FLAX

Flaxseed, not oil, and flaxbread are concentrated sources of lignans, plant based estrogens, which are digested, or metabolized, to enterolactone. Crushed or milled seeds increase absorption, and can be a simple way to get daily amounts into the diet. Studies are primarily in breast and prostate cancers, due to the plant based estrogen effects of lignans

Case control studies compare outcomes for higher vs lower dietary lignan consumption, or the resulting levels of enterolactone. The number of studies are limited, but consistently find significantly reduced relative risk levels in the post-diagnostic period. Often 25 to 30% improvements in relative overall surival, both breast cancer related and any-cause mortality. And for postmenopausal women especially ER- , this can be 50 to 70%. (see Examples)

Pilot studies show some evidence of reducing markers of cell proliferation levels, including reducing pre-cancer activity levels in high risk breast cancer cases.  The effects, in one study, are partly linked to reduced inflammatory marker c-reactive proteins ( See Highlights). Some of which relies on overall lignan consumption from all sources. Older research reported increased risk of breast cancer incidence in pre-menopausal women, which more recent studies have reversed.

Population or case controlled meta-analysis link higher pre-diagnostic dietary levels to lower incidence rates in breast cancer (see Examples). Studies show beneficial effects in vascular health through reduced blood pressure, and some anti-inflammatory actions in various auto-immune conditions including kidney protective. Evidence for anti-metastatic actions is limited, some reports highlight reduced VCAM-1 markers as proof of lower platelet adhesion.

Flax seeds can interact with hormones like estrogen, always seek qualified medical advice.

EXAMPLES OF IMPROVED OUTCOMES

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ANALYSIS

PRE-DIAGNOSIS OR PREVENTION

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ANALYSIS

Highlighted Studies

Stratification by menopause status showed that the risk reductions remained significant only for the postmenopause subgroup (HR = 0.66) [i.e 34% relative risk reduction] Both the estrogen receptor–positive (HR = 0.75) and estrogen receptor–negative (HR = 0.55) subgroups showed nonsignificant risk reductions. For all-cause mortality, stratification by nodal status showed that the risk reduction remained significant for node-negative cancer only (HR = 0.41)

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Among postmenopausal women only, those in the highest versus lowest quartile of lignan intakes had a statistically significant reduction in the risk of all cause mortality (HR 0.49, 95% CI 0.26–0.91) and a significantly reduced risk of breast cancer mortality (HR 0.29) [hazard ratio]. Higher intakes of dried beans (HR 0.61), but not fruits, vegetables, or grains, were also weakly associated with overall mortality. In summary, our results suggest that higher lignan intakes may be associated ...

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Higher serum enterolactone levels were associated with significantly reduced hazard ratios (HR per 10 nmol/L increment, HR for the highest quartile, 0.58; 95% CI, 0.34 to 0.99). For distant disease, HR was 0.94 per 10 nmol/L increment and 0.62 for the highest quartile. The highest quartile of serum enterolactone was associated with a significantly reduced risk of mortality only for estrogen receptor–negative tumors (HR, 0.27) but not for estrogen receptor–positive tumors (HR, 0.91)..Postm...

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The average duration on the diet was 34 days, during which time significant decreases were observed in total serum cholesterol, total testosterone , and free androgen index ..baseline and follow-up levels of prostate-specific antigen were 8.1 ± 5.2 ng/mL and 8.5 ± 7.7 ng/mL, respectively, for the entire sample ; however, among men with Gleason sums of 6 or less (n = 19), the PSA values were 7.1 ± 3.9 ng/mL and 6.4 ± 4.1 ng/mL (P = 0.10). The mean proliferation index was 7.4 ± 7....

