By Luke Fortney, MD,
Integrative Family Medicine Physician, Meriter Medical Group, Madison, Wisconsin Dr. Fortney reports no financial relationships relevant to this field of study.
Synopsis: Among men diagnosed with prostate cancer, those with the highest levels of plasma omega-3 fatty acids demonstrated an increased risk for developing prostate cancer, bringing into question various recommendations for increased omega-3 intake.
Source: Brasky TM, et al. Plasma phospholipid fatty acids and prostate cancer risk in the SELECT trial.J Natl Cancer Inst 2013; July 10 [Epub ahead of print].
Financial Disclosure: Integrative Medicine Alert's executive editor David Kiefer, MD, peer reviewer J. Adam Rindfleisch, MD, MPhil, AHC Media executive editor Leslie Coplin, and managing editor Neill Kimball report no financial relationships relevant to this field of study.
The role of omega-3 fatty acids in prostate cancer risk has been inconsistent and it has been difficult to draw practical and clinically useful conclusions from the research. Previous studies have shown an association with lower prostate-specific antigen (PSA) values and increased intake of omega-3s, to increased prostate cancer incidence in others. The case-cohort study by Brasky et al — a subanalysis of the larger SELECT trial (Selenium and Vitamin E Cancer Prevention Trial) — supports those previous reports that suggest a concern about increased prostate cancer risk and omega-3 fatty acids. In this recent study, researchers evaluated data from 834 men who eventually were diagnosed with prostate cancer, 156 of whom were found to have high-grade cancers. Compared to 1393 age- and race-matched controls, men with the highest levels of plasma omega-3 fatty acids demonstrated an increased risk in developing both low- and high-grade prostate cancers. Using proportional hazards models, the researchers estimated that omega-3s were associated with a 43% increased risk for prostate cancer overall and a 71% increase in aggressive prostate cancer (hazard ratio, 1.43 and 1.71, respectively). However, overall relative risk is small. Given the consistency of these results, the authors concluded that omega-3 fatty acids, in contrast to conventional wisdom, may be associated with prostate tumorigenesis.
This study has significant limitations. First, these data do not demonstrate a cause and effect relationship between fish oil intake and prostate cancer incidence or severity. Second, because the data were extracted retroactively from a larger, retrospective, case-control study that was not designed to determine if fish oil intake is implicated as either a benefit or risk in prostate cancer risk, controls for other potential factors that may influence risk are lacking. For example, the researchers did not assess any of the participants' dietary intake of omega-3s over time. Other important prostate cancer risk variables — such as smoking status, alcohol use, family history of prostate cancer, and obesity — were not adequately controlled in this study. Additionally, these results are based on only one measure of plasma omega-3 levels taken at one particular moment in time, which can be variable depending on a person's recent dietary habits and other behaviors. A better indicator of long-term omega-3 intake and tissue status is the "omega-3 index," which measures red blood cell levels of eicosapentaenoic acid (EPA) and docosapentaenoic acid (DHA). Although the data presented in this study hint at DHA possibly playing more of a role in prostate cancer risk compared to EPA, this distinction is not clear or definitive.
