Cancer and Omega 3: An Examination

Recent research has linked omega 3 consumption to prostate cancer. Is this a paradigm shifting epiphany or bad research?

After the discovery of the link between higher blood concentrations of omega 3 fatty acids and prostate cancer published this year in the Journal of the National Cancer Institute by Brasky et al. 1, are we to arrive at the conclusion that taking fish oil will increase the risk of prostate cancer? After all, it was found that men with omega 3 fatty acids in the highest quartile had a 44% increased risk of low-grade prostate cancer, a 71% increased risk of high-grade prostate cancer, and a 43% increased risk of total prostate cancer when compared to those in who fell in the lowest quartile. 2 Combined with its large sample size (2,227 men), this appears to be solid evidence linking omega 3s to malignancy. When taking a closer look at the methodology of the study in question, the ‘significant’ link appears to be spurious despite its large sample size.

First of all, the metric used to determine the amount of fatty acid intake was plasma levels. Plasma levels are only a short-term indicator of consumption, not an indicator of how much fish or fish oil was consumed over a lifetime or even for a year. When evaluating potential risks for cancer, any type of dietary intake or activity needs to be done over a period of years as the manifestation of cancer results from long term cellular stress and chronic inflammation. Plasma levels are potentially good markers to use if used repeatedly, not for only one time as they were used in the study. Perhaps many of the subjects in the highest quartile were not heavy fish eaters but rather had their levels recorded at a time that happened to be near their latest consumption of fish. Similarly, those in the lowest quartile may have had a history of high fish consumption that was recently cut down for whatever reason. There was no knowledge of the long term dietary intake of omega 3 fatty acids in the participants, so no meaningful connections can be gleaned.

Furthermore, the elevation of risk from the plasma levels in the lowest quartile compared to the highest quartile was deemed ‘statistically significant’, but alas, there is a world of difference between ‘statistically significant’ and ‘significant’. When it came to the differences between those who developed prostate cancer and those who did not develop prostate cancer, the perceived ‘significance’ disappeared. The average plasma level of total marine-derived omega 3 fatty acids (DHA+EPA+DPA) for those with prostate cancer was 4.66% at the time of testing while the average level for those without prostate cancer was 4.48%, a negligible difference. For plasma levels of just DHA and EPA, 3.52% was calculated for the no-cancer group, 3.66% for the total cancer group, 3.67% for the low-grade cancer group, and 3.74% for the high-grade cancer group.3The differences between the groups were minimal, but nevertheless ‘statistical significance’ was able to be reached due to the study’s large sample size. Looking at the actual numbers, real-life significance appears to be nil. It is, however, admittedly interesting that the fatty acid cancer connection was strongest for plasma DHA levels, which very well could be posing as a marker for a low fat diet/low total fat intake rather than a high amount of DHA and/or fish consumption.26 For a case-cohort study that cannot prove causality, much stronger data is needed to even hint at the suggestion. Regardless, bold claims from the study’s authors and premature conclusions made by the media can jeopardize the health of many.
According to Senior Research Scientist William S. Harris PhD, those who fell in lowest and high quartiles of EPA+DHA levels correspond to an HS-Omega 3 Index (measures red blood cell saturation of fatty acid, reflecting long term intake) of < 3.2% and >4.77% respectively. The catch is, the amount in the highest quartile is *not* high at all. It is disingenuous at best to proclaim that those who contracted prostate cancer had ‘high’ levels of plasma omega 3s (avg. 4.66%) if those without prostate cancer are said to have low levels in comparison (avg. 4.48%). In actuality, the ‘higher’ levels are quite low and do not even closely represent those supplementing with fish oil or even those with higher fish intake. In the Framingham Heart study, mean HS-Omega 3 Index levels for participants not taking fish oil and taking fish oil were 5.2% and 7.5% respectively 4. As we can see, even the values from the participants not supplementing are higher than the highest quartile in Brasky et al’s study. According to a case analysis done by the staff at Life Extension, a healthy diet containing moderate fish consumption resulted in an omega 3 red blood cell level equivalent to 6.06%. 5 A diet including supplementary fish oil (3.6g) led to an RBC equivalence level of 10.59%! 6 Again, the lower non-supplementary average is higher than the highest levels of the case-cohort study attempting to reveal how ‘high’ levels are detrimental. The findings in the recent report by Brasky et al. do not have any meaning for those who actually have high dietary or supplementary omega 3 intakes, as determining whether or not omega 3 supplementation or moderate to high fish consumption is hazardous is beyond the study’s predictive capacity. On the other hand, the results might be telling us that low fish intake increases the risk for prostate cancer, or at least does not protect against it.
