Fish and Prostate Cancer Risk: Fact or Fiction

By William Faloon, Luke Huber, ND, MBA, Kira Schmid, ND, Blake Gossard, Scott Fogle, ND

Prostate cancer is a slow developing malignancy that can take decades to manifest as clinically-relevant disease. Commonly recognized risk factors for contracting prostate cancer are diet, body mass, race, family history, hormone status, and age.15,16
An under-recognized risk factor associated with developing prostate cancer is coronary artery disease.17 We at Life Extension long ago observed that men with clogged coronary arteries often developed prostate cancer (and vice versa). A renowned prostate oncologist named Stephen Strum, M.D., made a similar observation and established a common factor behind coronary heart disease and prostate cancer, i.e., bone loss.
Coronary artery disease is clearly linked with osteoporosis,18 as lack of vitamin K preventscalcium from binding to bone and instead allows it to infiltrate and harden the arteries. The ensuing bone loss results in the excessive release of bone-derived growth factors that fuelprostate cancer propagation and metastasis.
Long after Dr. Strum published his elaborate correlation, a 2012 study of 6,729 men showedcoronary artery disease to be associated with a 35% increased risk of prostate cancer.17
The reason we bring up the connection of heart disease and prostate cancer is that the authors of the controversial study apparently failed to assess overall baseline health status of the study subjects. We initially suspected that men in the higher group of plasma omega-3 (which turned out to be low by our standards) were more likely to have coronary heart disease. That’s because men with heart disease are told by their cardiologists to eat less red meat and more cold-water fish. So it would not be surprising if the plasma percentage of omega-3 was higher in men with prostate cancer as they may have been trying to eat healthier to avoid bypass surgery or a sudden heart attack.
When we asked the authors of the report if they assessed the baseline cardiovascular status of the subjects, their reply was, “No, I don’t believe this to be the case.”

Family History Predisposition

If your father or brother develops prostate cancer, your odds of getting it are about 120% to 180%greater than if you don’t have this family history.19
In the report attacking omega-3s, men who contracted prostate cancer had almost double the proportion of first-degree relatives with a history of prostate cancer compared with controls. Although the study authors apparently attempted to control for this baseline risk factor through the use of statistical modeling of selected variables (multivariate analysis), this confounding factor calls into question much of this report’s negative findings, but was not even mentioned in the media’s rush to create headline grabbers.
Men with a family history of prostate cancer often have witnessed the long term death spiral that prostate cancer patients suffer through. As a result, they attempt to adapt healthier lifestyles to avoid becoming a victim of their hereditary genes.
Since eating well-done red meat has long been associated with increased prostate cancer risk, men with unfavorable family histories are more likely to include at least some cold-water fish in their diets, and therefore have higher omega-3 percentage plasma levels. This does not mean the marginally higher omega-3 caused their prostate cancer.
This is partially corroborated with the data from the study participants who did not develop prostate cancer, but had higher plasma percentage levels of pro-inflammatory omega-6 fats. This indicated these individuals had little concern about what they ate since they had about half the family history rate of prostate cancer.
Fortunately there may be ways to alter family history genetic predispositions for prostate cancer by eating lots of cruciferous vegetables, maintaining youthful hormone balance, ensuring optimalvitamin D status, and taking compounds that favorably alter gene expression like metformin andcurcumin.20-28

Baseline PSA Higher in Those Who Contracted Prostate Cancer

Prostate specific antigen (PSA) is a blood marker of prostate disease.
Standard laboratory reference ranges often allow PSA to reach 4.0 ng/mL before flagging a potential problem. A more progressive view of the PSA is that any number over 2.4 ng/mL should be viewed with suspicion, with a digital rectal exam performed and a follow-up PSA blood test done in three months.
Life Extension has published comprehensive articles about how to properly interpret PSA results, but to state it succinctly: Aging men with PSA readings greater than 2.4 ng/mL are at higher risk for developing clinically relevant prostate cancer and should initiate aggressive steps to reverse the underlying process.
In the report that associated higher omega-3 blood levels with increased prostate cancer incidence,41.1% of the men who went on to develop prostate cancer had baseline PSA readings greater than3.0 ng/mL. In the group that did not develop prostate cancer, only 7.3% has a PSA baseline reading greater than 3.0 ng/mL.
Although the study researchers attempted to statistically control for other confounding factors in their analysis like family history, age, and education level, this PSA finding implies that many of the men who developed prostate cancer already had it (pre-existing disease) when the baselineplasma omega-3 level was measured. This finding of 5.6 times more men who developed prostate cancer with a baseline PSA level greater than 3.0 ng/mL compared to the “no cancer” group is impossible to rationally discount. To reiterate, below is the data on the baseline PSA readings from the report the media used to discredit omega-3s:

