Cancer Epidemiol Biomark Prev. 2010 (Jul); 19 (7): 1696–1708 ~ FULL TEXT
Theodore M. Brasky, Johanna W. Lampe1, John D. Potter, Ruth E. Patterson, and Emily White1
Fred Hutchinson Cancer Research Center,
1100 Fairview Avenue North, M4-B402,
Seattle, WA 98109-1024, USA.
Dietary supplements taken for menopause have been associated with reduced risk of breast cancer. This study investigated the long-term use of supplements and breast cancer risk in 35,000 postmenopausal women, in the Vitamins and Lifestyle study. Supplemental fish oil use was associated with a 32% reduced risk of breast cancer and 10-year average use was suggestive of reduced risk for breast cancer. The authors conclude that fish oil intake may be inversely associated with breast cancer risk and that future research for fish oil in chemoprevention studies is warranted.
BACKGROUND: Use of nonvitamin, nonmineral "specialty" supplements has increased substantially over recent decades. Several supplements may have anti-inflammatory or anticancer properties. Additionally, supplements taken for symptoms of menopause have been associated with reduced risk of breast cancer in two case-control studies. However, there have been no prospective studies of the association between the long-term use of these supplements and breast cancer risk.
METHODS: Participants were female members of the VITamins And Lifestyle (VITAL) Cohort. Postmenopausal women, ages 50 to 76 years, who were residents of western Washington State, completed a 24-page baseline questionnaire in 2000 to 2002 (n = 35,016). Participants were queried on their recency (current versus past), frequency (days/week), and duration (years) of specialty supplement use. Incident invasive breast cancers (n = 880) from 2000 to 2007 were obtained from the Surveillance, Epidemiology, and End Results registry. Multivariable-adjusted hazards ratios (HR) and 95% confidence intervals (95% CI) were estimated by Cox proportional hazards models.
RESULTS: Current use of fish oil was associated with reduced risk of breast cancer (HR, 0.68; 95% CI, 0.50-0.92). Ten-year average use was suggestive of reduced risk (P trend = 0.09). These results held for ductal but not lobular cancers. The remaining specialty supplements were not associated with breast cancer risk: Specifically, use of supplements sometimes taken for menopausal symptoms (black cohosh, dong quai, soy, or St. John's wort) was not associated with risk.
CONCLUSIONS: Fish oil may be inversely associated with breast cancer risk.
IMPACT: Fish oil is a potential candidate for chemoprevention studies. Until that time, it is not recommended for individual use for breast cancer prevention.
From the FULL TEXT Article:
The prevalence of regular dietary supplement use in the United States has risen in recent decades , with substantial increases in non-vitamin, non-mineral “specialty” supplement use [1-3]. As supplements fall under the Dietary Supplements Health and Education Act (DSHEA) of the U.S. Food and Drug Administration (FDA), oversight of these compounds is limited. Although several researchers have examined trends, lifestyle characteristics, and health-related behaviors and beliefs of specialty supplement users [1, 2, 4], relatively little is known about the long-term health consequences of these compounds for risk of cancer and, specifically, breast cancer.
Results from a growing body of literature suggest that some such supplements have anti-cancer properties in vitro and in vivo [5-13]; however, the mechanisms of action for most compounds are not well understood. There is limited evidence that some specialty supplements, such as glucosamine, chondroitin, and fish oil may have anti-inflammatory properties [14-16]. Anti-inflammatory supplements are of interest because chronic inflammation has been linked to mutagenesis, mitogenesis, angiogenesis, anti-apoptosis, and metastasis - factors associated with cancer initiation and progression [17, 18]. Based on in vitro studies, one hypothesized mechanism by which inflammation contributes specifically to breast carcinogenesis is that increased PGE2 production promotes de novo estrogen synthesis in breast epithelia and stroma . A further rationale for examining use of anti-inflammatory supplements is that the use of non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit COX-2 and PGE2 synthesis, have been inversely associated with several cancers , including breast . In addition, supplements taken for symptoms of menopause have been recently associated with reduced risk of breast cancer in two case-control studies [22, 23].
To our knowledge, no prospective studies have evaluated the use of specialty supplements in relation to breast cancer risk. We describe here our investigation of the association between specialty supplement use and breast cancer risk in the VITamins And Lifestyle (VITAL) cohort.