Now that it is established that even the ‘higher’ plasma omega 3 levels in the cohort were low, it can be reasonably argued that if these plasma levels were indeed reflective of long term dietary habits, then there is a higher chance that the meager plasma levels depicted as ‘high’ were too low to protect against the ongoing inflammatory effects of higher levels of circulating omega 6 fatty acids. The anti-inflammatory benefits that omega 3 fatty acids confer occur only in an environment where omega 6 levels are kept low to moderate. Even with supplementation of omega 3 fatty acids, a net inflammatory effect will persist if the intake of dietary omega 6 is too high. Since the study by Brasky et al involved American men, it is very likely that the subjects consumed a diet rich in omega 6 and low in omega 3. Today, Western diets contain extremely skewed ratios of omega 6 to omega 3 fatty acids – 15:1 to 25:1 on average, and sometimes even higher! 7 In rats, the diets with high omega 6 and low omega 3 encouraged prostate tumor growth whereas the reverse (high omega 3/low omega 6) caused a “dramatic decrease” in tumor size. 8 To no surprise, the highest dietary omega 6/omega 3 ratios in men are significantly associated with an elevated risk of high-grade prostate cancer. 9 It is when the omega 6 fatty acids greatly outnumber the omega 3s that increases the risk of low-grade, high-grade, and overall prostate cancer, plus a host of other popular modern diseases. Given the overabundance of omega 6 sources in the Western diet, the men in the study by Brasky et al. would need at least plasma omega 3 levels twice as high to maintain a healthy 4:1 to 1: 1 omega 6/omega 3 ratio that would be protective against prostate cancer. Ideally, foods high in omega 6 fats such as grain products, processed foods, soy products, grain-fed meat & dairy, nuts & seeds, and vegetable oils would have to be drastically reduced in addition to achieving truly high plasma omega 3 levels to offset the threat of prostate and other cancers.
When perusing other data, there are mixed results concerning the role of omega 3 fatty acids in prostate cancer ranging from a 61% decreased risk to a 77% elevated risk.10 Let us indulge, for a moment, the possibly that increased amounts of fish consumption do significantly raise the risk of prostate cancer. Still … it is not helpful not knowing where the high levels of n-3 (omega 3) fatty acids are coming from – fish or fish oil supplements? If dietary fish are leading to prostate cancer, a very possible explanation may be that the consumption is coming from *fried* fish or large predatory fish. Unfortunately, it remains true today that deep-fried fish are a large source of fish consumption in Western diets. Eating fried fish was associated with a 32% increased risk of prostate cancer, likely due to the lipid peroxidation of vulnerable omega 3 fatty acids in fish, oxidation of accompanying cooking oils used during high-heat treatment, and the carcinogenic agents formed in the frying process since all fried foods were found to have similar risks. 11 Fried, but not other kinds of fish have also been associated with other adverse health outcomes such as atherosclerosic changes and heart failure. 27 28 Furthermore, a cohort study published around the same time as that of Brasky et al found fish oil consumption later in life to be linked with a reduced risk of advanced prostate whereas salted and smoked fish consumption was associated with a two-fold higher risk of prostate cancer in early and in later life. 29 High-heat cooking with increased ‘doneness’ and salt accelerate the oxidation process and form mutagenic compounds within the food to positively modify cancer risk.30-32 In this better-designed study, nearly 2300 men whose dietary information was assessed throughout various stages of life with food frequency questionnaires were followed for prostate cancer diagnosis and mortality over the course of several years. Case-cohort studies cannot confirm causality, but causality may be inferred with the existing knowledge of the aforementioned food preparation and components and the mechanisms by which they could lead to malignant changes. Consumption of raw and/or fish subjected to rapid and gentle heating will reduce excessive oxidation that could reverse or cancel out the widely reported benefits of fish oil. 30,49-50
Consumption of large predatory fish including shark, swordfish, king mackerel, and tilefish should also be controlled for as larger fish carry higher burdens of mercury. Mercury, whether it comes from fish or other sources, may not be sufficient to cause prostate cancer on its own, but it can certainly contribute as an underlying factor through its promotion of oxidative stress and inflammation. Its effect on prostate cancer in humans has not yet been investigated, but methylmercury exposure has been shown to upset the prostatic microenvironment in rats. 12 In almost all other fish outside of the aforementioned ones, mercury toxicity would not be a concern since other fish contain higher amounts of selenium to form complexes with mercury, inactivating its toxic effects on the body.