• 7.3% of the “No Cancer” group had PSA of ≥3.0
• 41.1% of the “Total Cancer” group had PSA of ≥3.0

This critical piece of data was ignored in the tabloid-like media articles that erroneously blamed the increase in prostate cancer on omega-3s.

Study Subjects do not Appear to Have Taken Fish Oil Supplements

Life Extension scientists repeatedly reached out to the authors of the negative report, but did not receive a response as to whether any attempt was made to ascertain the source of the omega-3 in the study subjects’ blood. We wanted to know if these men regularly ate cold-water fish or took at least some fish oil supplements.
Despite our requests, no clarification was made available by study authors as to the level of dietary supplementation with fish oil, and if so, the source of fish oil used in the study.
Based upon the very low plasma percentage levels of omega-3 fatty acids detected in the study, the implication is that dietary supplementation with fish oil likely did not occur. Instead, based upon the low levels of omega-3 plasma phospholipids detected, the source appears to have been primarily (potentially exclusively) diet only. As we will show soon, it appears that none of the men in this study consumed much in the way of cold-water fish either.

Omega-3 Levels Were Low in All Study Subjects

You will be shocked to learn how low the average plasma percentages of omega-3 were in all these study subjects, whether they were in the high or low rate of prostate cancer group.
Plasma phospholipid testing for fatty acids was used in this study. However, this type of fatty acid testing can vary widely depending upon short-term dietary intake. In contrast, long-term uptake by cells and tissues of the body is far less dependent upon short-term changes in diet. For this reason, erythrocyte (red blood cell) fatty acid indices are far better at evaluating cellular uptake over time as a result of fish ingestion and fish oil supplementation.
For example, data indicates that supplementing with about 2 grams of omega-3 fatty acids from fish oil leads to an increase in erythrocyte (red blood cell) omega-3 fatty acid percentage from about 4%at baseline to about 8% at eight weeks.13
In a case analysis conducted by Life Extension staff, a healthy diet that included fish but not fish oil supplementation resulted in an omega-3 red blood cell (RBC) equivalence level of 6.06%.
However, a standard diet supplemented with 3.6 grams of EPA/DHA from purified fish oil resulted in an omega-3 RBC equivalence level of 10.59%. Thus, compared to what can be achieved with a healthy diet alone, adding a high quality fish oil supplement can nearly double a person’s omega-3 RBC equivalence score, which is consistent with the published literature.
Therefore, if participants in the report alleging an association with fish and prostate cancer had been taking meaningful doses of fish oil supplements, their levels should have been substantially higher than what the study authors reported. Instead, for men in the prostate cancer group of this study, the percentage of plasma long-chain omega-3 fatty acids was only 4.66% … a lower level than historic baselines taking no supplemental omega-3s.13
The numbers below should clarify this glaring flaw that renders conclusions from this report claiming fish or fish oil increases prostate cancer utterly meaningless:

• Omega-3 RBC equivalence percentage of a moderate fish eater: 6.06%
• Omega-3 RBC equivalence percentage when taking 3.6 grams/day EPA/DHA: 10.59%
• Average long-chain omega-3 plasma percentage in study group with higher prostate cancer rates: 4.66%
• Average long-chain omega-3 plasma percentage in study control group (no prostate cancer): 4.48%

Figure 1: If you can’t see a difference in the two bars showing plasma percentage of omega-3s between men who contracted prostate cancer and those who did not, that’s because there is virtually no difference. The 0.18% variation could have resulted from men eating just a few ounces of fish the night before their one-time baseline blood draw. These low percentages of plasma omega-3s indicate these men were not taking fish oil supplements, nor were they eating much in the way of omega-3-rich foods in their diet.