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TABLE OF REFERENCES

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https://academic.oup.com/jncics/article/8/1/pkad104/7468128?login=false5Meta-analysisStratification by menopause status showed that the risk reductions remained significant only for the postmenopause subgroup (HR = 0.66, 95% CI = 0.53 to 0.84; I2 = 0%; P = .49 for heterogeneity and HR = 0.65, 95% CI = 0.51 to 0.82; I2 = 22.7%; P = .27 for heterogeneity, respectively). Both the estrogen receptor–positive (HR = 0.75, 95% CI = 0.56 to 1.00; I2 = 0%; P = .93 for heterogeneity) and estrogen receptor–negative (HR = 0.55, 95% CI = 0.28 to 1.08; I2 = 36.1%; P = .21 for heterogeneity) subgroups showed nonsignificant risk reductions. For all-cause mortality, stratification by nodal status showed that the risk reduction remained significant for node-negative cancer only (HR = 0.41The highest mean lignan intake in the included studies was 9 mg/day or higher. Significant risk reductions were found for prediagnostic and early postdiagnostic serum and/or plasma ENL with breast cancer–specific (28%) and all-cause (31%) mortality for both time frames, particularly for postmenopausal women (34% and 35%, respectively). For all-cause mortality, there was a 59% reduction for node-negative disease. The greatest risk reduction for mortality outcomes was at the highest serum and/or plasma ENL levels, (80 ng/L).
https://pmc.ncbi.nlm.nih.gov/articles/PMC2883619/4Meta-analysisAmong postmenopausal women only, those in the highest versus lowest quartile of lignan intakes had a statistically significant reduction in the risk of all cause mortality (HR 0.49, 95% CI 0.26–0.91) and a significantly reduced risk of breast cancer mortality (HR 0.29, 95% CI 0.11–0.76). Higher intakes of dried beans (HR 0.61, 95% CI 0.36–1.03), but not fruits, vegetables, or grains, were also weakly associated with overall mortality. In summary, our results suggest that higher lignan intakes may be associated with improved survival among postmenopausal women with breast cancer.In conclusion, this is, to our knowledge, the first report of inverse associations between dietary lignan intakes and mortality among women after a diagnosis of breast cancer. Our results further suggest that, although higher lignan intakes may be a marker of a diet high in plant foods, specific combinations of foods particularly high in lignans may be necessary to produce effects on mortality-related risk factors to subsequently impact survival.
https://ascopubs.org/doi/10.1200/JCO.2011.34.64784Meta-analysisHigher serum enterolactone levels were associated with significantly reduced hazard ratios (HRs) (HR per 10 nmol/L increment, 0.94; P = .04; HR for the highest quartile, 0.58; 95% CI, 0.34 to 0.99). For distant disease, HR was 0.94 per 10 nmol/L increment (P = .08) and 0.62 (95% CI, 0.35 to 1.09) for the highest quartile. The highest quartile of serum enterolactone was associated with a significantly reduced risk of death only for estrogen receptor–negative tumors (HR, 0.27; 95% CI, 0.08 to 0.87) but not for estrogen receptor–positive tumors (HR, 0.91; In conclusion, this is the first study showing that postdiagnostic enterolactone levels may be related to better survival after postmenopausal breast cancer. Further investigations in large prospective cohorts of patients with breast cancer are required to confirm our findings and to assess potential effect heterogeneity by ER status, adjuvant hormone therapy use, or genetic variants in the metabolism and biosynthesis of sex hormones.
https://aacrjournals.org/clincancerres/article/11/10/3828/186001/Dietary-Flaxseed-Alters-Tumor-Biological-Markers3.5Human studyThe results of this clinical trial are in agreement with previous clinical and preclinical studies showing antitumor effects of flaxseed in prostate cancer patients , carcinogen-treated rats , athymic mice with established ER-positive, or ER-negative breast cancers, and tumor-bearing transgenic mice. The 5% or 10% flaxseed diet used in the animal studies is approximately equivalent to 25 to 30 g of flaxseed given to patients with breast or prostate cancer, depending on the amount of other foods consumed. Our results are also in line with epidemiologic studies showing that high levels of lignan intake, plasma or urinary excretion of mammalian lignans or high levels of α-linolenic acid in adipose tissues are associated with a reduced risk of breast cancer.Its excellent tolerability, however, may make flaxseed particularly attractive for studies in breast cancer prevention, where healthy women should be offered well-tolerated interventions for long-term use. The interaction of flaxseed and its lignan and oil components with other hormonally active agents also needs to be addressed in the future. If the therapeutic index seen in this short-term study can be sustained over a long-term period, flaxseed, which is inexpensive and readily available, may be a potential dietary alternative or adjunct to currently used breast cancer drugs.
