Flax and Breast Cancer: A Systematic Review
Flax and Breast Cancer: A Systematic Review
Authors: Flower, G. Fritz, H. Balneaves, L.G. Verma, S. Skidmore, B. Fernandes, R. Kennedy, D. Cooley, K.
Publication Name: Inter. Canc. Ther.
Publication Details: DOI: 10.1177/1534735413502076
Flax is a food and dietary supplement commonly used for menopausal symptoms. Flax is known for its lignan, alpha linolenic acid, and fiber content, components that may possess phytogestrogenic, anti inflammatory, and hormone modulating effects, respectively. We conducted a systematic review of flax for efficacy in improving menopausal symptoms in women living with breast cancer and for potential impact on risk of breast cancer incidence or recurrence. We searched MEDLINE, Embase, the Cochrane Library, and AMED from inception to January 2013 for human interventional or observational data pertaining to flax and breast cancer. Of 1892 records, we included a total of 10 studies: 2 randomized controlled trials, uncontrolled trials, 1 biomarker study, and 5 observational studies. Nonsignificant (NS) decreases in hot flash symptomatology were seen with flax ingestion (7.5 g/d). Flax (25 g/d) increased tumor apoptotic index (P less than .05) and decreased HER2 expression (P less than .05) and cell proliferation (Ki 67 index; NS) among newly diagnosed breast cancer patients when compared with placebo. Uncontrolled and biomarker studies suggest beneficial effects on hot flashes, cell proliferation, atypical cytomorphology, and mammographic density, as well as possible anti-angiogenic activity at doses of 25 g ground flax or 50 mg secoisolariciresinol diglycoside daily. Observational data suggests associations between flax and decreased risk of primary breast cancer (adjusted odds ratio [AOR] equal 0.82; 95percent confidence interval [CI] equal 0.69 to 0.97), better mental health (AOR equal 1.76; 95percent CI equal 1.05 to 2.94), and lower mortality (multivariate hazard ratio equal 0.69; 95percent CI equal 0.50 to 0.95) among breast cancer patients. Current evidence suggests that flax may be associated with decreased risk of breast cancer. Flax demonstrates antiproliferative effects in breast tissue of women at risk of breast cancer and may protect against primary breast cancer. Mortality risk may also be reduced among those living with breast cancer. (Authors Abstract)
Flaxseed has been studied for its potentially beneficial physiologic effects, including proposed anticancer effects. Alpha linolenic acid has been shown to exert anti-inflamma¬tory activity and in animal models of premenopausal (high estrogen) breast cancer, it has been shown to have antiproliferative effects.
Flaxseed is also one of the most important sources of the lignan precursor secoisolariciresinol (SECO), which occurs as secoisolariciresinol diglycoside (SDG) oligomers bound to hydroxymethylglutaric acid in the flax seed coat. It has also been suggested that SECO itself may act as a lignan in the body. Plant lignans as a group consist of phenolic compounds including enterolactone (ENL) and enterodiol (ED) (as well as others that are classified as phytoestrogens) alongside isoflavones, coumestanes, mycotoxins, and stil¬benes. Although many foods contain lignans, flaxseed is unique in that it is the densest source of the lignan SDG, with between 60 and 300 mg lignans per 100 g serving. This diverse class of constituents is thought to possess vary¬ing degrees of both estrogenic and antiestrogenic effects in vivo, in conjunction with more direct antitumor effects. Through metabolism by intestinal microbes, plant lignans are converted into their active mammalian forms, ENL and ED. These metabolites appear to be responsible for some of the anticancer effects that have been attributed to lignans. The objectives of this systematic review are to assess the efficacy of flaxseed or its constituents, including flaxseed oil and flax lignans, in the management of hot flashes in women at risk of breast cancer incidence or recurrence and to deter¬mine the effect of this intervention on risk of breast cancer development, recurrence, or mortality.
