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Media Reports Miss Fatal Flaws in New Review of Omega-3/Cancer Evidence
1/30/2006
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Leading experts dismayed by author’s questionable conclusions; media headlines sow further confusion

by Craig Weatherby



Last week, the Journal of the American Medical Association (JAMA) released the results of a new review of the several dozen population studies that had collected data both on people’s estimated intake of omega-3 fatty acids and their health status.


The authors of this “meta-analysis” came to the conclusion—based on data experts consider inherently inadequate and unsuitable—that dietary omega-3 fatty acids are unlikely to prevent cancer.


Experts critique sweeping conclusion

  • "The authors’ interpretation that 'dietary supplementation with omega-3 fatty acids is unlikely to prevent cancer' is a regrettable oversimplification of an analysis that has many shortcomings."   —William E. M. Lands, Ph.D.
  • “The 38 studies are too heterogeneous—involving different population groups and different levels of fish oil consumption—to provide a definitive conclusion about whether fish oil reduces cancer risks.”  —Julie Buring, Sc.D., Harvard University

The fatty acid and cancer experts we consulted consider this statement an inexplicable, unjustified interpretation of the evidence. Consequently, their thoroughly odd conclusion does a serious public disservice.


Unfortunately, most of the media reports bore comparably stark headlines, such as “Omega-3 fats offer no cancer protection”, from Reuters’ wire-service story.


The main problem with these headlines—and the authors’ conclusion—is that the data examined by the authors of the new meta-analysis simply cannot support such a broad, negative statement.


According to the two experts with whom we spoke, the conclusion should have read something like this: “The available population studies lack sufficient relevant data to permit any meaningful conclusions about the ability of long-chain marine omega-3s to reduce the risk of any specific cancer.”


The new study is part of a larger project supported by the U.S. Department of Health & Human Services’ Agency for Healthcare Research and Quality (AHRQ) and the National Institutes of Health's (NIH) Office of Dietary Supplements (ODS) (In a prior evidence review, the ODS found that dietary fish helps protect against heart disease).


Study authors undermine their own conclusion
Even the study’s lead author—rheumatologist Catherine MacLean, M.D., Ph.D.—acknowledged in press reports that the data from the 38 studies they examined were not sufficient to rule out the possibility of an association between consumption of omega-3 fatty acids and reduced cancer risk.


And as Dr. MacLean’s team admit in the discussion section of the new meta-analysis, “Ample evidence from in vitro (i.e., cells in test tubes) and animal studies shows that EPA and DHA can inhibit the progression of tumors in various organs, particularly the breast and prostate.”


But in press interviews, Dr. MacLean contradicted her team’s clear affirmation that the anti-cancer effects of omega-3s  have been demonstrated convincingly in cell and animal studies, saying: "Omega-3 fatty acids appear not to affect the mechanism of cancer development."


If the researchers’ contradictory characterizations of their inherently flawed new findings inspire us to exclaim “huh?” they’re sure to confuse news consumers.


Experts challenge study’s design and conclusions

The two experts with whom we consulted—world renowned fatty acid researcher William E. M. Lands, Ph.D., and widely cited omega-3/cancer researcher W. Elaine Hardman, Ph.D.—agreed that most of the data from the studies examined in the new meta-analysis was either inadequate or unsuitable for the analytical purposes to which they were put.


They also agreed that these data shortcomings preclude any meaningful conclusions about the anti-cancer power of omega-3 fatty acids.


As Dr. Lands told Vital Choices, "The authors’ interpretation that 'dietary supplementation with omega-3 fatty acids is unlikely to prevent cancer' is a regrettable oversimplification of an analysis that has many shortcomings. We know much about the ways that marine omega-3s interact with omega-6s at the cellular level: enough to believe that they can inhibit the growth of some common forms of human cancer. Their actions via multiple biochemical pathways make them valuable anti-tumor agents that we gain from our food."

We've placed Dr. Lands' detailed comments in the box at the end of this article (see "Renowned researcher dissects new study").

