To our knowledge, this is the first investigation of the association between dietary lignan intakes prior to breast cancer diagnosis and all cause and breast cancer-specific mortality. We found substantially reduced risks of overall mortality, and especially breast cancer mortality, associated with higher lignan intakes in postmenopausal women only. As dried beans and legumes are rich sources of several phytoestrogens, it was not surprising that, in postmenopausal women, there was also a trend toward reduced mortality associated with higher dried bean intakes. On the other hand, the primary sources of lignans in our study were dark bread, peaches, coffee, broccoli, and winter squash, but no associations were observed between vegetables, fruits, and grains and survival. Whereas whole grains are particularly rich in lignans, our food frequency questionnaire asked limited questions concerning whole grain intake (dark bread and hot cereal). It is possible that whole grain intake was underestimated in our sample, or conversely, that intake of these foods was low.
Lignans are the predominant phytoestrogen in Western diets where soy consumption is relatively infrequent. Experimental, animal, and human studies have demonstrated that lignans express activities that could affect survival, in general as well as after a cancer diagnosis. In animal models, lignan supplementation has been shown to reduce tumor growth and metastasis [18
] and to decrease expression of tumor growth factors such as IGF or EGFR [45
]. In human studies of breast and prostate cancer, lignan supplementation decreased tumor cell proliferation as measured by Ki-67 and increased apoptosis [47
]. The antipromotional and antiproliferative activities of lignans could potentially improve survival through reduction of tumor progression and recurrence. In addition to tumor growth inhibition, other potential mechanisms by which lignans might affect survival include antioxidant, anti-estrogen, and other hormonal activities [49
It is unclear why no associations were observed between lignan intakes and mortality among premenopausal women. Breast cancer among premenopausal women tends to be more aggressive, often ER negative, and associated with poorer survival [53
]. Although we have previously shown inverse associations between higher lignan intakes and risk of ER negative premenopausal breast cancer [35
], it is possible that the characteristics of tumor type in this group of women exceeds the capability of lignans to affect tumor growth and metastasis, or that premenopausal breast cancer progresses through pathways that are not affected by mechanisms associated with lignans.
A potential limitation of our study is that we had only one measure of diet prior to breast cancer diagnosis. The women with breast cancer in our study may have changed their diet after diagnosis. However, these changes would most likely be to increase fruit, vegetable, and whole grain intakes, resulting in higher lignan intakes, and our results may be, in fact, somewhat underestimated. On the contrary, women with more advanced disease may have poorer diets because of disease and treatment related lack of appetite, although in these data, there was no association between lignan intakes and stage or ER status (data not shown). Finally, as individual treatment data were unavailable, we were unable to include this variable in our analyses. Although it is possible that women with better diets may have better treatment options, we observed no associations between lignan intakes and income (as a proxy for access to treatment) in these data (data not shown). Replication of these findings in prospective studies of women with breast cancer with repeated measures of diet following diagnosis is needed to confirm our results.
We were also limited in our ability to stratify our analyses by ER status. Although strongly associated with mortality in these data, ER status was not available for approximately 25% of the women. However, inclusion of this variable (coded negative, positive, or missing) in the Cox proportional hazards models had essentially no impact on the hazard ratios. Furthermore, the total number of events in this study was relatively small, and the number of ER negative cancers even smaller. Future investigations in this area involving larger numbers of ER negative cancers are warranted.
To the best of our knowledge, ascertainment of vital status by the National Death Index was very good in our study, although we cannot exclude the possibility of passive loss to follow up. Furthermore, although our follow up was relatively brief (9–125 months), we observed approximately 14% mortality rate, which is reasonably consistent with national rates for breast cancer, but somewhat lower than New York State breast cancer mortality rates (20%) [56
]. In addition, comparisons of descriptive characteristics between women who died with those still living at the end of follow-up identified established risk factors related to mortality suggesting that our sample was reasonable representative of the general population of 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.