Observational studies reviewed suggest that flax or flax-derived lignan consumption may decrease risk of breast cancer when adequate amounts are consumed 32 g ground flax or 163 mg lig¬nans daily or weekly in one study, respectively). Flax appears to also possess antitumor activity. Studies by Thompson and Fabian indicate that flax increases tumor apoptotic index, decreases HER2 expression, and decreases tumor cell proliferation (Ki-67 labeling index) in breast cancer patients, while a biomarker study suggests that flax may have anti angiogenic activity in breast tissue. These biomarker studies suggest that consumption of flax¬seed at 25 g per day, containing 50 mg SDG, may contribute to overall antitumor effects. Population studies point to a potential role of dietary plant lignans in the prevention of cancer. A low-estrogen environ¬ment may be required for the protective effects of plant lignans, such as those found in flax, to become clinically relevant. Alternatively, preclinical studies indicate that flax may pos¬sess aromatase inhibitory effects that have more impact on postmenopausal populations. The potentially protective effects of flax merit further investigation to identify the populations that may benefit most from this intervention.
In vitro, flaxseed metabolites such as ENL have been shown to interact with estrogen receptors, behaving as weak estrogen agonists. While this action may be of concern to women with breast cancer, flaxseed administration appears to have no significant effect on endogenous estro¬gen levels in the majority of human trials, either in women with cancer or in healthy women. Conversely, studies that do report significant changes cite decreases in serum estrogen levels, suggesting reduced exposure to endoge¬nous estrogen over time with flaxseed consumption. To date, studies assessing the effect of flax on risk of breast cancer have not identified a clearly differential effect according to ER status.
Flaxseed and SDG have been shown to possess antiproliferative, anti-angiogenic, and pro-apoptotic effects in vivo, resulting in decreased tumor size, multi¬plicity, and a reduction in metastases. Markers of disease progression including VEGF79 and CRP80 are also attenu¬ated by this intervention. Preliminary human studies appear to support these results, demonstrating that 50 mg of SDG significantly reduces HER2 expression and cell prolifera¬tion while increasing apoptosis. In addition to its direct antitumor effects, flaxseed may be chemoprotective through its influence on endogenous estrogen activity. As weak aromatase inhibitors, flaxseed metabolites may in theory decrease serum estrogen levels, although this action has not been demonstrated in the lit¬erature. This effect may be enhanced by the association of lignan-containing foods with higher levels of sex hormone-binding globulin. As a weak estrogen agonist, ENL may competitively inhibit and decrease the effect of endoge¬nous estrogen on the estrogen receptor and target tissues, in theory providing some protection against breast cancer.
The available evidence does not support the use of flaxseed for the management of hot flashes in women at risk of or surviving breast cancer; however, there is a need for further investigations assessing higher dosages of flax or flax lignans in a controlled manner. Although improvements in hot flash scores were seen in the 2 trials included for review, effects could not be distinguished from that of placebo. Observational data suggest that flaxseed may be protective against breast cancer, with intakes of ¼ cup (32 g ground flaxseed) or approximately 160 mg SDG demonstrating the strongest can¬cer protective effects thus far. Biomarker studies in breast cancer patients indicate increased tumor cell apoptosis, decreased HER-2 expression, decreased tumor cell prolifera¬tion, and anti-angiogenic activity in vivo at doses between 25 g ground flax or 50 mg SDG per day. Additional studies spe¬cifically assessing flaxseed consumption are needed to accu¬rately ascertain potential effects. Evidence pertaining to the metabolites that may be derived from flaxseed implies a pro¬tective effect, particularly in postmenopausal women. Animal data point to broad, anticancer effects of flaxseed as an inter¬vention, but should be interpreted with caution until they can be corroborated by evidence in humans. Information pertain¬ing to potential drug interactions is incomplete but current literature does not suggest negative effects. Current evidence suggests that flax consumption may decrease risk of breast cancer development and may exert antitumor effects in women with breast cancer when used at doses of 25 g ground flaxseed or 50 mg SDG per day. (Editors comments)