In this cohort of 35,016 women living in western Washington State, current use of fish oil supplementation was associated with reduced risk of breast cancer. The reduced risk was restricted to women with ductal but not lobular carcinoma, and perhaps, local but not regional or distant disease. We observed no meaningful interaction with current use of fish oil and factors associated with chronic inflammation. Other specialty supplements were not associated with risk.
Fish oil primarily contains the long-chain omega-3 (ω-3) polyunsaturated fatty acids (PUFAs), docosahexaenoic (DHA) and eicosapentaenoic (EPA) acid. It is generally marketed for its cardioprotective benefit. To our knowledge, there are no previous studies which have examined the type of fish oil supplementation that is currently common in the US (from fish high in EPA and DHA) with breast cancer risk. However, investigators of a population-based case-control study in Ontario, Canada, examined cod liver oil supplementation with breast cancer risk [33, 34]. They observed a 24% reduction in breast cancer risk with cod liver use ≥1/week during adolescence (OR 0.76, 95% CI: 0.62-0.92) . Similar reductions in risk were evident for use up to age 54 years, though they did not reach statistical significance . It was further reported that the association did not differ by hormone receptor status . Cod liver oil differs from fish oil in its lower content of ω-3 PUFAs and is used primarily as a source of vitamins A and D . Because of these differences, it is unclear whether the observed associations in the Canadian study are attributable to cod liver oil’s vitamin or fatty-acid content.
The association of fish or ω-3 PUFA intake from diet with breast cancer has been examined in several cohort studies [36-44]. Generally, no association has been seen . However, results of a prospective study of women in Singapore, where fish intake is much higher than that of the US, showed an inverse association between dietary ω-3 PUFA from marine sources and breast cancer risk (RR 0.72, 95% CI: 0.53-0.98) . The only cohort studies in which individual associations of EPA and DHA intake from diet with risk of breast cancer have been examined are the Nurses’ Health Study and the Netherlands Cohort [36, 42]. No association was found in either study [36, 42]. In contrast, Saadatian-Elahi et al.  conducted a meta-analysis of studies that analyzed blood biomarkers of fatty acids in association with breast cancer risk. They found inverse associations for total ω-3 PUFAs (RR 0.61, 95% CI: 0.40-0.93), as well as for EPA (RR 0.69, 95% CI: 0.45-1.05), and DHA (RR 0.68, 95% CI: 0.44-1.04) . For all but EPA, the association persisted when the analysis was restricted to post-menopausal women . Thus the associations we observed between fish oil supplement use and breast cancer risk are consistent with studies of biomarkers of ω-3 PUFA intake and breast cancer, but not with prior studies of self-report of dietary intakes of ω-3 PUFAs.
These differences among studies may be explained by the poor measurement precision of self-reported diet. Another explanation may be that the daily dose of ω-3 PUFA intake from fish oil supplements is likely to be much higher than most people in the US consume from diet. Eighty-three percent of fish oil users in our study took fish oil ≥4 times a week; 60% were daily users. Based upon the University of Minnesota Nutrition Data System for Research (NDS-R) software , a single 4 ounce (112 gram) serving of fatty fish (e.g., salmon) contains 330mg EPA and 1080mg DHA, whereas other types of fish have lower values. Although concentrations vary by manufacturer, participants who used fish oil supplements probably consumed the equivalent of 33%-77% of a serving of high ω-3 fish each day that the supplement was used.
Current, but not former use of fish oil was inversely associated with breast cancer risk. It may be that current use reported at baseline is a surrogate for use after baseline closer to the incident cancer (0-7.3 years after baseline). If use in the more distant past does not represent the exposure window of etiologic relevance, our finding of no association with former use and no clear trend with amount of use in the 10 years prior to baseline is explained.
In this study, current use of fish oil was associated with reduced risk of invasive ductal carcinoma but not invasive lobular carcinoma. Although the mechanism is not clear, other exposures are differentially associated with ductal vs. lobular cancer. For example, exposures that act by modifying circulating hormones, such as alcohol use and combined postmenopausal hormone therapy, appear to have greater associations with lobular or mixed ductal-lobular cancers [48, 49]. We additionally found a reduction in risk of local but not regional or distant disease. It may be that any anti-cancer effect of fish oil may be insufficient to protect against tumors already established at the time when supplementation began or with aggressive phenotypes. Similar phenomena have been previously reported. Authors of the Prostate Cancer Prevention Trial found a protective effect of finasteride on early, but not late-stage, prostate cancer . In the Women’s Health Initiative trial of combined hormone therapy, a protective effect was observed only for early stage colorectal tumors .
