirmed that marine omega-3 fatty acids play a role in prostate cancer occurrence," corresponding author Theodore Brasky, a research assistant professor at the Ohio State University Comprehensive Cancer Center in Columbus, Ohio, said in a press release. "It's important to note, however, that these results do not address the question of whether omega-3's play a detrimental role in prostate cancer prognosis."
The authors said they were surprised that omega-3 fatty acids increased the risk of prostate cancer, because the compound has been shown to lower inflammation. Inflammation problems have been linked to the growth and development of many other cancers. They still do not know why the fish oils may be so bad for this particular disease, but they suspect that the omega-3 fatty acids may turn into a compound in the body that can damage cells and DNA. This in turn may affect the body's natural defenses against disease.
Omega-3 fatty acids have previously been linked to protective benefits against heart disease and Alzheimer's.
Dr. Anthony D'Amico, chief of radiation oncology at Brigham and Women's Hospital in Boston, noted to HealthDay that the findings did not mean that omega-3 fatty acids caused the cancers, but that they just were strongly linked to increased occurrence of the disease. He added that the researchers had to look at other factors that may have caused the prostate cancer in the male subjects before saying for sure that omega-3 fatty acids was the main reason for their disease.
"All of these studies on associations, which is what this is, are hypothesis-generating because they are looking back in time," D'Amico, who was not involved in the study, explained. "It's not a cause and effect."
Prostate cancer usually affects older men. PSA tests can be used to screen for prostate cancer, but the American Urological Association said in May that they do not recommend that men 55 and under do the procedure, and advise against it for men over 80 who have a life expectancy of less than 10 to 15 years. Men between 55 and 69 should talk to their doctors to see if the test is right for them. The U.S. Preventative Services Task Force submitted a similar recommendation that healthy men should not get a PSA test in 2012.
The PSA blood test looks for prostate-specific antigen (PSA) levels. But, a prostate cancer diagnosis may cause more harm because the test may pick up slow growing tumors that do not pose any health dangers. Biopsies, surgeries and radiation may cause more side effects, including urinary incontinence, impotence and other complications that could lead to death.
Dr. Iain Frame, director of research at Prostate Cancer U.K., said to the Telegraph that if men are concerned about their prostate cancer risk, they should talk to a medical professional.
"Omega 3, such as is found in oily fish, has been the focus of a large amount of research in recent years, the majority of which points to it having wide ranging health benefits when eaten as part of a balanced diet," he said. "Therefore we would not encourage any man to change their diet as a result of this study, but to speak to their doctor if they have any concerns about prostate cancer."
The study was published in the Journal of the National Cancer Institute on July 11.
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JNCI Journal of the National Cancer Institute Advance Access published July 10, 2013
Theodore M. Brasky, Amy K. Darke, Xiaoling Song, Catherine M. Tangen, Phyllis J. Goodman, Ian M. Thompson,
Frank L. Meyskens Jr, Gary E. Goodman, Lori M. Minasian, Howard L. Parnes, Eric A. Klein, Alan R. Kristal
Plasma Phospholipid Fatty Acids and Prostate Cancer Risk in the SELECT Trial
In conclusion, in this large, prospective study of plasma phospholipid fatty acids and prostate cancer risk, contrary to our expectations, we found that long-chain ω-3 PUFA overall, and DPA and DHA in particular, were associated with strong, linear increases in prostate cancer risk. We note that this is not a novel finding because it has been reported previously in two other prospective blood biomarker studies that have examined the associations between long-chain ω-3 PUFA and prostate cancer risk. Whereas a lack of coherent mechanism has led authors of previous studies, including us, to consider these findings suspect, their replication here strongly suggests that long-chain ω-3 PUFA do play a role in enhancing prostate tumorigenesis. As has been made evident from many other clinical trials of nutritional supplements and cancer risk, the associations of nutrients with chronic disease are complex and may affect diseases differently.
Long-chain ω-3 PUFA have been widely promoted for prevention of heart disease and cancer. Both this study and a recent meta-analysis of clinical trials showing no effects of long-chain ω-3 PUFA supplementation on all-cause mortality, cardiac death, myocardial infarction, or stroke (48) suggest that general recommendations to increase long-chain ω-3 PUFA intake should consider its potential risks.