Dr. Hardman and Dr. Lands concurred that most of the 38 studies examined in the new meta-analysis suffer from fatal flaws that render them virtually useless for the purpose of measuring the actual power of omega-3s to reduce specific cancer risks in humans:


Shortcomings of most studies in the meta-analysis

  • Failed to determine or consider two key factors: omega-6 intake and overall dietary patterns over time.
  • Did not distinguish between intake of plant omega-3s versus intake of marine omega-3s, or between lean and fatty fish, whose omega-3 content can vary by factors of 10 to 20.
  • Participants’ diets were relatively low in fish (e.g., one-half serving per week), hence also low in marine omega-3s in many of the studies that showed no cancer-preventive benefit.
  • Cancers take years or decades to develop, but most of the population studies took only brief snapshots of participants’ dietary habits.

Dr. Lands points out that in order to determine the anti-cancer potential of any given dietary factor, analysts need either or (preferably) both of two things:

  1. A very large body of relevant, critical, and contextual data from a number of uniformly designed population studies, to allow adjustment for confounding factors and permit apples-to-apples comparisons; or
  2. A substantial amount of evidence from repeated experimental studies in cell cultures and animals.

Both Dr. Hardman and Dr. Lands believe that because we currently lack enough well-designed, similarly structured population studies to enable credible conclusions, evidence from test tube and animal studies provide the best gauge of omega-3’s actual cancer-preventive potential.


At the moment, we appear much closer to crossing Dr. Lands’ second evidentiary threshold—i.e., having sufficient high-quality experimental data—than we are to having enough complete, contextual data from uniformly designed population studies.


Let’s take a closer look at the reasons why Drs. Lands and Hardman consider the new, headline-making meta-analysis fatally flawed.


Details of the new meta-analysis

The authors of the new meta-analysis considered only studies with a “prospective cohort design” that included information on participants’ omega-3 consumption levels.  In prospective cohort studies, researchers follow a group of volunteers over time, and collect information on their diets and health status, periodically.


The reviewers identified 38 “prospective cohort” population studies from the U.S. and six other countries that covered 11 different types of cancer, whose study groups ranged in size from 6,000 to 121,000 participants.


More than half of the studies covered by the meta-analysis focused on breast, colorectal, or prostate cancer. The rest collected data regarding rates of cancers of the mouth, throat, bladder, lung, ovaries, skin, pancreas, and stomach, as well as non-Hodgkin's lymphoma.


The authors found that among 65 estimates of the association between omega-3 fatty acid consumption and cancer, only eight were statistically significant, and many of the studies presented conflicting evidence for an association between omega-3s intake and cancer risk.


Dr. MacLean’s team came to this sweeping negative conclusion, which as the other experts we’ve quoted say, appears unjustified in view of the extreme limitations of the studies examined:  "A large body of literature spanning numerous cohorts from many countries and with different demographic characteristics does not provide evidence to suggest a significant association between omega-3 fatty acids and cancer incidence. Dietary supplementation with omega-3 fatty acids is unlikely to prevent cancer."


Animal studies of marine omega-3s and cancer

Vital Choices readers will recall that we’ve reported positive research findings from recent test tube and animal studies that helped document and define significant anti-cancer effects of long-chain, “marine” omega-3s (See “Omega-3s: Start 'em Early to Stop Breast Cancer,” “Fish Cuts Risk of Colorectal Cancer, Red Meat Raises It,” “More Evidence That Fish Oil Inhibits Breast Cancer,” and “Omega-3s and fish seen to reduce breast cancer risk”).


We heard a compelling presentation by cancer researcher W. Elaine Hardman, Ph.D. at last December’s Seafood & Health conference, during which she summarized recent findings that further support the hypothesis that marine omega-3s exert multiple anti-cancer effects.


