Friday, July 26, 2013

Science Round-Up Seconds: DHA + EPA + DPA & Prostate Cancer - Auxiliary Data on the Effect of Fish & Fish Oil on Prostate-, Breast- and Colorectal Cancer

Did the media hype surrounding the "Fish Oil Promotes Prostate Cancer" break this poor critter's neck?
I guess you will all have listened to the Science Round-Up live, right? No? Well then I'd suggest you do that now, because I am not going to waste any more time on the breakfast or sweetener study, but felt inclined to take another look at the fish / fish oil and prostate cancer issue.

Why? Well, I have written tons about breakfast (read it), the circadian rhythm (read it) and by good way too much about sweeteners (look here) in the past to reiterate that in the absence of any new scientific evidence whatsoever.

"Fish oil promotes prostate cancer! What shall we do?"

While I am not sure that someone actually wrote that, it is only natural for the layman to assume that taking fish oil capsules and even eating fish would be detrimental to his prostate health, once he is confronted with scientific evidence not just from one study, but actually from a meta analyses of what the researchers deem to be the "currently available literature". This lends a whole new level of credibility to the results the scientists observed in the male subjects from the SELECT trial; a trial, of which you will probably remember, that it is the study that found that vitamin E + selenium supplementation area associated with higher risks of prostate cancer.

All that lends the recent "fish oil is killing you" study the aura of a controlled intervention study. And that despite the fact that the Brasky study is nothing but another non-specific cross-analysis of the associations between high serum levels of long-chain omega3-PUFAs and prostate cancer. A study that delivers no information whatsoever on where the DHA, EPA and DPA (an intermediate form) came from and a study that does not tell you, whether the levels have been high before and remained high afterwards or were high because the subjects were afraid to develop prostate cancer and started to supplement with fish oil. Yes, even Carl's hypothesis that having prostate cancer will increase the enzymatic cascade that produces EPA and DHA from short chain omega-3s could be possible - at least the study at hand would not be able to rule it out.

Now, you've heard most of that on the Science Round-Up, yesterday. So let's rather take a look to the left and the right to get a better grasp of the current state of the art... ah, I mean research:
  • "No association was found between overall fish consumption in early or midlife and prostate cancer risk." (Torfadottir. 2013) This is the conclusion of an Icelandic study from April this year. The study was nested among the 2268 men aged 67-96 years in the AGES-Reykjavik cohort study and produced another surprising result: While high fish consumption in early- and midlife was not associated with overall or advanced prostate cancer,
    "[..] a high intake of salted or smoked fish was associated with a 2-fold increased risk of advancedprostate cancerboth in early life (95% CI: 1.08, 3.62) and in later life (95% CI: 1.04, 5.00)." (Torfadottir. 2013)
    An observation which clearly brings us back to the previously made reservations with respect to the absence of any reliable data on where the "fish oil" in the blood of the subjects in the Brasky study came from. It also stands in line with the results of Stott-Miller et al. (2013), who report a +32% increased prostate cancer risk for men consuming fried fish more than once a week.
    Figure 1: Overall fish oil consumption and risk of prostate cancer (Torfadottir. 2013)
    Talking about fish oil, if you take a look at figure 1 you can see that it had non-significant protective effects when consumed irregularly in mid and late life, but was (likewise not stat. sign.) associated with a higher risk of developing prostate cancer in early life.
  • The role of docosapentaenoic acid (DPA) remains elusive. While the Brasky study suggests that it's "bad stuff", another recently published paper identified DPA as a marker that "is linked with reduced total prostate cancer risk" (Sorongon-Legaspi. 2013).

    Figure 2: Omega-3 levels and prostate cancer risk (Sorongon-Legaspi. 2013; DPA highlighted in red); enzymatic cascade that converts ALA in 5 steps to DHA
    If you take a look at the figure on the right, you will see that ALA, EPA and DHA, alone, which are #1, #4 and #6 on the enzymatic cascade that converts short chain (ALA) to long chain omega-3 fatty acids (see figure 2, right), have no effect on prostate cancer at all. DPA, on the other hand, is - in this analysis (!) - associated with a 24.4% reduced risk for prostate cancer.

    How that's supposed to work, though eludes me. And in the absence of a mechanistic explanation of this statistical feature, we should be careful to clutch at straws, when we do, on the other hand, negate the risk Brasky et al. observed.
  • If you already have prostate cancer high levels of DHA, the "bad prostate cancer omega-3" actually appear to protect you from dying. A recently published study by Epstein et al. (2013), for example, found
    "Among all men, those with the highest omega-3 docosahexaenoic acid and total marine fatty acid intakes were 40% less likely to die from prostate cancer (P(trend) = 0.05 and 0.04, respectively)." (Epstein. 2013)
    On the other hand, the 525 Swedish men with prostate cancer in Örebro County (1989-1994) who were the subjects in Epstein et al.'s study were at 2x higher risk of dying, when their overall fat intake was high. This is something that cannot be excluded in the Brasky, respectively SELECT trial either - after all an overall high fat intake will bring about higher LC omega-3 PUFA levels than a lower fat intake with the same ratio of LC omega-3 PUFAs in it.
Now in the absence of any reasonable explanation for the observations and in view of the fact that you would have to expect that the same effects should be observed in other forms of tissue, if the effects were related to the negative effects of rancid fish oils, as they have been observed by Garcıá-Hernándéz et al. (2013) in a recently published study (a detailed discussion of the results will follow on the weekend). The latter, i.e. a risk increase for other types of cancers has yet not been reported. We do in fact have evidence to the exact opposite, i.e. a reduced cancer risk for...
  • colorectal cancer incidence (case-control studies) -- risk reductions of -26% for high total LC-PUFA intakes (Kimura. 2007); -38%  for EPA > 442mg/d and -37% for DHA > 587mg/d  (Theodoratou. 2007) and -39% for total LC-PUFA > 180mg/d; -35% for EPA > 50mg/day (!) and -42% for DHA >110mg/day (Kim. 2010)
  • breast cancer incidence (case control studies) -- risk reductions of -49% for total LC-PUFA > 550mg/day; -73% for EPA > 1.39% of total fat in erothrocytes; -94% for DHA > 4.79% of total fat intake (Kuriki. 2007); -50% for EPA > 101mg/day (Kim. 2009) and -56% for DHA >213mg/day (Kim. 2009); -49% for EPA = 0.69 of total fat in erothrocytes (Shannon. 2009)
These results are supported by beneficial results from prospective cohort studies and in-vitro evidence for these and other forms cancer. So, if there was a mechanism to explain the increased cancer risk, it must be prostate specific and until we have not found this very mechanism, I doubt the relevance of the associations that were observed and reviewed by Brasky et al. in their latest paper.