Abstract
Background Studies of dietary ω-3 fatty acid intake and prostate cancer risk are inconsistent; however, recent large prospective studies have found increased risk of prostate cancer among men with high blood concentrations of long-chain ω-3 polyunsaturated fatty acids ([LCω-3PUFA] 20:5ω3; 22:5ω3; 22:6ω3]. This case-cohort study examines associations between plasma phospholipid fatty acids and prostate cancer risk among participants in the Selenium and Vitamin E Cancer Prevention Trial.
Methods Case subjects were 834 men diagnosed with prostate cancer, of which 156 had high-grade cancer. The subcohort consisted of 1393 men selected randomly at baseline and from within strata frequency matched to case subjects on age and race. Proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI) for associations between fatty acids and prostate cancer risk overall and by grade. All statistical tests were two-sided.
Results Compared with men in the lowest quartiles of LCω-3PUFA, men in the highest quartile had increased risks for low-grade (HR = 1.44, 95% CI = 1.08 to 1.93), high-grade (HR = 1.71, 95% CI = 1.00 to 2.94), and total prostate cancer (HR = 1.43, 95% CI = 1.09 to 1.88). Associations were similar for individual long-chain ω-3 fatty acids. Higher linoleic acid (ω-6) was associated with reduced risks of low-grade (HR = 0.75, 95% CI = 0.56 to 0.99) and total prostate cancer (HR = 0.77, 95% CI = 0.59 to 1.01); however, there was no dose response.
Conclusions This study confirms previous reports of increased prostate cancer risk among men with high blood concentrations of LCω-3PUFA. The consistency of these findings suggests that these fatty acids are involved in prostate tumorigenesis. Recommendations to increase LCω-3PUFA intake should consider its potential risks.
Inflammation plays a role in the etiology of many cancers. The strongest evidence for an inflammatory component in prostate carcinogenesis is based on the characteristics of a precursor lesion, proliferative inflammatory atrophy, which is an area of highly proliferative but atrophic epithelial cells with notable inflammatory infiltrates (1,2). Considerable research has addressed whether factors that affect inflammation are associated with prostate cancer risk. With the exception of obesity, which is associated with increased inflammation and higher risks of high-grade prostate cancer (3,4) and prostate cancer death (5,6), studies on lifestyle factors associated with reduced inflammation, including use of aspirin (7,8) and nonsteroidal anti-inflammatory drugs (8) and statins (9) and consumption of long-chain ω-3 fatty acids (10-12) (here defined as eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids), have been inconsistent.
We recently reported, using data and serum collected in the Prostate Cancer Prevention Trial, that high concentration of serum phospholipid long-chain ω-3 fatty acids, which is a biomarker of usual ω-3 fatty acid intake (13), was associated with a large increase in the risk of high-grade prostate cancer (14).
We also found that high concentrations of trans-fatty acids, which are associated with increased inflammation (15,16), were associated with reduced risk of high-grade prostate cancer (14). These findings were counter to expectations but raised the possibility that high intakes of ω-3 fatty acids, for example through use of fish oil supplements, could increase the risk of clinically significant, high-grade prostate cancer.
Here we replicate these analyses using data and plasma collected in the Selenium and Vitamin E Cancer Prevention Trial (SELECT; trial registration: clinicaltrials.gov identifier NCT00006392]. Given the widespread use of ω-3 fatty acid supplements (17,18), an ongoing clinical trial testing ω-3 fatty acid supplementation for cancer and cardiovascular disease prevention (19), and the purported health benefits of consuming fatty fish (20,21), it is important to further investigate whether high consumption of ω-3 fatty acids could contribute to prostate cancer risk.
Methods
The Selenium and Vitamin E Cancer Prevention Trial
SELECT was a randomized, placebo-controlled trial that tested whether selenium and vitamin E, either alone or combined, reduced prostate cancer risk (22,23). Briefly, in 427 participating sites across the United States, Canada, and Puerto Rico, black men aged 50 years or older or men of all other races aged 55 years or older who had no history of prostate cancer and who had a serum prostate-specific antigen of 4ng/mL or less and nonsuspicious digital rectal exam were eligible to participate. Between July 2001 and May 2004, 35 533 men were block-randomized by study site to one of four groups: selenium + vitamin E; vitamin E + placebo; selenium + placebo; or placebo + placebo. On September 15, 2008, the Data and Safety Monitoring Committee recommended the discontinuation of the trial supplements because of no observed evidence of a protective effect and no likelihood of an effect given current rates of cancer in each arm (22). In 2011, after an additional 54 464 person-years of follow-up, we reported that vitamin E, in contrast with a placebo, increased prostate cancer risk by 17% (24). All men provided written informed consent, and study procedures were approved by local institutional review boards for each participating study center.