There may be no need to provide any more rebuttal than the numbers posted above. They make it clear that the average subject in their groups were consuming very little cold-water fish and certainly no meaningful fish oil supplement. Their entire study population was so negligible in omega-3 that no relevant correlation can be drawn for health conscious people today choosing omega-3-rich foods (like cold-water fish) and high-potency fish oil supplements.
Yet based on this study of men who consumed relatively no omega-3s, frenzied news reporters were advising the public to stop eating cold-water fish and avoid omega-3 supplements.

Virtually No Difference in Omega-3 in Men Who Developed Prostate Cancer

When reading the frantic news reports, you would have thought the omega-3 difference in men with up to 71% increased risk of prostate cancer must have been huge.
At Life Extension, our very first reaction was that the researchers were comparing cardiac patients who gobbled down huge amounts of fish oil supplements to normal individuals who consume relatively little omega-3s. Our initial assumption was that since heart disease patients have higher prostate cancer rates, then that would explain why higher omega-3 could be mistakenly associated with increased prostate cancer risk, since heart disease patients are known to consistently take high-potencies of omega-3s through diet and supplements. How wrong our early conjecture was!
It turns out that the differences in omega-3 plasma phospholipid levels between groups were slight. In fact they were so close that we at Life Extension would classify them all as being too narrow to extrapolate meaningful data.
Our goal is to get the red blood cell (RBC) omega-3 index values in Life Extension members to8%-11% as this level was shown to offer the greatest protection against sudden myocardial infarction, yet the average quartile for plasma long-chain omega-3 fatty acids in the prostate cancer cases in the report associating fish oil with prostate cancer was only 4.66%.
Now look how narrow the difference is between men with higher prostate cancer rates. In the group whose average baseline blood draw showed 4.48% plasma long-chain omega-3 fatty acids, there was no increased prostate cancer risk. But if the omega-3 percentage average went up to 4.66%(about 1/5 of one percent), prostate cancer rates skyrocketed, according to the report’s authors.
We’re talking here of a difference of 0.18% in the percentage of plasma omega-3 fatty acids that supposedly caused a 43% to 71% increase in prostate cancer incidence. Dedicated fish oil supplement users, on the other hand have over 100% higher omega-3 levels than seen in this study of men who apparently consumed little cold-water fish and no omega-3 supplements.
To put this into real-world perspective, the trivial difference (0.18%) in plasma omega-3 between men with no prostate cancer and those with prostate cancer could occur if a man ate just a few ounces of a cold-water fish like salmon the night before.
Remember, plasma phospholipid testing for fatty acids was used in this study. However, this type of fatty acid testing can vary widely depending upon short-term dietary intake. In contrast, long-term uptake by cells and tissues of the body is far less dependent upon short-term changes in diet. For this reason, the omega-3 RBC equivalence score is far better at evaluating cellular uptake over time as a result of fish ingestion and fish oil supplementation.
There was only one baseline blood draw. The men were followed up to six years (low-grade and high-grade cancer), with a smaller group followed up to nine years to see who would get high-grade prostate cancer. Those who developed prostate cancer were then compared against their baseline blood draw done years earlier.
This kind of methodology is open to misinterpretation and errors even if there were large variances in omega-3 fatty acid percentages, but the 0.18% difference is so tiny that it has no relevance to aging humans who choose to include omega-3-rich foods in their diet and supplement with fish oil.
This may be the first study that seeks to discredit a food/supplement (i.e., omega-3s), where the human subjects were not even taking a fish oil supplement nor ingesting significant amounts of an omega-3 food.
A 0.18% difference in plasma omega-3 fatty acids between men who contracted prostate cancer and those who did not is infinitesimally small. To extrapolate a conclusion from this very small difference that eating fish or taking fish oil supplements is risky, false, misleading, and meaningless … but it did generate a lot of news headlines.
Life Extension is concerned that some men will decrease consumption of omega-3s resulting in a devastating increase of their triglycerides, thrombotic, inflammatory and atherogenic risks. An epidemic of coronary artery blockage and ischemic stroke will soon follow.