Her slide presentation included a detailed explanation of the mechanisms by which omega-3s inhibit cancer, which she summarized in three bullet points:

  • “Preclinical [i.e., cell and animal] studies indicate that n-3 [omega-3] fatty acids should be beneficial for cancer treatment.”
  • “Mechanistic studies indicate feasible mechanisms for the influence of n-3 [omega-3] fatty acids on tumor growth, survival and response to chemotherapy.” [Mechanistic cell or biochemical studies probe the processes involved in or responsible for an anti-cancer effect.]
  • “Limited clinical studies that are available indicate that n-3 [omega-3] fatty acids have been beneficial during cancer therapy or may reduce risk for breast cancer.”

I asked Dr. Hardman about the authors’ casual, perplexing dismissal of evidence from existing cell and animal studies that tested the anti-cancer effects of omega-3s.


She acknowledged that some older animal studies employed unrealistically high doses of fish oil—e.g., 20 percent of the diet by weight—but noted that she has already documented potent anti-cancer effects in recent animal studies that used much lower doses.


The omega-3 doses tested in Dr. Hardman’s most recent studies—which equal only three to four percent by weight of the test rodents’ diet—translate into human therapeutic doses of about five grams of long-chain omega-3s (i.e., 8 to 10 standard capsules) of a standard, concentrated fish oil, which will consist of about 50 percent marine omega-3s (EPA and DHA).


And, she hopes to conduct animal studies that employ increasingly lower omega-3 doses, to define the minimum dietary intake parameters within which marine omega-3s can exert anti-cancer effects.


In fact, despite the authors’ rather dismissive remark—which appears unjustified—the results of scientifically credible animal and cell culture investigations already support the hypothesis that marine omega-3s possess substantial anti-cancer properties.


How do omega-3s curb cancer growth?

Most cancers take years, even decades, to grow from a few isolated cells to the large, aggregated numbers that constitute tumors and pose real threats.  And there is no guarantee that any one cancer cell will become a threat. Early-stage cancers can be—and often are—eliminated or stymied indefinitely by immunological responses hostile to the survival or growth of malignancies.


Prominent among these immunological factors are 1) positive dietary influences on the capacities of the body’s immune system; and 2) negative impacts on the biochemical and cellular mechanisms that promote cancer growth: specifically, the undesirable effects of omega-6 fatty acids, which compete in the same metabolic pathways influenced by omega-3s.  Omega-3s have been shown to act against cancer growth in both ways.


Experiments conducted in cell cultures and animals indicate that marine omega-3s interfere with three processes that turn isolated, harmless cancerous cells into substantial, spreading, life-threatening malignancies (medical term in parentheses):

  1. Grow via uncontrolled cell division (proliferate)
  2. Spread through the body (metastasize) and invade organs (invasiveness)
  3. Secure new, tumor-feeding blood supplies (angiogenesis)

And, unlike chemotherapy drugs, marine omega-3s inhibit cancer via multiple mechanisms: a rare attribute that makes it much harder for tumors to adapt to the inhibitory effects of dietary omega-3s.


But one key aspect of omega-3s’ anti-cancer effects—their metabolic competition with pro-inflammatory, conditionally pro-cancer omega-6 fatty acids—has gone largely unnoticed by the media, and is even overlooked by many researchers.


This incomplete understanding of the dietary context in which budding cancers either fade or flourish is just one of the many flaws that seriously undermine the new meta-analysis.


Study overlooks omega-6 intake and its pro-cancer effects

The authors of the new meta-analysis must be aware that one of the key ways in which omega-3s inhibit cancer is by competing metabolically with dietary omega-6s—and with omega-6s produced by cancer cells—which help them thrive and subvert the body’s immune response.


Yet, of the 38 studies the new meta-analysis considered, only one included detailed data on the participants’ omega-6 and omega-3 intake. Tellingly, the results of this study showed that breast cancer risk increased significantly as omega-3 intake fell and omega-6 consumption rose.