https://www.goldjournal.net/article/S0090-4295(01)01014-7/abstract3.5Human studyThe average duration on the diet was 34 days (range 21 to 77), during which time significant decreases were observed in total serum cholesterol (201 ± 39 mg/dL to 174 ± 42 mg/dL), total testosterone (422 ± 122 ng/dL to 360 ± 128 ng/dL), and free androgen index (36.3% ± 18.9% to 29.3% ± 16.8%) (all P <0.05). The baseline and follow-up levels of prostate-specific antigen were 8.1 ± 5.2 ng/mL and 8.5 ± 7.7 ng/mL, respectively, for the entire sample (P = 0.58); however, among men with Gleason sums of 6 or less (n = 19), the PSA values were 7.1 ± 3.9 ng/mL and 6.4 ± 4.1 ng/mL (P = 0.10). The mean proliferation index was 7.4 ± 7.8 for the historic controls versus 5.0 ± 4.9 for the diet-treated patientsThe distribution of the apoptotic indexes differed significantly (P = 0.01) between groups, with most historic controls exhibiting TUNEL categorical scores of 0; diet-treated patients largely exhibited scores of 1. Both the proliferation rate and apoptosis were significantly associated with the number of days on the diet ... These pilot data suggest that a flaxseed-supplemented, fat-restricted diet may affect prostate cancer biology and associated biomarkers. Further study is needed to determine the benefit of this dietary regimen as either a complementary or preventive therapy.
https://pmc.ncbi.nlm.nih.gov/articles/PMC3624628/3.5Human studyProstate cancer is unique in that most cases will remain indolent, while only some will become virulent. Therefore, some men will choose active surveillance rather than more aggressive treatment. Flaxseed supplementation has yet to be tested in men who choose active surveillance, but based on our findings that it is safe, inexpensive, easy to obtain, and its metabolic products reduce cell proliferation, flaxseed supplementation may present an opportunity for future chemopreventive research. Additional studies using flaxseed supplementation in this unique patient population are therefore warranted. In conclusion, this study provides direct evidence that dietary intake of plant lignans via flaxseed supplementation inhibits cancer cell growth and possibly reduces tumor angiogenesis in patients with prostate cancer.In this study, we observed that the total enterolignans and enterolactone were associated with the antiproliferative effects in the target tissue, as indicated by a significant inverse correlation between these plant lignan metabolites and Ki67 staining in prostate tumor tissue. The magnitude of these associations ranged from modest to moderate in significance. There also was a suggestion that higher enterolactone was associated with hindered tumor angiogenesis by lower tumor expression of VEGF. Conversely, we observed no association between enterolignans and reduced activation of inflammatory pathways in the prostate as manifested by NFκB activity, a finding consistent with a study by Heymach et al.21 Therefore, these study findings support that enterolignans, and specifically enterolactone, are likely to exert chemoprotective effects by hindering cell proliferation and possibly reduced tumor angiogenesis.
https://www.frontiersin.org/articles/10.3389/fnut.2018.00004/full3Meta-analysisThe majority of experimental studies conducted showed that flaxseed increases or maintains tamoxifen’s efficacy on the decrease of tumor growth on cell proliferation and on the increase of apoptosis. It is however necessary to conduct more clinical trials to confirm the association and respective efficacy of flaxseed with tamoxifen. In several experimental studies, diets including 5 or 10% of flaxseed (approximately 25–30 g of flaxseed daily, in humans) inhibited the growth of the ER+ in human breast cancer cells injected in mice. The same happened with the growth of the ER−. Flaxseed also reduced the metastasis of ER− breast tumor.During clinical trials, researchers have concluded that flaxseed has the potential to reduce the growth of tumors in patients with breast cancer, mainly postmenopausal women, and decrease the risk of this type of cancer. Although many of the studies reported in this paper concluded that flaxseed intake may be related to the decreased risk of breast cancer and also to the reduction of the tumor’s growth and size, some studies including premenopausal and postmenopausal women did not show the same results.