Regular consumption of rancid, oxidized fish oil might also be behind some of the contradictory results. Capsules are the most popular method of taking fish oil, so it is impossible for the consumer to know whether or not the product is spoiled unless these capsules were broken and tasted. When polyunsaturated fats such as omega 3 fatty acids become oxidized, malondialdehyde is produced, which is capable of causing DNA damage that culminates in carcinogenesis. In rats, malondialdehyde resulted in liver tumors and skin cancer when applied topically.13 Upon ingestion of highly unstable marine oil, plasma and urinary levels of malondialdehyde become significantly increased in humans. 14 15 In a very recent study published in the International Journal of Food Science and Nutrition, negative effects were observed from highly oxidized omega 3 supplements, which sharply contrasted to the positive effects achieved from the less oxidized capsules. 16 To much dismay, almost all studies involving fish oil do not control for the possibility of oxidation, leading to null or negative results.
The most convincing evidence for omega 3’s favorable effects on prostate cancer can be found in population studies. If high(er) consumption of omega 3 fatty acids led to a greater risk of prostate cancer, then this should be reflected in populations with higher intakes of fish, such as the Japanese and the Eskimos. Instead of observing increased occurrences of prostate cancer, these populations have the lowest instances of prostate cancer. One study noted an inverse relationship between fish intake and prostate cancer in Japanese men. 17 Those who strongly adhere to the Mediterranean diet — a diet high in fish — also have decreased risks of prostate cancer, specifically a 22% reduced risk of mortality according to a recent Harvard study. 18 The strongest cases against the putative cancer-causing effects of fish oil feature two very large studies – one containing Swedish men and the other with American men. After a 30 year follow-up in the study involving 6272 Swedish men, it was found that men who ate no fish had a two-fold to three-fold higher frequency than those with moderate and high intakes of fish. 19 The American study comes from the Health Professionals Follow-up Study, which was established in 1986 that followed up with 47,882 of the participants out of 51,529 that were excluded for different reasons (e.g. preexisting cancers, lack of dietary data, missing date of birth, etc). To the delight of the omega 3 advocates, the men consuming fish over three times per week were found to have an overall reduced risk of prostate cancer, especially for metastatic cancer. These associations remained after adjusting for possible confounding factors such as ancestry, smoking, exercise, body mass index, PSA exams, vasectomy, vitamin D, retinol, lycopene, fructose, and red meat.20 Other than omega 3 consumption and direct associations with prostate cancer, it is also noted – from several studies – that higher serum levels are inversely related to the rate of telomere shortening (1 standard deviation increase in blood level correlating with a 32% reduction in telomere attrition/shortening in one study), especially as a result of a lower omega-6/omega-3 ratio, and even activation of telomerase (i.e. lengthening) has occurred when supplemented (as 3 grams) along with other healthful lifestyle change (e.g, stress management, exercise, increase in plant-based foods). 34-37 Maintaining telomere length is crucial; as biomarkers of lifepsan, they are related inversely to cancer incidence and cancer-related mortality. 48
The striking discordance between the dubious study from Brasky et al. and the ongoing empirical evidence demonstrating positive outcomes in fish-consuming people is indeed fishy (pun intended). When taking consideration to include the further evidence of fish oil protecting AGAINST pre-cancerous DNA damage (8-hydroxydeoxyguanosine) in cigarette smokers, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) dose dependently inhibiting growth in human prostate cancer cell lines, and sensitizing human prostate cancer cells to growth arrest by decreasing inflammation-induced tumor growth by attenuating NF-κB (nuclear factor kappaB) activity 47, 21,25, logic leads us to support the hypothesis that omega 3 fatty acids are anti-cancerous as opposed to the alternative pro-cancer hypothesis derived from a flawed conclusion in faulty study.