Renowned researcher dissects new study
Pioneering fatty acid researcher Dr. William E. M. Lands, author of more than 250 scientific papers, provided us with his expert analysis of the new study, to which we've added explanatory notes [in brackets]:

  • "The lack of association among many poorly defined dimensions does NOT support the authors' global conclusion that ‘dietary supplementation with omega-3 fatty acids is unlikely to prevent cancer’."
  • "Trying to find statistical significance among diverse dimensions of poorly defined and over-simplified terms [e.g., “cancer” and “omega-3s”] can easily lead to no clear association."
  • "The authors do not report or evaluate the background [consumption levels] of competing omega-6 fats [i.e., competing with omega-3s for metabolic influence] among the diverse [study] groups;"
  • "They do not separately evaluate the tumor incidence associations for shorter and longer forms of dietary omega-6 and omega-3 fats [e.g., short-chain, plant-derived omega-3s versus long-chain, fish-derived “marine” omega-3s, which exhibit much stronger anti-cancer effects in cell and animal studies]";
  • "They do not report or evaluate whether the diet differences gave [i.e., produced] important statistical differences in the fatty acid compositions of the tissues in which the tumors occurred." [That is, tissue levels offer a far more reliable guide to intake of omega-3 and omega-6 EFAs.]
  • "The results evaluated seem unconnected with much prior evidence of omega-6 eicosanoid [i.e., prostaglandin] precursors promoting tumor proliferation [see “Study overlooks omega-6 intake”, below] and its inhibition by non-steroidal anti-inflammatory agents [aspirin-type drugs, which, like omega-3s, inhibit production of the inflammatory omega-6-derived prostaglandins that aid cancer growth]." — William E.M. Lands, Ph.D.

This result—which is unsurprising in light of the findings from cell and animal studies—points up a critical flaw that Dr. Lands found was common to most of the population studies in question: an absence of detailed data on participants’ omega-6 intake.


Why are omega-6 intake levels as important to cancer growth as intake of marine omega-3s?


The body uses omega-3 and omega-6 essential fatty acids (EFAs) to produce chemicals called prostaglandins.  These ephemeral, hormone-like substances—which first gained public notice as the focus of the bestselling “Zone Diet” books—produce or amplify our cells’ adaptive responses to internal conditions, including infection, inflammation, and cancer.


Each type of EFA yields different prostaglandins, with omega-3 EFAs yielding anti-inflammatory types and omega-6 EFAs yielding pro-inflammatory prostaglandins. (Technically speaking, omega-3 and omega-6 EFAs are the “substrates” on which enzymes act to produce anti-inflammatory or pro-inflammatory prostaglandins, respectively.)


As the authors of another recent meta-analysis (Terry PD, et al 2003) noted, the inflammatory prostaglandins produced from omega-6 fats—especially one called PGE2—have been linked to cancer promotion in animal experiments of mammary tumor development, test tube studies of the proliferation of breast and prostate cancer cells, and human studies examining fish oil intake in relation to cancer cell proliferation rates and synthesis of PGE2.


And these authors also noted that tumor cells typically produce large amounts of inflammatory PGE2, which impedes immune system function. They also note that marine omega-3s inhibit conversion of omega-6 fats to PGE2, and that EPA and DHA also inhibit enzymes that convert omega-6s to other inflammatory prostaglandins that suppress apoptosis (programmed cancer-cell death), stimulate angiogenesis (creation of blood supplies to tumors), and enhance the persistence and invasiveness of tumors.


America’s omega-6 overload promotes cancer

The standard American diet is virtually defined by over-consumption of omega-6 fats, while—thanks to Americas’ low fish intake—dietary excesses of omega-3s are virtually unknown.


The common, chronic dietary imbalance in favor of omega-6 intake is proven to promote inflammation—which helps drive the growth of certain cancers—and encourages cancer growth by metabolic means independent of inflammation.


The chief dietary sources of omega-6 EFAs are the vegetable oils—chiefly corn, canola, soy, sunflower, and safflower oils—omnipresent in the processed, packaged and frozen foods that dominate the American diet. Americans also consume excess omega-6 fats from corn fed beef, pork and chicken.


Most nutrition researchers believe that humans should ingest omega-3 fats and omega-6 fats in a one-to-two or one-to-three ratio (i.e., one gram of omega-3s for every two or three grams of omega-6s), but the average American consumes 10 to 30 times as much omega-6 fat as omega-3 fat.