Case Subject and Subcohort Selection
This study is a case-cohort design nested within SELECT. Case subjects included in these analyses were men with baseline blood samples available for analysis who were diagnosed with incident, primary prostate cancers before July 31, 2009. Most cases (94.4%) were detected by prostate-specific antigen and/or digital rectal exam screening, which was suggested annually but not required. Screening procedures were reported annually. At each study contact, participants reported new cancer diagnoses to study staff, who then obtained pathology reports and, when possible, tissue. Almost all cases included in these analyses (92.6%; 842 of 909) were reviewed centrally for pathological confirmation and grading using the Gleason system (25). For 26 cases where tissue was not available, Gleason scores were abstracted from local pathology reports. High-grade tumors were defined as Gleason scores 8 to 10 and 7 (4 + 3); low-grade tumors were Gleason scores 2 to 6 and 7 (3 + 4).
A subcohort representative of SELECT participants was created a priori as the comparison group for this and other biomarker studies using the following approach. Men randomized into the study were stratified into nine age/race cohorts: aged less than 55 years (black men only), and aged 55 to 59 years, aged 60 to 64 years, aged 65 to 69 years, and aged 70 years or greater for both black men and men of all other races. Beginning in 2005 and annually until 2009, men with new diagnoses of prostate cancer had matching men randomly selected for the subcohort from the set of men with blood samples available within the same age-race stratum. A ratio of 1:3 was used for black men and 1:1.5 for men of other races.
Because of the high cost of phospholipid fatty acid assays, only the case subjects diagnosed through 2007 and their corresponding frequency-matched subcohort were planned for this analysis. This comprises 834 case subjects diagnosed during the first 6 years of the trial, plus 1393 men in the corresponding subcohort. Twenty-nine men in the subcohort were diagnosed with prostate cancer. Subsequently, based on new findings of associations of fatty acids with high-grade cancer only (14), 75 additional men diagnosed with high-grade prostate cancer in years 8 and 9 of the trial were added to this study. Thus, three groups were evaluated in this analysis: 1) 834 men diagnosed with cancer before May 18, 2007, including 69 for whom grade was not available; 2) 684 men diagnosed with low-grade cancer before May 18, 2007; and 3) 156 men diagnosed with high-grade cancer before July 31, 2009.
Data Collection and Laboratory Methods
Data on demographic and health-related characteristics were collected at baseline by self-administered questionnaire. Study staff measured height and weight, which were used to calculate body mass index (kg/m2). Venous blood samples were collected at baseline and refrigerated and shipped overnight to the specimen repository where the samples were combined, centrifuged, aliquoted, and stored at -70oC until analysis (26). Detailed methods for the phospholipid fatty acid assay have been published elsewhere (27). Briefly, total lipids were extracted from plasma, and phospholipids were separated from other lipids by one-dimensional thin-layer chromatography (28). Fatty acid methyl ester samples were prepared by direct transesterification and separated by gas chromatography (29). Fatty acid composition is expressed as the weight percentage of total phospholipid fatty acids. A lab quality control sample of pooled plasma from healthy volunteers was run with each batch of study samples. Samples from case subjects and the subcohort were analyzed annually in the same batches, and all laboratory personnel were blinded to the status of the samples. Coefficients of variation (standard deviation/mean) for fatty acids were as follows: α-linolenic acid (ALA; 18:3ω3), 2.8%; eicosapentaenoic acid (EPA; 20:5ω3), 2.8%; docosapentaenoic acid (DPA; 22:5ω3), 1.4%; docosahexaenoic acid (DHA; 22:6ω3), 1.5%; linoleic acid (LA; 18:2ω6), and 0.6%; arachidonic acid (AA; 20:4ω6), 0.8%. Because of their low concentrations, trans-fatty acids were grouped as trans-16:1 (16:1ω7t + 16:1ω9t), trans-18:1 (18:1ω6t + 18:1ω7t + 18:1ω8t + 18:1ω9t + 18:1ω10-12t), and trans-18:2 (18:2ω6tt + 18:2ω6ct + 18:2c6tc), with coefficients of variation of 5.4%, 4.3%, and 6.9%, respectively.
