Flaxseed and breast cancer: what should we tell our patients?

In the United States alone, there are approximately 2.6 million survivors of breast cancer. This population is highly motivated to initiate lifestyle changes in diet and exercise to improve their prognosis. Dietary lignans have been identified as potentially protective against breast cancer via estrogen-dependent and independent anticarcinogenic activity. Lignans are bioactive, non-nutrient, noncaloric phenolic plant compounds that are found in large amounts in flaxseeds and sesame seeds and in small amounts in whole grains, legumes, and certain fruits and vegetables (Table 1). For example, one half cup of whole wheat meal is estimated to provide approximately 325 g lignans, whereas one half cup of flaxseed provides approximately 275,000 g lignans. In humans, lignans are metabolized by the gut microflora into enterolignans; enterolactone is the main metabolite. Therefore, enterolactone concentrations in serum, plasma, and urine have been used as biomarkers of dietary lignans. The article by Buck et al that accompanies this editorial investigates the association of enterolactone with breast cancer outcomes. Specifically, the authors found that among 1,140 patients with breast cancer who were postmenopausal, serum enterolactone concentrations in the highest quartile were associated with an approximate 40% reduced risk of overall mortality (hazard ratio, 0.58; 95% CI, 0.34 to 0.99) and distant disease (hazard ratio, 0.62; 95% CI, 0.35 to 1.09). Although this is the first such study in survivors of breast cancer, these findings are supported by a recent meta-analysis that indicates that enterolactone biomarkers are associated with a statistically significant 28% reduced risk of incident breast cancer. The use of serum enterolactone as an exposure measure offers many advantages in comparison with assessment of dietary intake. Use of a biomarker eliminates the considerable error and bias in dietary self-reporting. In addition, this biomarker bypasses numerous problems that are associated with establishing the lignan content of foods, which can vary substantially within a food according to variety, crop season, location, and processing methods. Finally, the reliability coefficient for serum enterolactone is 0.55, which suggests that this measure provides a reasonably robust estimate of usual exposure. Given this objective evidence that a biomarker of lignan intake improves breast cancer outcomes, should we declare success and recommend that our patients with breast cancer supplement their diet with flaxseed? When considering the study by Buck et al, it is instructive (and sobering) to recall the demise of the carotenoid hypothesis regarding -carotene and chemoprevention of lung cancers. In the 1980s, there was considerable epidemiologic evidence that higher dietary intake of fruits and vegetables and blood levels of -carotene (a marker of fruit and vegetable intake) were associated with a lower risk of epithelial cancers. These epidemiologic studies were bolstered by laboratory research that identified several plausible biologic mechanisms by which -carotene could act to reduce tumor incidence. In response, two large trials were launched to test the effect of -carotene supplements on lung cancer incidence in high-risk populations (eg, smokers). Unexpectedly, both trials found that -carotene supplementation increased the incidence of lung cancers as well as cardiovascular and all-cause mortality. A subsequent review of randomized trials of antioxidant supplements, including 25 trials of -carotene, concluded that use of this supplement increased overall mortality by 7% (relative risk, 1.07; 95% CI, 1.02 to 1.11). These findings reversed the trend toward widespread use of -carotene supplements and fortification of common foods with this compound and likely resulted in many lives saved. A striking observation in both of these trials was that higher baseline serum -carotene concentrations were strongly associated with a reduced risk of lung cancer, although supplementation with -carotene in this same population increased the risk of lung cancer. A number of interpretations of these apparently paradoxical findings have been put forward. For example, it is possible that the physiological effects of relatively low blood concentrations of compounds (such as -carotene or enterolactone) obtained from a mixed diet do not predict the effect of high-dose supplementation, particularly in an Table 1. Major Food Sources of Lignans