https://aacrjournals.org/cebp/article/17/11/3241/66980/Enterolactone-Is-Differently-Associated-with3Meta-analysisDietary fiber, as well as fruits and berries, and high-fiber bread showed statistically significant correlations with enterolactone (r, 0.13-0.22). Smoking and obesity were associated with lower enterolactone concentrations. Enterolactone concentrations above the median (16 nmol/L) were associated with reduced breast cancer risk when compared with those below [odds ratio, 0.75; 95% confidence interval (95% CI), 0.58-0.98]. The reduced risk was only observed for ERα [positive (+); odds ratio, 0.73; 95% CI, 0.55-0.97] and ERβ [negative (−)] tumors (odds ratio, 0.60; 95% CI, 0.42-0.84), with significantly different risks for ERβ (−) and ERβ (+) tumorsIn conclusion, enterolactone is positively correlated to a high-fiber diet, and this study supports other studies suggesting that enterolactone is a marker of a healthy lifestyle. The protective association between enterolactone and breast cancer is more evident in tumors that express ERα but not ERβ. Thus, fiber-rich diets and lifestyles linked to high levels of enterolactone are associated with lower risk for tumors [that is, ERα (+)] that are common in industrialized countries of today, especially when the antagonistic influence of ERβ is absent. The findings will need to be confirmed by other studies, especially the associations observed between enterolactone and breast cancer risk among ERβ (−) tumors.
https://pubmed.ncbi.nlm.nih.gov/16679865/3Meta-analysisMedian plasma enterolactone concentrations in cases and controls were 6.3 and 9.7 nmol/l, respectively, and median genistein concentrations were 4.5 and 3.7 nmol/l, respectively. Premenopausal breast cancer risk decreased with increasing plasma enterolactone concentrations. Adjusted odds ratios (95% confidence intervals) were 0.42 (0.20–0.90) and 0.38 (0.17–0.85) (P for trend 0.007) for women in the third and fourth quartile of plasma enterolactone compared to those in the lowest quartile. There was no significant association between plasma genistein concentration and premenopausal breast cancer risk.Using biomarkers of phytoestrogen intake, we confirmed the strong inverse association between enterolactone and premenopausal breast cancer risk as found with dietary intake estimates. This result gives support to the potential role of mammalian lignans for breast cancer prevention among premenopausal women in Western populations.
https://pubmed.ncbi.nlm.nih.gov/21340481/3Meta-analysisDuring a median of 10 years after breast cancer diagnosis, 111 women died (80 from breast cancer). When comparing women with enterolactone levels above the median (>20.5 nmol/l) to those with lower levels, decreased hazard rates (HR) were seen for both all-cause mortality (HR: 0.47; 95% confidence interval: 0.32-0.68) and breast cancer mortality (HR: 0.56; 95% confidence interval: 0.36-0.87). Higher prediagnostic plasma levels of enterolactone were found related to lower mortality among breast cancer patients. . Compared to women that died during the follow-up 193 period, women alive by 31/12 2008 seemed to have higher plasma levels of enterolactone at 194 baseline, more often have low (grade I) than high (grade III) tumor grade, more often be diagnosed 195 with an estrogen receptor positive tumor, were more often HRT users at baseline, had a smaller 196 tumor and were more likely to be free of positive lymph nodes at diagnosis. No clear differences 197 were seen for age at diagnosis, alcohol intake, BMI, or length of school education.
https://www.nature.com/articles/66041752.5Meta-analysisAmong the 51 823 postmenopausal women in the Swedish Mammography Cohort, we investigated breast cancer risk in relation to the FFQ-based estimated lignan intake by oestrogen receptor (ER) and progesterone receptor (PR) subtypes. A significant 17% risk reduction for breast cancer overall in the high lignan quartile was observed, especially among PMH user, but no heterogeneity across ER/PR subtypes.Overall, we observed a statistically significant inverse association between lignan intake and breast cancer risk . Compared to women in the lowest quartile (<712 μg day−1), the multivariable adjusted relative risks (RR) for the highest quartile (⩾1036 μg day−1) were 0.83 ) for overall, 0.86 for ER+PR+, 0.77 for ER+PR−, 0.92 for ER−PR−. There was no evidence for heterogeneity in the results between the ER+PR+ and other subtypes
https://link.springer.com/article/10.1007/s10552-013-0155-72.5Human studyFlaxseed or flax bread was consumed at least weekly by 21 % of women... flaxseed was associated with a significant reduction in breast cancer risk (odds ratio (OR) = 0.82), as was consumption of flax bread OR = 0.77 5 points better]This Canadian study is, to our knowledge, the first to report on the association between flaxseed alone and breast cancer risk and has found that flaxseed intake is associated with a reduction in breast cancer risk. As dietary intake of flaxseed is modifiable, this finding may be of public health importance with respect to breast cancer prevention.