However, much of the omega-3 fat Americans consume is the short-chain type found primarily in nuts and seeds, which is far less useful than long-chain omega-3s, which influence inflammation levels and cancer growth much more strongly.  And, most people only convert one to five percent of the sole plant-derived omega-3 (called ALA) to long-chain marine omega-3s (EPA and DHA).


Unfortunately, many consumers are being misled by food marketers into thinking they are getting useful, long-chain marine omega-3s from “omega-3-fortified” foods, when most of these foods actually contain short-chain omega-3s from plant sources (mostly flaxseed).


While soy, walnut, and canola oils offer a more favorable ratio of omega-3 to omega-6 fats than corn, sunflower, or safflower oils do, they still contain much more omega-6 fat than omega-3 fat, and therefore contribute to the dietary imbalance that’s generally considered to fuel cancer growth.



Sources

  • MacLean CH, Newberry SJ, Mojica WA, Khanna P, Issa AM, Suttorp MJ, Lim YW, Traina SB, Hilton L, Garland R, Morton SC. Effects of omega-3 fatty acids on cancer risk: a systematic review. JAMA. 2006 Jan 25;295(4):403-15. Review.
  • Lands WEM. Fish, Omega-3, and Health, 2nd Edition. AOCS Press 2005. Champaign, Illinois.
  • Bagga D, Anders KH, Wang HJ, Glaspy JA. Long-chain n-3-to-n-6 polyunsaturated fatty acid ratios in breast adipose tissue from women with and without breast cancer. Nutr Cancer. 2002;42(2):180-5.
  • Hardman WE. (n-3) fatty acids and cancer therapy. J Nutr. 2004 Dec;134(12 Suppl):3427S-3430S. Review.
  • Hardman WE. Maternal or offspring consumption of omega 3 fatty acids to prevent breast cancer. Proc Amer Assoc Cancer Res 2005;46:3472.
  • Hardman WE, Sun L, Short N, Cameron IL. Dietary omega-3 fatty acids and ionizing irradiation on human breast cancer xenograft growth and angiogenesis. Cancer Cell Int. 2005 Apr 28;5(1):12.
  • Terry PD, Rohan TE, Wolk A. Intakes of fish and marine fatty acids and the risks of cancers of the breast and prostate and of other hormone-related cancers: a review of the epidemiologic evidence. Am J Clin Nutr. 2003 Mar;77(3):532-43. Review.
  • Terry PD, Terry JB, Rohan TE. Long-chain (n-3) fatty acid intake and risk of cancers of the breast and the prostate: recent epidemiological studies, biological mechanisms, and directions for future research. J Nutr. 2004 Dec;134(12 Suppl):3412S-3420S. Review.
  • Rose DP. Effects of dietary fatty acids on breast and prostate cancers: evidence from in vitro experiments and animal studies. Am J Clin Nutr. 1997 Dec;66(6 Suppl):1513S-1522S. Review.
  • Rose DP, Connolly JM. Omega-3 fatty acids as cancer chemopreventive agents.
  • Pharmacol Ther. 1999 Sep;83(3):217-44. Review.
  • Rose DP, Connolly JM. Antiangiogenicity of docosahexaenoic acid and its role in the suppression of breast cancer cell growth in nude mice. Int J Oncol. 1999 Nov;15(5):1011-5.
  • Rose DP, Connolly JM. Regulation of tumor angiogenesis by dietary fatty acids and eicosanoids. Nutr Cancer. 2000;37(2):119-27. Review.
  • Huang YC, Jessup JM, Forse RA, Flickner S, Pleskow D, Anastopoulos HT, Ritter V, Blackburn GL. n-3 fatty acids decrease colonic epithelial cell proliferation in high-risk bowel mucosa. Lipids. 1996 Mar;31 Suppl:S313-7.
  • Personal communication with William E. M. Lands, Ph.D. January 27, 2006.
  • Personal communication with W. Elaine Hardman, Ph.D. January 27, 2006.

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