The story of prostate cancer is a messy one at best. While prostate cancer is the leading diagnosed cancer in men and second leading cause of cancer-related death among men in the United States, only 2.8% of men ultimately die from complications directly related to prostate cancer itself. The lifetime risk for being diagnosed with prostate cancer is 15.9%, while 70% of deaths due to prostate cancer occur after 75 years of age. Even though the majority of men will eventually harbor prostate cancer cells if they live long enough, detection typically will either be elusive with screening or result in morbidity from invasive testing and treatment. This being said, it is still challenging to determine exactly which prostate cancers will go on to be aggressive and life-threatening and which are slow-growing and benign.1
Detection is further complicated by the fact that PSA screening is incomplete at best. In its most recent update, the United States Preventative Services Task Force simply recommends against PSA-based screening for prostate cancer (D recommendation). This evaluation is based largely on the fact that approximately 80% of positive PSA tests are actually false-positives. A third of men who eventually undergo prostate biopsy testing report major problems later. Five out of 1000 men will go on to die within 1 month of prostate cancer surgery, while up to three of 10 will experience significant morbidity such as urinary incontinence, bowel dysfunction, persistent pain, and erectile dysfunction. As such, there is convincing evidence that PSA screening leads to significant overdiagnosis and resulting treatment complications.1
With this being said, many men and their physicians look toward prevention to avoid this dilemma altogether. Prostate cancer risk is affected variably by age, race, dietary factors, weight, and chronic diseases such as diabetes, obesity, and cardiovascular disease. In general, prostate cancer mortality is significantly lower among Japanese men, but this cultural protection is lost among Japanese men who migrate to the United States and adapt Western habits, including a standard American diet (SAD). For comparison, this effect is also seen in Polish immigrants.2
It is easy to see why so much emphasis has been directed toward environmental factors in prostate cancer risk. As such, it has long been supposed that the fatty acid content of varying diets plays a significant role in prostate tumorigenesis. For example, the omega-6 to omega-3 fatty acid ratio of the SAD is 15:1, as opposed to 4:1 in a traditional Japanese diet. It has been proposed that omega-3s slow down tumorigenesis, induce apoptosis, decline proliferation, diminish PSA doubling time, and inhibit androgen-sensitive proliferation of prostate cancer cells as possible mechanisms. Recent studies have even demonstrated that omega-3s were able to prevent progression of laboratory human prostate cancer cell lines, while omega-6s accelerated their growth.3 Another study went further in showing that a diet rich in omega-3s in mice slowed down prostate tumorigenesis.4 In a well-done, randomized, controlled study published in 2013 by Safarinejad et al, the case for omega-3s' role in decreasing prostate cancer risk went even further in showing that supplementation with omega-3s actually decreased PSA levels among healthy men. In addition, PSA levels increased significantly over 12 weeks among participants who were given omega-6 fatty acid supplements.
Because lifestyle changes, especially dietary factors, appear to significantly affect the risk for developing prostate cancer, clinicians and patients are in need of guidelines and evidence-based recommendations that may favorably improve their chances. The omega-3 narrative in prostate cancer prevention appeared to be gaining momentum until Brasky et al released their findings showing that omega-3s may actually accelerate prostate cancer among men who have already been diagnosed. If we accept the authors' conclusions, the omega-3 fatty acid and prostate cancer story appears to share similarities with the vitamins and lifestyle (VITAL) study from 2008, which reported higher incidence of lung cancer among smokers who supplemented with vitamin E.6 In both instances, the trail of evidence appeared to be going in one direction, when the narrative took an abrupt turn among a certain demographic. It has been proposed that high-dose omega-3 supplementation — similar to vitamin E supplementation in smokers — may actually increase oxidative stress, resulting in further DNA damage and thereby increasing the risk for prostate cancer. This mechanism also may be at work in people who have several cardiovascular risk factors, as seen in a recent study in the New England Journal of Medicine that showed no improvement in morbidity or mortality when supplemented with 1 g of omega-3 fatty acids daily.7
In general, while the evidence overall supports the health and safety claims of omega-3s — particularly through eating a healthful diet8 — patients diagnosed with prostate cancer or those at high risk for prostate cancer would be well-advised to use some caution with supplementation of high doses of omega-3s in the context of obesity, smoking, or eating a SAD. Nonetheless, the mystery of what lifestyle factors, in what patients, and how various dietary components contribute to prostate cancer continues. For example, one study showed that Yup'ik Eskimos in Alaska, who eat a traditional diet that includes consumption of up to 20 times more omega-3 fatty acids compared to people living in the lower 48 states, have lower rates of diabetes and obesity.9 In another study of Inuit communities in Canada, where smoking rates are higher than other Canadian region, no increase of prostate cancer incidence was reported.10 Finally, a similarly designed cohort study found that in a setting of very high fish consumption, no association was found with early or midlife prostate cancer risk, while salted or smoked fish may increase the risk of advanced prostate cancer.11
1) In this study, among men who are eventually diagnosed with prostate cancer, those with the highest short-term and isolated plasma omega-3 fatty acids levels also appeared to have increased risk of developing both low- and high-grade prostate cancers.
2) There are many significant methodological concerns limiting the clinical relevance of the study results.
3) Although there is continuing discrepancy in the medical literature, overall recommendations for patients will largely remain unchanged. For prostate cancer mortality prevention, clinicians are advised to continue encouraging patients adhere to a healthy lifestyle, which means eating a variety of healthy whole foods (including foods high in omega-3 fatty acids such as salmon up to twice a week),12 getting regular exercise, keeping body mass index < 30, and avoiding tobacco.13