Results Are Completely Inconsistent With the Known Biology, Pathophysiology, and Biochemistry of Prostate Cancer

A fundamental aspect of quality research is consistency, and repeatability.
Stated another way, for a medical finding to be considered valid, the results should not contradict well-established facts involving known biology, physiology, biochemistry, etc. Furthermore, the finding should be repeatable by other scientists.
The report attacking omega-3s is inconsistent with a variety of aspects of the well-established scientific and medical literature.
For example, upon close inspection of the data (and not simply a top-line, parroted response by the mainstream media eager to generate headlines), non-smokers had more aggressive prostate cancer, and non-drinkers (alcohol) had higher risk of prostate cancer, and prostate cancer case subjects were less likely to report a history of diabetes than controls.
Based upon these results, the implication is that men who wish to avoid prostate cancer should consume excess calories and develop diabetes, drink alcohol heavily, and abuse tobacco.
This is completely inconsistent with well-established science, and utter nonsense.
In fact, numerous scientific studies show fish oil omega-3 fatty acids offer significant protective benefit for prostate health.

Fish Oil Omega-3 Fatty Acids Offer the First Line of Defense Against Prostate Cancer

In contrast to this attack on omega-3s, the scientific literature overwhelmingly identifies diets high in omega-6 fats, trans-fatty acids, and saturated fats as associated with greater prostate cancer risk, whereas increased intake of long-chain omega-3 fats from fish has been shown to reduce risk. Based on consistent findings across a wide range of human populations, scientific research has identified why eating the wrong kinds of fatty acids provokes a stimulatory effect on prostate cancer.29,30
To ascertain what occurs after dietary fatty acids are consumed, the biochemical pathway for fatty acid metabolism provides the answers. For example, let us assume that for dinner, you eat a steak (a source of saturated fat, as well as arachidonic acid) and a salad, along with a typical salad dressing rich in linoleic acid, an omega-6 fat (e.g., safflower oil).

Biochemically, omega-6 fat readily converts to arachidonic acid in the body. In response, the body attempts to compensate for excess arachidonic acid through the 5-lipoxygenase (5-LOX) pathway. Multiple studies strongly show that 5-LOX enzymatic by-products like leukotriene B4 and 5-HETE directly stimulate prostate cancer cell proliferation through several well-defined mechanisms.31-36
For example, arachidonic acid is metabolized by 5-LOX to 5-hydroxyeicosatetraenoic acid (5-HETE), a potent survival factor that prostate cancer cells use to escape destruction.37,38 Consuming a diet of foods rich in arachidonic acid, or precursors to arachidonic acid like the omega-6 fat linoleic acid, directly provokes the production of dangerous 5-LOX metabolic by-products, which can promote the progression of prostate cancer. In addition to 5-HETE, 5-LOX also metabolizes arachidonic acid into leukotriene B4, a potent pro-inflammatory agent that causes destructive reactions throughout the body and inflicts severe damage to the arterial wall.39-41
If arachidonic acid levels are reduced, a corresponding suppression of the 5-LOX products 5-HETE and leukotriene B4 will occur. A wealth of scientific research clearly demonstrates that supplementation with long-chain fatty acids like EPA and DHA from fish oil can help reduce the production of arachidonic acid-derived eicosanoids in the body.42
In contrast with the misinterpreted results presented in this report of men who were not consuming significant amounts of omega-3s, many other clinical studies indicate substantial benefit with omega-3 fatty acid intake in prostate cancer.

Additional Studies Indicate Substantial Benefit With Increased Intake of Omega-3 Fatty Acids

The report attacking omega-3s conflicts with prior studies demonstrating that increased intake of omega-3 fats has been shown to reduce prostate cancer risk and diets high in omega-6 fats are associated with greater risk. The analysis also suggests a relationship between increased omega-6 fatty acid levels and decreased risk of prostate cancer, which is, again, utterly inconsistent with the known pro-inflammatory effects of omega-6 fatty acids.

