Omega-3 fatty acids for breast cancer prevention and survivorship

Omega-3 and omega 6 fatty acids are incorporated at different rates in different tissues and tissue components. Levels as a percentage of total fatty acids vary tremendously between tissues/organs although, with supplementation, levels of EPA and DHA rise in a fairly proportional manner [44]. Substantial increases in monocyte membrane DHA and EPA and decreases in monocyte AA may be seen as early as 1 week after beginning supplementation and do not change dramatically over the ensuing several weeks [9,26]. The time to EPA maximum uptake is ~2 weeks in plasma triglycerides, 3 weeks in serum cholesterol esters, ~2 months in red blood cells (RBCs), and >12 months for most types of adipose tissue. The highest levels of EPA and DHA in the blood are generally in the RBC membranes (RBC phospholipids), plasma phospholipids, and cholesterol esters and platelets, although mononuclear cells also contain appreciable amounts [45]. The concentration of EPA and DHA in subcutaneous or breast adipose is 1/10 or less of that in the blood compartments [44]. DHA is generally much higher than EPA in most body organs, including the brain and retina, but its incorporation into RBCs lags behind EPA [26,28,29,46]. Women generally have higher levels of EPA and DHA than men following equivalent dosing, and older women have higher levels than younger women [45]. Individuals who take fish oil supplements tend to take them daily whereas consumption of fish may be more intermittent. Browning and colleagues determined in a 12-month study of adults taking identical weekly doses of EPA + DHA that those taking continuous daily doses had higher EPA and DHA levels in monocytes and platelets than those taking intermittent doses [47].

For clinical trials, chronic exposure is generally assessed by measuring EPA, DHA, and AA RBC phospholipids, although some investigators feel that monocyte or platelet phospholipid measures are superior to those in RBCs [29].

Results of case–control studies, particularly when questionnaires are used as the primary measure of exposure, are mixed, probably reflective of the accuracy of recall and food frequency questionnaires in estimating dietary intake. There is no significant association between total fish intake and breast cancer particularly in populations where total fish and fatty fish consumption tends to be low [48,49]. EPA and DHA content varies tremendously by type of fish, which may not be well specified in the questionnaires. However, two case–control studies (one from Mexico and another from the United States) using dietary recall instruments suggest breast cancer risk reduction in premenopausal women with higher intakes of omega-3 fatty acids from diet and supplements [50,51].

Measurement of the fatty acid composition in blood cell membranes (phospholipids) and adipose is thought to be a good indicator of chronic exposure to omega-3 and omega-6 fatty acids and thus avoids some of the problems with dietary recall. A nested case–control study within a prospective cohort of women in Shanghai China, a population with relatively high fish intake, found that total omega-3 fatty acids and EPA in red cells were associated with significantly lower risk of proliferative breast disease and breast cancer [52,53]. Similar findings were reported in a Japanese cohort where total omega-3, EPA, and DHA in red cells was inversely associated with breast cancer risk [54]. Another case–control study suggested reduced risk of breast cancer with higher ratios of omega-3 to omega-6 in breast adipose [55]. No association was reported between the risk biomarker mammographic breast density and omega-3 fatty acids [56].

Although one is not likely to achieve EPA + DHA intake in human trials at the same percentage of calories as in animal prevention trials, doses of EPA and DHA ethyl esters up to ~7 g/day given to healthy women are well tolerated [62]. A dose of 3.4 g/day DHA + EPA ethyl esters, providing ~ 2% of calories, is US Food and Drug Administration approved for treatment of hypertriglyceridemia. Importantly, this dose should produce an EPA + DHA:AA ratio approaching equivalence and thus provide an anti-inflammatory effect.

Human studies in healthy individuals show little effect of marine PUFA on blood inflammatory biomarkers, although a recent randomized trial in healthy young adults given 0, 300, 600, 900, or 1,800 mg/day EPA + DHA for 5 months showed a marginal decrease in serum tumor necrosis factor alpha (P = 0.08) but no change in interleukin-6 [63].

Human studies in inflammatory disorders show little evidence of a systemic anti-inflammatory effect such as reduction of cytokines or prostaglandin E₂ levels with doses of combined EPA + DHA less than ~3.5 g/day and/or EPA-alone doses <2.7 g/day [26,64]. However, experts in this area suggest that systemic measures of cytokines in inflammatory conditions are likely to be insensitive compared with measuring conditions in the tissue of interest [65].

Signori and colleagues are conducting a trial of raloxifene 30 mg, raloxifene 60 mg, Lovaza™ (GlaxoSmithKline) 4 g, Lovaza™ 4 g + raloxifene 30 mg, or no intervention in postmenopausal women with >25% breast density. No change with Lovaza™ has been found in the first 46 women in secondary endpoint blood risk biomarkers such as insulin-like growth factor I and insulin-like growth factor-binding protein 3 or the inflammatory marker high-sensitivity C-reactive protein [66].

We have completed separate pilot studies of 3.4 g/day EPA + DHA ethyl esters (4 g Lovaza™) administered for 6 months to explore effects on benign breast tissue risk biomarkers for breast cancer in premenopausal and postmenopausal women at increased risk for breast cancer. Favorable modulation of several tissue risk biomarkers for breast cancer was observed [67,68].

