Just the Flax – Lignans and Postmenopausal Breast Cancer
Abstract & Commentary
By Russell H. Greenfield, MD, Editor
Synopsis: In a case-control study using a biomarker for lignan intake, women with breast cancer who had higher levels of the biomarker post-diagnosis had a reduced risk of mortality over a median follow-up period of 6 years compared to women with low levels of the biomarker.
Source: Buck K, et al. Serum enterolactone and prognosis of postmenopausal breast cancer. J Clin Oncol 2011;29:3730-3738.
Estrogenic compounds called lignans are found in a variety of vegetables, fruits, seeds, and grains, and may possess both estrogen-dependent and estrogen-independent anticancer activity. The authors of this population-based case-control study sought to evaluate the relationship between post-diagnostic serum levels of enterolactone, the primary metabolite of dietary lignans and thus a biomarker of dietary lignan intake, and both distant disease-free survival (DDFS) and overall survival (OS) in postmenopausal women with breast cancer.
The study sample was made up of German women aged 50-74 years (mean age 63 years) with histologically confirmed primary invasive (stages I to IV) or in situ breast cancer diagnosed between 2002-2005 (n = 1,140). Personal interviews were conducted at baseline to collect demographic and other information, including possible risk and prognostic factors. At the same visit, non-fasting blood samples were obtained for measurement of enterolactone levels. The median time between breast cancer diagnosis and blood collection was 101 days (range 2 to 1,112 days; standard deviation, 179 days). The first 160 blood samples were measured in duplicate to assure minimal variation in results.
A subject's vital status through the end of 2009 was ascertained via local population registries. Data regarding development of cancer recurrence and secondary tumors were collected via self-report during follow-up telephone interviews conducted in 2009, or through clinical records and attending physicians, or both. Endpoints of interest were DDFS and OS. Only patients with early-stage disease (stages 0 to IIIA) were included in the analysis of DDFS.
Analyses were stratified by age at diagnosis (in 1-year categories). Multivariate analyses were adjusted for traditional prognostic factors including tumor size, node status, metastatic spread, grade, and ER/PR status. Body mass index, mode of tumor detection (self-examination vs. routine screening mammography, for example), history of hormone replacement therapy, diabetes, and leisure time physical activity since the age of 50 years were accounted for in the final multivariate models.
The overall median enterolactone level was 20.8 nmol/L (interquartile range, 34.6 nmol/L), with levels differing significantly between participants who had died (median, 17.0 nmol/L) and those who were still alive (median, 21.4 nmol/L; P = 0.04). High enterolactone levels were associated with tumors that were smaller, lower grade, hormone receptor-positive, and physician-detected compared with participants with lower enterolactone levels. Those with high enterolactone levels were more likely to have used hormone replacement therapy, not to have received chemotherapy, have a lower BMI, and have a never/past smoking history.
During a median follow-up time of 6.1 years after diagnosis (range, 0.2 to 7.7 years), 162 deaths occurred in the sample, 124 (76.5%) of which were from breast cancer. In the 962 patients with early-stage disease included for the DDFS analysis, 124 distant recurrences or deaths occurred. Higher serum enterolactone levels were associated with a significantly reduced hazard ratio (HR) for overall mortality (multivariate HR per 10 nmol/L increment, 0.94; 95% confidence interval [CI], 0.88-1.00; P = 0.04). The highest vs the lowest enterolactone quartile was associated with a significantly reduced risk for death (multivariate HR, 0.58; 95% CI, 0.34 to 0.99). Serum enterolactone level also was associated with a non-statistically significant reduction in HR for distant disease (multivariate HR, 0.94; 95% CI, 0.87-1.01; P = 0.08 per 10 nmol/L increment and 0.62; 95% CI, 0.35-1.09 for the highest quartile).
In the subgroup of 902 early-stage (stages I to IIIA) patients with breast cancer who receive standardized adjuvant treatment, the HR for death associated with highest vs lowest enterolactone levels was not substantially different compared with that for the total population (P for heterogeneity = 0.94), but the finding did not achieve statistical significance (multivariate HR, 0.95; 95% CI, 0.88-1.02 per 10 nmol/L increment and HR, 0.56; 95% CI, 0.27-1.14 for the highest quartile).
The association between enterolactone and overall mortality was not significantly heterogeneous for time between diagnosis and blood collection below or above the median, with HRs for death for the highest compared with the lowest quartile of 0.60 (95% CI, 0.27-1.32) and 0.59 (95% CI, 0.26 to 1.34), respectively (P for heterogeneity = 0.98). Significant heterogeneity was not found between the 827 subjects who did not receive chemotherapy or with blood collected before chemotherapy (73%) and patients with blood collected after the start of chemotherapy (multivariate HR, 0.56; 95% CI, 0.25-1.25 and HR, 0.38; 95% CI, 0.16-0.90 for the highest quartile; P for heterogeneity = 0.57). Looking at ER/PR status, the association between enterolactone level and overall mortality was statistically significant only for ER-negative tumors in the highest compared with the lowest quartile (HR, 0.27; 95% CI, 0.08-0.87). Effect heterogeneity by tumor size or by grade was also not observed.
The researchers concluded that postmenopausal patients with breast cancer who have high post-diagnostic serum enterolactone levels may have improved survival.
Once ingested as food, lignans are metabolized by the gut microbiota to enterolignans and subsequently absorbed. They have features in common with estrogens and can bind to estrogen receptors, thus blocking the body's estrogen from interacting with those same receptors. In this way, lignans potentially could confer a cancer protective effect. In addition, animal data suggest non-estrogen dependent inhibition of tumor growth and spread. A number of human studies have suggested a beneficial role for lignans in the setting of ER negative breast cancer.
The current study measured enterolactone levels as a biomarker of lignan ingestion and metabolism, thereby avoiding the pitfalls of recall bias inherent with dietary questionnaires; however, levels were obtained only once and only after the diagnosis of breast cancer had been made. Results speak only to the degree of short-term lignan intake, and the study authors state their results may not reflect enterolactone levels pre-diagnosis.
A very good commentary found in the same edition of the journal1 cautions that it is far too early to jump on the flaxseed wagon with respect to women with breast cancer (flaxseeds contain a high concentration of lignans). The author notes that many variables have yet to be fleshed out, including the bioavailability of lignans from different food sources, and the impact of changes in the colonic microenvironment on lignan metabolism. Plus, we are discussing a phytoestrogen, and there is much that needs to be better understood about the activity of different plant-based estrogens in the body. In addition, the data discussed here are observational in nature.
Keeping all this in mind, however, any intervention that might provide a 40% reduction in risk of death, as found in this study, should get people's attention and be re-examined as soon as possible.
Adding a tablespoon of ground flaxseed to one's cereal, smoothie, or salad has long been a general health recommendation proffered by some health care practitioners, and may be a reasonable option for women who have been diagnosed with breast cancer, especially ER negative breast cancer. But ingesting lignans as part of a healthy diet is very different from the taking of supplemental lignans, and the latter cannot be supported on the basis of this study's findings alone.
1. Patterson RE. Flaxseed and breast cancer: What should we tell our patients? J Clin Oncol 2011;299:3723-3724.