• A 2010 meta-analysis found a 63% reduction in prostate cancer death rates in those with higher fish consumption.1
• A 2004 study of 47 ,866 men found a trend toward decreased risk of prostate cancer with increasing levels of EPA and DHA.2
• A 2007 Harvard study of 14, 916 men found lower incidence of prostate cancer in men who had higher levels of long chain omega-3 fatty acids.3
• A 2013 Harvard study of 293, 464 men found increased omega-3 fatty acid intake was associated with significantly lower rate of fatal prostate cancer.4
• A 2012 Harvard study of 525 men found a 40% lower prostate cancer death rate among men with the highest intake of marine fatty acids.5
• A 2011 Duke University study found an increased omega-6:omega-3 ratio (i.e., more omega-6 and less omega-3) was associated with a significantly elevated risk of high grade prostate cancer.6
• A 1999 New Zealand study found significantly lower rates of prostate cancer with higher blood levels of EPA and DHA.7
• A 1999 Korean study found increased blood levels of omega-3 fatty acids associated with lower rates of prostate cancer and benign prostatic hyperplasia.8
• A 2003 prospective study reported “that men with high consumption of fish had a lower risk of prostate cancer, especially for metastatic cancer.”10
• A 2010 study that evaluated nutrient intake and prostate cancer risk concluded “High intake of omega-6 fatty acids, through their effects on inflammation and oxidative stress, may increase prostate cancer risk.”43
• The University of Chicago conducted a study published in 2004 that showed PSA levels rose in tandem with the omega-6 to omega-3 ratio in Jamaican men whose PSA was >10 ng/mL. The researchers noted “Increased levels of Omega6 PUFAs and the ratio of Omega6/Omega3 PUFAs in Jamaican men are associated with an increased mean PSA level and risk of prostate cancer.”44
• In addition to the clinical trial literature indicating consistent benefits with omega-3 fatty acid intake, traditional Japanese and Mediterranean diets rich in omega-3 fatty acids show a strong, consistent risk reduction in prostate cancer vs. Western diets rich in omega-6 and saturated fat.

Traditional Diets in Japan and The Mediterranean Region High in Fish are Protective Against Prostate Cancer

The results set forth by authors of the negative report on fish oil that omega-3 intake may be linked to prostate cancer are inconsistent, and in abject contrast, to longstanding evidence that diets high in marine lipids, such as the traditional Japanese diet and the Mediterranean diet, are protective against prostate cancer.
For example, the traditional Japanese diet, rich in omega-3 fatty acids from fish, confers protection against prostate cancer, as does the relatively high intake of fermented soy products and relatively low levels of saturated fat.45 The characteristics of the traditional Japanese diet high in soybean products, high in fish, and low in red meat are highly relevant in prostate cancer biology. In all likelihood, the traditional Japanese diet reduces the risk of prostate cancer through a combination of characteristics that generate a synergistic, anti-cancer effect (on prostate cancer).
Likewise, the protective properties of the Mediterranean diet in relation to heart disease and prostate cancer risk are well-established. Several aspects of this dietary pattern are protective, including regular consumption of small fish (smaller fish are less likely to contain contaminants than larger predatory fish such as tuna), high olive oil intake (there is synergy between olive polyphenols and fish oil), high daily ingestion of fresh vegetables, whole fruits (not pasteurized fruit juice rich in concentrated fructose), high-fiber cereals and legumes, and low intake of saturated animal fats and red meat.46