Statistical Analysis
Total long-chain ω-3 PUFA was calculated as the sum of EPA, DPA, and DHA. Fatty acids were categorized into quartiles based upon their distributions among the subcohort. Geometric means and 95% confidence intervals (CI) are given for each fatty acid, and weighted t tests were used to test differences between the case subject groups and noncase subjects.
Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals for the association between plasma phospholipids and risk of prostate cancer. Separate models were fit for all prostate cancers, low-grade prostate cancers and high-grade prostate cancers. The proportionality assumption in Cox proportional hazards models was tested by including an interaction term between each fatty acid and time. Of the 30 models, the assumption was violated in the following instances: ALA (high-grade), DPA (high-grade), trans-fatty acid (TFA) 18:2 (low-grade and high-grade) (Supplementary Methods, available online).
Associations are given for phospholipid fatty acids expressed as quartiles, contrasting quartiles 2, 3, and 4 with quartile 1, and additionally given as continuous hazard ratios. Because some fatty acids represent greater proportions of total weight than others, continuous hazard ratios have been adjusted to represent a 50% increase in fatty acid proportion. Tests for linear trend (P trend) across categories were calculated by treating categorical variables as continuous in regression models (30).
Additional covariables in multivariable regression models included education, history of diabetes, family history of prostate cancer, and SELECT intervention assignment. All statistical analyses were performed using SAS version 9.2 software (SAS Institute, Cary, NC). All statistical tests were two-sided, and P less than .05 was considered statistically significant.
Meta-analysis
A meta-analysis was conducted to compare our results for individual and total long-chain ω-3 PUFA with previous prospective biomarker studies of these fatty acids and prostate cancer risk overall and by grade. Associations between long-chain ω-3 PUFA and prostate cancer stratified on grade in the Multiethnic Cohort (31) were provided by personal communication (S. Park, October 2012). Risk estimates and 95% confidence intervals contrasting highest with lowest quantiles of exposure to EPA, DHA, and total long-chain ω-3 PUFA were abstracted from individual studies and combined under a fixed effects meta-analysis model (32) using STATA Release 12 (StataCorp LP, College Station, TX). Forest plots were used to display the results from individual studies and I 2 statistics are given as measures of heterogeneity between studies.
Results
Table 1 gives baseline demographic and other characteristics and cancer outcomes of the SELECT study population by Gleason grade. Low- and high-grade prostate cancer case subjects were more educated, had a higher prostate-specific antigen score, and had a larger proportion of first-degree relatives with a history of prostate cancer compared with noncases. Low-grade case subjects were less likely to report a history of diabetes than noncase subjects. Body mass index, pack-years of smoking, or use of aspirin did not differ between case subjects and noncase subjects. Only four cancers, three high-grade and one unknown grade, were diagnosed with advanced stage disease (T3); approximately 26% were diagnosed with Stage T2, and the remainder were diagnosed at stage T1.
Table 2 gives age- and race-matched means of plasma ω-3, ω-6, and trans-fatty acids for cancer case subjects and the subcohort. The mean percentages of total long-chain ω-3 PUFA were statistically significantly higher in total, low-, and high-grade prostate cancer case subjects compared with the subcohort. The percentages of the three individual long-chain ω-3 fatty acids-EPA, DPA and DHA-were also higher but did not all reach statistical significance in the smaller group of high-grade prostate cancer case subjects. Mean percentages of each TFA (18:1, 18:2, and 16:1) were statistically significantly higher among total and low-grade prostate cancer case subjects compared with the subcohort, although differences were small. Mean TFA 16:1 was higher in the high-grade prostate cancer case subjects only. Mean proportions of ALA, LA, and AA were similar across groups.