Bottom line: Call me a stubborn physicist, but as long as I don't understand or at least have a hypothesis that would point towards an underlying mechanism that could explain the association of high serum levels (not high intake) of long-chain omega-3 fatty acids and the incidence of prostate cancer, I don't believe that it is relevant.

"Are You Going to Die From or With Prostate Cancer? Plus: What Can be Done to Influence This Fate?" Learn more about prostate cancer in the SuppVersity Prostate Cancer Special (read more)
And let's be honest, that the exact opposite appears to be the case for almost all other forms of cancer does not exactly support the notion that this very mechanism even exist.

I still don't discard the possibility and in view of the fact that I've never been an advocate of fish oil supplements, this is not exactly a reason for me to go back on my previous recommendation to keep your intake of omega-6 fatty acids "low" (compared to that of your fellow inhabitants of the Western Obesity Belt) and include fatty fish in your diet at least once, better twice a week. Don't fry it, and don't put it into the smoker and you will live happily ever after.

Well, no not exactly; but even if the likelihood that you develop prostate cancer increases, the established benefits of the inclusion of fish in your diet - here is just one of the most recent examples: -16% all-cause mortality, -37% risk of dying from ischemic stroke and -39% for dying from the consequences of diabetes (results based on data from 134,296 men and women in Takata. 2013) - certainly outweigh the potential increase in prostate cancer risk.

  • Brasky TM, Darke AK, Song X, Tangen CM, Goodman PJ, Thompson IM, Meyskens FL Jr, Goodman GE, Minasian LM, Parnes HL, Klein EA, Kristal AR. Plasma Phospholipid Fatty Acids and Prostate Cancer Risk in the SELECT Trial. J Natl Cancer Inst. 2013 Jul 10. [Epub ahead of print]
  • Epstein MM, Kasperzyk JL, Mucci LA, Giovannucci E, Price A, Wolk A, Håkansson N, Fall K, Andersson SO, Andrén O. Dietary fatty acid intake and prostate cancer survival in Örebro County, Sweden. Am J Epidemiol. 2012 Aug 1;176(3):240-52. 
  • Kimura Y, Kono S, Toyomura K, et al. Meat, fish and fat intake in relation to subsite-specific risk of colorectal cancer: The Fukuoka Colorectal Cancer Study. Cancer Sci. 2007; 98:590 – 597. 
  • Kim J, Lim SY, Shin A, et al. Fatty fish and fish omega-3 fatty acid intakes decrease the breast cancer risk: a case-control study. BMC Cancer. 2009; 30:216 – 226.
  • Kim S, Sandler DP, Galanko J,et al.Intake of polyunsaturated fatty acids and distal large bowel cancer risk in whites and African Americans. Am J Epidemiol. 2010; 171:969 – 979. 
  • Kuriki K, Hirose K, Wakai K, et al. Breast cancer risk and erythrocyte compositions of n-3 highly unsaturated fatty acids. Japanese Int J Cancer. 2007; 121:377 –385.
  • Shannon J, King IB, Lampe JW,et al. Erythrocyte fatty acids and risk of proliferative and nonproliferative fibrocystic dis ease in women in Shanghai, China.Am J Clin Nutr. 2009; 89: 265 – 276.
  • Sorongon-Legaspi MK, Chua M, Sio MC, Morales M Jr. Blood level omega-3 Fatty acids as risk determinant molecular biomarker for prostate cancer. Prostate Cancer. 2013;2013:875615.
  • Stott-Miller M, Neuhouser ML, Stanford JL. Consumption of deep-fried foods and risk of prostate cancer. Prostate. 2013 Jun;73(9):960-9.
  • Takata Y, Zhang X, Li H, Gao YT, Yang G, Gao J, Cai H, Xiang YB, Zheng W, Shu XO. Fish Intake and Risks of Total and Cause-specific Mortality in 2 Population-based Cohort Studies of 134,296 Men and Women. Am J Epidemiol. 2013 Jul 1;178(1):46-57.
  • Theodoratou E, McNeill G, Cetnarskyj R, et al. Dietary fatty acids and colorectal cancer: a case-control study. Am J Epidemiol. 2007; 166:181 – 195. 
  • Torfadottir JE, Valdimarsdottir UA, Mucci LA, Kasperzyk JL, Fall K, Tryggvadottir L, Aspelund T, Olafsson O, Harris TB, Jonsson E, Tulinius H, Gudnason V, Adami HO, Stampfer M, Steingrimsdottir L. Consumption of fish products across the lifespan and prostate cancer risk. PLoS One. 2013 Apr 17;8(4):e59799.