Fish oil may be associated with a reduction of breast cancer risk because of its anti-inflammatory properties. EPA and DHA are thought to reduce inflammation through the inhibition of Nuclear Factor kappa-B (NF-κB) , which acts as a transcription factor for targets associated with inflammation, including interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2) . Because EPA and DHA are incorporated into cell phospholipids at the expense of arachidonic acid (ω-6 PUFA), they reduce the reservoir of arachidonic acid for COX-2 to synthesize prostaglandin E2 (PGE2) .
Animal and human studies support fish oil as having anti-inflammatory and possibly other properties that could reduce breast cancer risk. Experimental studies in rodents have shown a reduction in PGE2 levels and mammary tumor incidence with diets high in ω-3 PUFAs found in fish oil [53-55]. In humans, dietary intake of ω-3 PUFAs or fish has been inversely associated with blood concentrations of inflammatory markers C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and IL-6 [32, 56]. A recent randomized trial of ω-3 PUFA supplements reported that the supplements reduced circulating CRP and TNF-α ; moreover, these markers have been associated with breast cancer risk in some epidemiologic studies [58, 59]. However, earlier findings from randomized trials of ω-3 PUFA supplementation in humans have been inconsistent in observing an effect on these or other immune markers, in part due to limited power .
We found no association of other specialty supplements with breast cancer risk. Our findings are in contrast to previously published work [22, 23]. Obi et al.  conducted a large, population-based case-control study of 10,121 postmenopausal women in northern and southwestern Germany. They reported inverse associations with breast cancer for use of black cohosh (OR 0.80, 95% CI: 0.63-1.00) and a borderline inverse association with phytoestrogens from soy and red clover supplements (OR 0.64, 95% CI: 0.39-1.05) . When the authors combined several herbal preparations including black cohosh, St. John’s wort, soy, and other preparations, they reported a 25% reduction in breast cancer risk (Ever vs. Never, OR 0.74, 95% CI: 0.63-0.87) . We attempted to replicate their findings and combined ever use of specialty supplements taken for climacteric symptoms; we observed no association. In another population-based case-control study, Rebbeck et al.  observed a reduction in breast cancer risk with ever use of black cohosh (OR 0.47, 95% CI: 0.27-0.82), and a borderline risk reduction with use of ginseng (OR 0.74, 95% CI: 0.53-1.06). It is unclear why our findings differ from that of the two case-control studies. Differences may be explained by differences in study design, differences in dose under study, or chance; in the study by Rebbeck et al. , exposure frequencies were quite low.
Our study has several strengths. To our knowledge ours is the first prospective study designed specifically to investigate the association of specialty supplements with cancer risk. We targeted supplement users for recruitment, and we had detailed assessment of current and long-term specialty supplement exposure. Another strength of the study is that we were able to adjust our analyses for known and suspected indications for supplement use, thereby correcting for potential confounding by indication. Additionally, follow up on the cohort was 95% complete: therefore, bias due to differential loss to follow-up is not likely to explain our findings.
This study is not without limitations. First, we did not query participants on the dose used for specialty supplements. One reason for this is that there is evidence that the advertised dose can vary substantially from that of the actual supplement . Another limitation is that supplement use was ascertained from participants through self-report. Although we did not conduct a validity study on our data on specialty supplements, we did conduct a study on the reliability and validity of our measures of 10-year average use of vitamin and mineral supplements . The intraclass correlation coefficients for test-retest reliability at baseline and after 3 months varied between 0.69 for beta-carotene and 0.84 for folic acid, which provides some assurance that our measure of specialty supplements is reasonably accurate. The prospective nature of the study design ensures that any error from self-report is likely to be non-differential. Power was limited by the relatively low prevalence of use of some specialty supplements (e.g., black cohosh, dong quai). Finally, despite the support from epidemiologic studies of biomarkers of fatty acids and breast cancer risk and the biologic plausibility, our finding for fish oil supplements could be due to chance, because we examined 15 specialty supplements.
In summary, this is the first prospective study to report on the association of specialty supplements with breast cancer risk. Our finding of a reduced risk of breast cancer with use of fish oil warrants further study of this agent, focused particularly on timing of exposure and dose, as well as on mechanisms of action that might explain differences by tumor stage or histologic type. Until these results are replicated, fish oil supplements should not be promoted for reduction of breast cancer risk.