Table 3 gives associations between plasma phospholipid fatty acids and risk of total, low-grade, and high-grade prostate cancer. Associations between fatty acids and prostate cancer risk did not differ by SELECT treatment assignment; therefore only combined analyses are presented. Higher total long-chain ω-3 PUFA were associated with increased risks of total, low-, and high-grade cancer. Compared with men in the lowest quartile of total long-chain ω-3 PUFA, men in the highest quartile had 44% (95% CI = 8% to 93%), 71% (95% CI = 0% to 194%), and 43% (95% CI = 9% to 88%) increased risks for low-grade, high-grade, and total cancer, respectively. In continuous models, each 50% increase in total long-chain ω-3 PUFA was associated with a 22% to 25% increased cancer risk. Results for the individual long-chain ω-3 PUFA were similar, but effect sizes tended to be smaller and not all reached statistical significance. Of the major ω-6 PUFA, higher linoleic acid was associated with 25% (95% CI = 1% to 44%) and 23% (95% CI = -1% to 41%) reduced risks of low-grade and total cancer, respectively; however there was no dose response. Of the TFAs, there was weak evidence that higher TFA 16:1 was associated with increased risk, based on statistically significant or borderline significant trends across quartiles of exposure. However, none of the confidence intervals at the highest level of exposure excluded 1.00. The other classes of TFAs, ALA (a plant-based long-chain ω-3 PUFA), and AA (ω-6 PUFA) were not associated with risk.
In a sensitivity analysis, we repeated the analyses using continuous measures of fatty acids after truncating the lowest and highest 5% of values to test whether associations were being driven by outliers. There were no appreciable differences when outliers were removed (data not shown). To address the potential for spurious associations to arise because of the measurement of fatty acids as proportion of total weight rather than absolute concentration (33) and to address the question of the importance of the ω-3/ω-6 ratio, long-chain ω-3 and ω-6 PUFA were included together in regression models predicting total, low-, and high-grade prostate cancer risk. Findings for total long-chain ω-3 PUFA adjusted for ω-6 PUFA were only slightly attenuated. The continuous multivariable-adjusted hazard ratios predicting total, low-, and high-grade prostate cancer risk, respectively, were 1.16 (95% CI = 0.98 to 1.36), 1.15 (95% CI = 0.97 to 1.36), and 1.40 (95% CI = 1.03 to 1.92) (data not shown). The associations for LA were no longer statistically significant; however the point estimates were mostly unchanged (data not shown). Because it is possible that the positive association between long-chain ω-3 PUFA and prostate cancer risk is explained by increased cancer screening among high consumers of ω-3 PUFA, in a separate sensitivity analysis, we censored noncase subjects at the date of their last screening test. Results were largely unchanged; hazard ratios for associations between total long-chain ω-3 PUFA and total, low-, and high-grade prostate cancer were 1.44 (95% CI = 1.09 to 1.90), 1.44 (95% CI = 1.07 to 1.94), and 1.67 (95% CI = 0.96 to 2.90), respectively.
Discussion
In this large, prospective trial, high plasma phospholipid concentrations of long-chain ω-3 PUFA were associated with statistically significant increases in prostate cancer risk. These associations were similar for low- and high-grade disease and for EPA, DPA and DHA, which are anti-inflammatory, metabolically interrelated ω-3 fatty acids derived from oily fish and fish oil supplements. Findings for linoleic and arachidonic acids, the primary ω-6 fatty acids associated with increased inflammation (34), were inconsistent: concentrations of linoleic acid above the lowest quartile were associated with reduced cancer risk, with no evidence of a linear trend, and concentrations of arachidonic acid were not associated with cancer risk. Findings for TFA, which are also associated with increased inflammation (15,16), were similarly inconsistent: there were weak positive associations of TFA 16:1 fatty acids with cancer risk, and no associations of TFA 18:1 and 18:2 fatty acids with risk. Taken together, these findings contradict the expectation that high consumption of long-chain ω-3 fatty acids and low consumption of ω-6 fatty acids would reduce the risk of prostate cancer.
Figures 1 and 2 give results of our meta-analyses of studies reporting associations between EPA or DHA and prostate cancer risk, respectively (14,31,35-39). The two studies published before 2007 (37,39) contribute little to these meta-analyses because of their small sample sizes. Among the four large and more recent studies, three support the findings of a positive association of high ω-3 fatty acids with risk reported here (14,31,40), albeit with some inconsistencies regarding cancer grade and/or specific ω-3 fatty acid, and one study (35) reported inverse associations. For EPA, only the relative risk (RR) for high-grade cancer is notable, but it does not reach statistical significance (RR = 1.29, 95% CI = 0.97 to 1.72). For DHA, the summary relative risks for total (RR = 1.16, 95% CI = 1.03 to 1.31), low-grade (RR = 1.20, 95% CI = 1.04 to 1.38) and high-grade cancer (RR = 1.48, 95% CI = 1.10 to 1.99) are positive and statistically significant. Meta-analyses for total long-chain ω-3 fatty acids are difficult to interpret because this measure is omitted from some reports and, when given, defined variously as 1) ALA, EPA plus DHA; 2) EPA, DPA plus DHA; or 3) EPA plus DHA. However, based on those studies that have reported this measure (14,31,35), the summary relative risks for total, low-, and high-grade cancer are 1.14 (95% CI = 0.99 to 1.32), 1.14 (95% CI = 0.98 to 1.33) and 1.51 (95% CI = 1.08 to 2.11), respectively (Figure 3).