There is one possibility to consider, however. Despite the many weaknesses of Brasky et al’s study, let us go back to the associated risks with fish oil, namely the 71% increased risk for high-grade prostate cancer that was significantly higher than both the overall risk and the risk for low-grade cancer. Why would the risk for high-grade cancer be so much higher? The likely answer is that elevated amounts of *oxidized* DHA, one of the major omega 3 fatty acids in fish oil, can trigger angiogenesis, which is the growth of new blood vessels required for healing and reproduction. Tumors depend on this process for growth; without angiogenesis, tumors cannot grow and spread through tissues. 22 This process is facilitated by the formation of CEP (carboxyethylpyrrole) upon oxidation of DHA-containing lipids.23 Through CEP, angiogenesis is stimulated … fueling tumor growth and metastasis. 24 Thus, high omega 3 intake can become a driving force behind high-grade cancer *if* oxidation is rampant. Thankfully, worries of oxidation can be remedied through antioxidant support, mainly selenium, zinc, lycopene, vitamin C, and curcumin. This may be why the Health Professionals Follow-up Study’s positive association between dietary fish and decreased cancer risks did not extend to fish oil supplements. 20 Dietary fish not only deliver EPA and DHA omega 3 fatty acids, but also mineral antioxidants like zinc and selenium. Mega-dosing omega 3 fish oil in the presence of a SAD (Standard American Diet) low in antioxidants may do more harm than good. High(er) doses of EPA and DHA administration nearing 3.5 grams have, in the long-term, modestly increased oxidative stress/lipid perioxidation in absence of true antioxidant support as measured by TBA-MDA.38 When omega 3 fatty acids are supplied in reasonable dosages and are combined with antioxidant supplementation, symptoms of lipid peroxidation and general oxidative stress (e.g. malondialdehyde/MDA, plasma lipid hydroperoxides, F(2)-isoprostanes, C-reactive protein/CRP, interleukin-6/IL-6 are decreased despite warnings of the contrary. 39-46 must be accompanied by antioxidants so oxidation is mitigated.
Minimizing the risk of prostate cancer will involve increasing omega 3 intake, but mainly reducing the ratio of omega 6 to omega 3 to 4:1 to 1:1, with 2.3:1 being the realistic ideal. The more omega 3 fats are consumed, the more antioxidants are needed to overcome oxidation, so rather than mega-dosing omega 3, it is generally preferred to lower all omega 6 sources in the diet so less omega 3 is needed to create a favorable ratio. Because of omega 3’s propensity for oxidation, fish high in selenium and low in mercury are the best way to raise omega 3 PUFAs. Complimentary DHA and EPA through supplementation should come from reputable companies that ensure quality products. Despite being fresh upon consumption, these fatty acids remain fragile and in this case especially there is such a thing as ‘too much of a good thing’. Very large amounts of omega 3 fatty acids (~6g) can and do lead to increased oxidation in healthy humans regardless of whether or not they were ingested unoxidized, even with antioxidant co-administration. 33 Unbiased reviews on oxidization status and the level of contamination in popular omega 3 products can be found on http://www.ifosprogram.com (The International Fish Oil Standards Program).
Look for products formulated with *natural* vitamin E (d-alpha tocopherol) rather than the synthetic form of the vitamin (dl-alpha-tocopheryl) to help protect the fish oil from spontaneous oxidation. And finally, if only one lesson can be learned, remember to make sure antioxidant status is replete when omega 3 is taken and to combine that with dietary omega 6 reduction for optimal effects.
References:
1. Brasky TM, Darke AK, Song X, et al. Plasma Phospholipid Fatty Acids and Prostate Cancer Risk in the SELECT Trial. J Natl Cancer Inst. 2013; published online ahead of print, doi: 10.1093/jnci/djt174
2. Ibid.
3. Ibid.
4. http://www.framinghamheartstudy.org
5. William Faloon, Luke Huber, ND, MBA, Kira Schmid, ND, Blake Gossard, Scott Fogle, ND. Fish and Prostate Cancer Risk: Fact or Fiction. [Internet] Available from: http://www.lef.org/featured-articles/fish-and-prostate-Cancer-Risk-Fact-or-Fiction.htm
6. Ibid.
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