A study of particular interest is the ongoing VITAL trial (NCT01169259) which aims to randomize over 28,000 men and women to vitamin D3 (2,000 IU/day), omega-3 fatty acids (840 mg EPA + DHA), both, or none, with a primary outcome of reduction in risk for cancer, stroke, and other diseases. Eligible women must be age 55 years and over.

Higher intakes of EPA and DHA from dietary sources were reported to be associated with a 25% reduction in breast cancer recurrence and improved overall mortality in a large cohort of over 3,000 women with early stage breast cancer followed for a median of 7 years [69]. One reason for this observation may be enhancement of at least some types of chemotherapeutic cytotoxicity, which has been reported for concomitant administration of DHA with anthracyclines [70,71]. This enhanced cytotoxicity probably results from alteration in membrane lipid rafts, which increases surface expression and clustering of the death receptor CD95 in mammary cancer cell lines treated with EPA and DHA and doxorubicin [72]. Improved outcome with DHA added to chemotherapy in a small phase II trial has been reported in metastatic breast cancer patients [73]. This observation raises the question of whether cardiac toxicity might also be increased by adding EPA or DHA to anthracyclines, but this does not appear to be the case at least in rats [74].

Cardiac events are the second most common cause of mortality in women with breast cancer, and the most common cause of death for women with stage I breast cancer over the age of 65. EPA and DHA reduce triglycerides and platelet aggregation and are thought to have an anti-arrhythmic effect. EPA and DHA supplementation have been noted to be associated with reduced cardiac deaths in the general population [75,76]. A highly purified prescription strength form of ~3.4 g/day EPA and DHA (Lovaza™, formerly omacor, 4 g/day) is US Food and Drug Administration approved for treatment of hypertriglyceridemia and has been shown to reduce triglycerides and nonhigh-density lipoproteins to a greater extent than a statin alone in individuals with mixed dyslipidemia and triglycerides >200 mg/dl [77]. This highly purified prescription formulation has also been shown to reduce cardiac events and mortality in individuals with a prior myocardial infarction at lower doses of 1 g/day [77]. However, a recent secondary prevention trial with 1 g/day EPA and DHA compared with 1 g/day olive oil did not show any cardioprotective effect [78]. A recent meta-analysis of EPA and DHA in moderate doses also showed no benefit [79]. The cause of these discrepancies is open to speculation. Possibilities include the following: 1) a lack of additional benefit for EPA + DHA in women with cardiac disease already on optimal medical management; 2) the placebo, often olive oil, may also have cardiovascular benefit; 3) or the highly purified forms of EPA + DHA may have special properties such as lower reactive oxygen species than less purified forms of fish oil [80]. Trials such as the VITAL trial in women without a prior history of heart disease will be of great interest.

Loss of bone density and increased fracture rate are a side effect of premature menopause caused by cytotoxic chemotherapy or surgical ovarian ablation in premenopausal women or use of aromatase inhibitors in postmenopausal women. EPA and DHA probably inhibit RANK ligand and osteoclast formation [81]. A small randomized pilot trial suggests that 3 g/day EPA and DHA inhibits bone reabsorption in individuals taking aromatase inhibitors [82]. The anti-inflammatory activity and beneficial effects of EPA and DHA on rheumatoid arthritis have led to a clinical trial of high-dose EPA and DHA versus placebo in women who have aromatase inhibitor-induced arthralgias. This cooperative group study of 262 women has been reported in abstract form and no benefit was observed [83]. A small randomized trial of omega-3 fatty acids to protect against taxane-induced neuropathy suggests benefit [84] and further studies are needed.

EPA and DHA help prevent obesity and insulin resistance particularly in animal models fed a high-fat diet [85,86], but effects in humans have yet to be proven. Sarcopenic weight gain is common during adjuvant chemotherapy for breast cancer. The anabolic effects of EPA and DHA might help reduce muscle mass loss and weight gain during treatment and weight gain following diagnosis, but studies in this area have yet to be conducted [87,88]. Results of the Muscle Mass, Omega-3, Diet, Exercise and Lifestyle (MODEL) trial in healthy individuals aged >70 years examining the effects of 90 minutes of exercise weekly, vitamin D3 (2,000 IU/day) or 1 g EPA and DHA daily are awaited with interest [89].

Cognitive abnormalities are observed in 20 to 70% of women after chemotherapy depending on the agents used, intensity and duration of treatment, predisposing factors, and type and scoring of cognitive tests [90,91]. DHA is the most abundant PUFA in the brain and is involved in multiple functions including cell signaling, neurogenesis, neuroprotection, and learning and memory [18]. A number of epidemiologic studies show a 40 to 50% reduction in risk of multicause dementia with increased dietary intake of DHA or increased blood levels of DHA [19]. In meta-analyses, DHA supplementation improves attention, processing speed and immediate recall, learning, and memory in individuals with cognitive impairment without dementia but not in those with dementia [92,93]. Probable mechanisms include suppression of oxidative stress [94], decreases in proinflammatory lipid derivatives from AA, an increase in inflammation resolving and protective lipid derivatives, enhanced production of neurotransmitters [95], and reduced production and accumulation of amyloid B peptide toxin [19]. Doses of DHA administered as supplements for cognitive improvement are generally in the range of 1,800 mg/day. Studies utilizing DHA or DHA + EPA as a neuroprotectant during chemotherapy are needed.