We discuss findings for the remaining fatty acids briefly because this study contributes only modestly to this literature. Our finding of no association of ALA with prostate cancer risk is consistent with the majority of studies, which also reported no association (14,31,35,36,38,39). Results from previous studies that examined ω-6 and TFA are inconsistent. Among the seven prospective studies of ω-6 PUFA (14,31,35-39,41), two reported inverse associations for LA (35,38), and, similar to our study, all others reported no associations. No studies have found associations of AA with risk. Three previous studies have examined the association between TFA and prostate cancer (14,42,43). No previous study found the increased risk of prostate cancer associated with TFA 16:1 reported here. One study reported statistically significant increases in nonaggressive cancer associated with TFA 18:1 and TFA 18:2 (42), and we have previously reported inverse associations of these fatty acids with risk (14). Given the inconsistency of these findings, we judge it unlikely that intakes of either ω-6 PUFA or TFA are associated with prostate cancer risk.
Long-chain ω-3 PUFA have many physiological effects. They are considered anti-inflammatory because of due their multiple effects on inflammation pathways, such as inhibition of tumor necrosis factor alpha and modification of eicosanoid activity, and they also affect cell permeability, gene expression, and signal transduction (44). It is unclear why high levels of long-chain ω-3 PUFA would increase prostate cancer risk, and further study will be needed to understand the mechanisms underlying the findings reported here.
This study had several strengths. Its design is prospective, and it is based on a large number of prostate cancer case subjects. The SELECT trial had near-complete (>95%) follow-up of participants, thereby minimizing the potential for attrition bias (22). Additionally, we were able to rigorously evaluate and rule out the potential for confounding by screening behavior. Lastly, we were able to replicate major findings on long-chain ω-3 PUFA from our prior work. There also were some limitations. Expressing fatty acids as weight proportions (33,45) could create spurious results because an increase in the percentage of one type of fatty acid requires a decrease in others (33); however, given the very low concentrations of ω-3 PUFA, it is unlikely that their variability, which is strongly related to dietary intake, would be strongly affected by proportions of other phospholipid fatty acids. There is also an inverse association of ω-3 with ω-6 PUFA; however, in secondary analyses that controlled associations of long-chain ω-3 with ω-6 fatty acids, associations of ω-3 fatty acids with prostate cancer risk were unchanged. Factors other than diet affect proportions of phospholipid essential fatty acids. For example, in feeding studies a low-fat diet modestly increases the blood proportion of long-chain ω-3 PUFA (46); however, these effects are small compared with those due to supplementation (47). Lastly, model assumptions were violated for four models; however, assumptions were not violated in those measures for which we show statistically significant associations.
In conclusion, in this large, prospective study of plasma phospholipid fatty acids and prostate cancer risk, contrary to our expectations, we found that long-chain ω-3 PUFA overall, and DPA and DHA in particular, were associated with strong, linear increases in prostate cancer risk. We note that this is not a novel finding because it has been reported previously in two other prospective blood biomarker studies that have examined the associations between long-chain ω-3 PUFA and prostate cancer risk. Whereas a lack of coherent mechanism has led authors of previous studies, including us, to consider these findings suspect, their replication here strongly suggests that long-chain ω-3 PUFA do play a role in enhancing prostate tumorigenesis. As has been made evident from many other clinical trials of nutritional supplements and cancer risk, the associations of nutrients with chronic disease are complex and may affect diseases differently. Long-chain ω-3 PUFA have been widely promoted for prevention of heart disease and cancer. Both this study and a recent meta-analysis of clinical trials showing no effects of long-chain ω-3 PUFA supplementation on all-cause mortality, cardiac death, myocardial infarction, or stroke (48) suggest that general recommendations to increase long-chain ω-3 PUFA intake should consider its potential risks.
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