Flaxseed Lignans and Cancer

Lignans are phenolic compounds found frequently in fiber-rich plants, such as flax (Linum usitatissimum). Flax is particularly high in the lignans secoisolariciresinol diglucoside (SDG), SECO, and matairesinol. SDG is converted in the human colon by bacteria into the mammalian lignans enterodiol and enterolactone. Flaxseed, its lignans, and enterolactone have been studied for anticancer activity in vitro, in animal models, and among humans.¹

Epidemiologic studies have evaluated both serum lignan concentrations and dietary intake for an association with cancer risk for several solid tumor types. Randomized controlled trials have evaluated the effect of dietary flaxseed on tumor tissue markers, with promising results.

A randomized controlled trial of cancer prevention or treatment has not, however, yet been conducted.

Breast Cancer

Several epidemiologic studies evaluated serum concentrations of enterolactone and breast cancer risk and prognosis. A study of 1250 postmenopausal breast cancer cases and 2164 from a population-based study demonstrated that high levels of serum enterolactone were significantly associated with a reduced risk of breast cancer (odds ratio [OR], 0.65; 95% CI, 0.52-0.83; P-trend = <.0001).² This association was evident for hormone receptor–positive disease, but was greatest with hormone receptor–negative disease. HER2 expression did not affect the associations.

A prospective cohort study of 2182 patients aged 50 to 74 years at breast cancer diagnosis demonstrated that high enterolactone concentrations were significantly associated with decreased all-cause mortality (hazard ratio [HR], 0.94; 95% CI, 0.90-0.98), breast cancer–specific mortality (HR, 0.94; 95% CI, 0.89-0.99), and distant disease–free survival (HR, 0.94; 95% CI, 0.90-0.98) among women with stage 0 to IIIA disease.³

Using another approach, a study of 2999 breast cancer cases and 3370 healthy controls demonstrated that breast cancer risk was significantly reduced by dietary consumption of flaxseed (OR, 0.82; 95% CI, 0.69-0.97) and flax bread (OR, 0.77; 95% CI, 0.67-0.89).⁴

Dietary flaxseed may also have an effect on tumors. Tumor tissue was assessed from a trial that randomly assigned patients with newly diagnosed breast cancer to receive a muffin containing 25 g of flaxseed or placebo at the time of diagnosis and then at the time of definitive surgery. Urine samples and dietary questionnaires were also collected.⁵ The flaxseed arm demonstrated a significant reduction in markers of tumor growth including Ki-67 labelling index (34.2%; P = .001), c-ERBB2 expression (71%; P = .003), and an increase in apoptosis (30.7%; P = .007). Mean urinary lignan excretion was also increased in the flaxseed group compared with the placebo group.

Another study conducted among postmenopausal women receiving aromatase inhibitors demonstrated that flaxseed consumption trended toward a reduction in estrogen receptor (ER) beta expression by 40%, but these findings were not significant.⁶ Urinary enterolactone excretion was lower among patients receiving flaxseed plus an aromatase inhibitor compared with flaxseed alone, suggesting that aromatase inhibition may somehow affect enterolactone concentrations.

Prostate Cancer

A meta-analysis of case-control and cohort studies that included 11,346 cases and 140,177 controls found no association between enterolactone, matairesinol, secoisolariciresinol, or total lignans and prostate cancer.⁷ A systematic review came to a similar conclusion: most epidemiologic studies found no association between prostate cancer risk and dietary intake of flaxseed lignans or serum levels of enterolactone.⁸

Clinical studies, however, found that dietary flaxseed affected tumor markers.⁸ In a study of men with prostatic intraepithelial neoplasia, 30 g per day of flaxseed for 6 months decreased serum total prostate specific antigen (PSA) and the proliferation rate of benign epithelial cells. Another study among men with prostate cancer with a planned prostatectomy who received 30 g of flaxseed per day for about 34 days demonstrated decreased total testosterone and free androgen levels, decreased tumor proliferation index among men with a Gleason score of 6 or less, and increased tumor apoptotic scores. A similar study also demonstrated lower tumor proliferation rates with 30 g per day of flaxseed consumed by men awaiting prostatectomy.

Another study of men with localized prostate cancer showed that 30 g per day of flaxseed for about 30 days increased urinary concentrations of flaxseed lignans, and these concentrations were significantly associated with Ki–67 tumor expression.⁹

Conclusions

Epidemiologic data of flaxseed dietary intake and high enterolactone serum concentrations — as well as in-human biomarker studies conducted in a randomized controlled design — suggest that flaxseed consumption may reduce the risk of breast cancer. The data are less clear for prostate cancer, but biomarker studies suggest that consumption of 30 g per day of flaxseed can reduce PSA levels and tumor proliferation rate. Larger studies are needed to validate the effect of flaxseed consumption on cancer prevention or treatment.

References

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3. Seibold P, Vrieling A, Johnson TS, et al. Enterolactone concentrations and prognosis after postmenopausal breast cancer: assessment of effect modification and meta-analysis. Int J Cancer. 2014;135:923-33. doi: 10.1002/ijc.28729
4. Lowcock EC, Cotterchio M, Boucher BA. Consumption of flaxseed, a rich source of lignans, is associated with reduced breast cancer risk. Cancer Causes Control. 2013;24:813-6. doi: 10.1007/s10552-013-0155-7
5. Thompson LU, Chen JM, Li T, Strasser-Weippl K, Goss PE. Dietary flaxseed alters tumor biological markers in postmenopausal breast cancer. Clin Cancer Res. 2005;11:3828-35.
6. McCann SE, Edge SB, Hicks DG, et al. A pilot study comparing the effect of flaxseed, aromatase inhibitor, and the combination on breast tumor biomarkers. Nutr Cancer. 2014;66:566-75. doi: 10.1080/01635581.2014.894097
7. Zhang Q, Feng H, Qluwakemi B, et al. Phytoestrogens and risk of prostate cancer: an updated meta-analysis of epidemiologic studies. Int J Food Sci Nutr. 2017;68:28-42. doi: 10.1080/09637486.2016.1216525
8. Saarinen NM, Tuominen J, Pylkkänen L, Santti R. Assessment of information to substantiate a health claim on the prevention of prostate cancer by lignans. Nutrients. 2010;2:99-115. doi: 10.3390/nu2020099
9. Azrad M, Vollmer RT, Madden J, et al. Flaxseed-derived enterolactone is inversely associated with tumor cell proliferation in men with localized prostate cancer. J Med Food. 2013;16:357-60. doi: 10.1089/jmf.2012.0159