Benefit Clearly Outweighs Risk for Fish Oil Supplementation Among Men

Overwhelming evidence currently available strongly favors fish oil supplementation for most aging humans.
Fish oil and greater marine omega-3 intake have repeatedly and consistently been shown to reduce cardiovascular risk across multiple types of studies. For example:
A randomized, placebo-controlled trial found 1,800 mg of combined EPA plus DHA was associated with a 10% lower rate of cardiac events, 12% lower rate of non-fatal infarctions, and an almost 11%lower rate of cardiac deaths.47
In a large intervention study, 18,000 patients were randomized to receive either a statin medication alone or a statin plus 1,800 mg of EPA-fish oil daily. After five years, those with a history of coronary artery disease had a 19% lower rate of major coronary events in the statin-plus EPA-fish oil group compared to the statin-only group.48
A randomized, double-blind, placebo-controlled trial with chronic hemodialysis patients found that1,700 mg of omega-3 fatty acids daily was associated with a 70% reduction in the relative risk of myocardial infarction.49
A randomized, controlled trial using 3,300 mg of EPA and DHA (and then a decreased dosage) found a trend toward lower cardiovascular event occurrence with fish oil supplementation. Sevencardiovascular events occurred in the placebo group (not given fish oil) while only twocardiovascular events occurred in the fish oil-supplemented group during the study.50
A meta-analysis with an average fish oil dose of 3,700 mg found lowered systolic blood pressure by an average 2.1 mmHg and diastolic by 1.6 mmHg.51
In a randomized trial with peripheral arterial disease patients, 2,000 mg of omega-3 fatty acids daily resulted in a 49% improvement in flow-mediated dilation, a marker of endothelial cell health.52
The GISSI-Prevenzione study (a large, randomized, controlled trial) found that 1,000 mg/day of EPA and DHA in 11,323 patients with a history of recent myocardial infarction reduced the risk of total mortality by 20% and sudden death by 45%.53,54
The DART study — a randomized, controlled trial that examined the effects of advising 2,033 subjects to increase dietary fatty fish — revealed a 29% reduction in all-cause mortality compared with those not advised.55
A 2009 meta-analysis of randomized, controlled trials found that dietary supplementation with omega-3 fatty acids reduced the incidence of sudden cardiac death in subjects with prior myocardial infarction.56
Another 2009 meta-analysis of randomized, controlled trials found that dietary supplementation with omega-3 fatty acids reduced the risk of cardiovascular death, sudden cardiac death, all-cause mortality, and non-fatal cardiovascular events in patients with a history of certain cardiovascular events or risk factors.57
A 2008 meta-analysis found a significant reduction in death from cardiac causes with fish oil supplementation.58
A 2002 meta-analysis of randomized, controlled trials concluded that omega-3 fatty acids reduced overall mortality, mortality due to myocardial infarction, and sudden death in patients with coronary heart disease.59

Will this Flawed Report Prompt an Epidemic of Prostate Cancer?

Regrettably, the public is poorly served by relying on a sound-bite frenzied news media for health data, which often involves parading a provocative medical headline without a deep, thorough evaluation of the study’s validity.
This “science by ambush” denies an opportunity for meaningful rebuttal, since the media never wants to admit last week’s headline news story was bogus.
The average percentage difference (0.18%) of plasma long-chain omega-3 fatty acids from a singlebaseline test renders this study meaningless. The authors don’t even know if their study subjects were eating fish or taking fish oil supplements. We at Life Extension have criticized certain studies that solely rely on food questionnaires, but this attack on omega-3s didn’t even attempt to ascertain if study subjects were ingesting the nutrient (omega-3s) in question. Yet its authors presumptuously warn of potential risks in consuming supplemental omega-3s!
The lack of rigor, as well as multiple layers of methodological problems and errors, notwithstanding the complete lack of consistency with the known, well-established biology and biochemistry of prostate cancer should prompt outrage in the scientific and medical community.
The danger of this deeply flawed, compromised analysis is that aging men obtaining health information through the mainstream media will cease omega-3 fatty acid ingestion.
The consequences may be profound if aging men shun omega-3 fatty acid supplementation as a result of this flawed study and follows its implied recommendations to consume more omega-6 fats, which enhance inflammation and create a better environment for prostate cancer, as well as cardiovascular disease to flourish.
Although the researchers attempted to statistically model (through multivariate analysis) and control for some (but not all) critical, confounding risk factors like family history, the higher baseline PSA readings (implying more preexisting cancers) and positive family history (1st degree male relative with prostate cancer) in men who went on to develop prostate cancer raise concerns for the integrity of the analysis results. Along with these confounding factors, the marginal difference in baseline plasma omega-3 levels of men who later developed prostate cancer cannot rationally implicate omega-3s as having a causal or causative effect. The plasma omega-3 levels of the entire study group showed consumption of omega-3 from food was inadequate and intake of meaningful fish oil supplementation non-existent.
Educated health consumers should continue to ingest omega-3 fatty acids.
This report will be updated as more of Life Extension’s scientific advisors provide their input.

Copyright 2014. All rights  reserved.  Reprinted with exclusive permission of “Life Extension Magazine.”

See original article at LEF.org

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