https://onlinelibrary.wiley.com/doi/10.1002/ijc.316472.5Meta-analysisENL concentrations were significantly inversely associated with ACM, BCSM and DDFS (per doubling of ENL concentrations: HRs 0.93 [0.87, 0.99], 0.91 [0.84, 0.99] and 0.92 [0.87, 0.99]), after adjusting for prognostic factors and BMI. Estimated 18, 14 and 12% of the effects of ENL on ACM, BCSM and DDFS, respectively, were mediated through CRP. No mediational effect of IL-10 was found. We provide first evidence that the proinflammatory marker CRP may partially mediate the association of ENL with postmenopausal breast cancer survival, which supports hormone-independent mechanisms.There is growing evidence that lignan exposure improves postmenopausal breast cancer survival. Both hormone-dependent and -independent effects have been postulated as underlying biological mechanisms, but these still have to be fully elucidated. Using data from 1,743 postmenopausal breast cancer patients, here the authors provide first evidence that the protective effects of lignans (measured as the major metabolite enterolactone) on breast cancer survival may be partially mediated by the inflammatory marker C-reactive protein, which supports the involvement of hormone-independent mechanisms
https://journals.sagepub.com/doi/10.1177/15347354135020762.5Observational 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 cancer protective effects thus far. Biomarker studies in breast cancer patients indicate increased tumor cell apoptosis, decreased HER-2 expression, decreased tumor cell proliferation, and anti-angiogenic activity in vivo at doses between 25 g ground flax or 50 mg SDG per day. Additional studies specifically assessing flaxseed consumption are needed to accurately ascertain potential effects. Evidence pertaining to the metabolites that may be derived from flaxseed implies a protective effect, particularly in postmenopausal women.
https://www.cambridge.org/core/journals/british-journal-of-nutrition/article/dietary-flaxseed-lignan-extract-lowers-plasma-cholesterol-and-glucose-concentrations-in-hypercholesterolaemic-subjects/EBD7101B3AD73A68DDDA08D670FF996C2Human studySignificant treatment effects were achieved (P < 0·05 to < 0·001) for the decrease of total cholesterol (TC), LDL-cholesterol (LDL-C) and glucose concentrations, as well as their percentage decrease from baseline. At weeks 6 and 8 in the 600 mg SDG group, the decreases of TC and LDL-C concentrations were in the range from 22·0 to 24·38 % respectively (all P < 0·005 compared with placebo). For the 300 mg SDG group, only significant differences from baseline were observed for decreases of TC and LDL-C. A substantial effect on lowering concentrations of fasting plasma glucose was also noted in the 600 mg SDG group at weeks 6 and 8, especially in the subjects with baseline glucose concentrations ≥ 5·83 mmol/l (lowered 25·56 and 24·96 %; P = 0·015 and P = 0·012 compared with placebo, respectively). Plasma concentrations of secoisolariciresinol (SECO), enterodiol (ED) and enterolactone were all significantly raised in the groups supplemented with flaxseed lignan. The observed cholesterol-lowering values were correlated with the concentrations of plasma SECO and ED (r 0·128–0·302; P < 0·05 to < 0·001). In conclusion, dietary flaxseed lignan extract decreased plasma cholesterol and glucose concentrations in a dose-dependent manner.. Based on limited publications relevant to this subject(Reference Cunnane, Hamadeh, Liede, Thompson, Wolever and Jenkins33–Reference Cunnane, Ganguli, Menard, Liede, Hamadeh, Chen, Wolever and Jenkins35), we did expect that the flaxseed extract or lignan may have some favourable effect on fasting blood glucose. A dietary flaxseed study by Lemay et al. (Reference Lemay, Dodin, Kadri, Jacques and Forest34) reported that 40 g crushed flaxseed/d consumed over 2 months significantly lowered fasting glucose concentration by 5·3 % from pretreatment levels in twenty-five menopausal women. Two previous publications(Reference Cunnane, Hamadeh, Liede, Thompson, Wolever and Jenkins33, Reference Cunnane, Ganguli, Menard, Liede, Hamadeh, Chen, Wolever and Jenkins35) reported that dietary flaxseed could decrease postprandial blood glucose response by 27 % and increase glucose tolerance after a glucose load in young healthy subjects (area under the curve of glucose level increment was 73 mmol/l × 90 min with a flaxseed diet and 92 mmol/l × 90 min with a control diet.). In the present study, the mechanism for the observed dose-dependent lowering effect on fasting blood glucose concentrations deserves to be further explored. Nevertheless, its clinical significance is important, particularly in those subjects with higher baseline glucose concentrations ( ≥ 5·83 mmol/l or 1050 mg/l).

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