FROM: JAMA 2009 (Dec 9); 302 (22): 2437–2443 ~ FULL TEXT
Xiao Ou Shu, MD, PhD; Ying Zheng, MD, MSc; Hui Cai, MD, PhD; Kai Gu, MD;
Zhi Chen, MD, PhD; Wei Zheng, MD, PhD; Wei Lu, MD, PhD
Department of Medicine,
Vanderbilt Epidemiology Center,
2525 West End Ave, Ste 600,
Nashville, TN 37203-1738, USA.
Context Soy foods are rich in isoflavones, a major group of phytoestrogens that have been hypothesized to reduce the risk of breast cancer. However, the estrogen-like effect of isoflavones and the potential interaction between isoflavones and tamoxifen have led to concern about soy food consumption among breast cancer patients.
Objective To evaluate the association of soy food intake after diagnosis of breast cancer with total mortality and cancer recurrence.
Design, Setting, and Participants The Shanghai Breast Cancer Survival Study, a large, population-based cohort study of 5042 female breast cancer survivors in China. Women aged 20 to 75 years with diagnoses between March 2002 and April 2006 were recruited and followed up through June 2009. Information on cancer diagnosis and treatment, lifestyle exposures after cancer diagnosis, and disease progression was collected at approximately 6 months after cancer diagnosis and was reassessed at 3 follow-up interviews conducted at 18, 36, and 60 months after diagnosis. Annual record linkage with the Shanghai Vital Statistics Registry database was carried out to obtain survival information for participants who were lost to follow-up. Medical charts were reviewed to verify disease and treatment information.
Main Outcome Measures Total mortality and breast cancer recurrence or breast cancer–related deaths. Cox regression analysis was carried out with adjustment for known clinical predictors and other lifestyle factors. Soy food intake was treated as a time-dependent variable.
Results During the median follow-up of 3.9 years (range, 0.5–6.2 years), 444 deaths and 534 recurrences or breast cancer–related deaths were documented in 5033 surgically treated breast cancer patients. Soy food intake, as measured by either soy protein or soy isoflavone intake, was inversely associated with mortality and recurrence. The hazard ratio associated with the highest quartile of soy protein intake was 0.71 (95% confidence interval [CI], 0.54–0.92) for total mortality and 0.68 (95% CI, 0.54–0.87) for recurrence compared with the lowest quartile of intake. The multivariate-adjusted 4–year mortality rates were 10.3% and 7.4%, and the 4–year recurrence rates were 11.2% and 8.0%, respectively, for women in the lowest and highest quartiles of soy protein intake. The inverse association was evident among women with either estrogen receptor–positive or –negative breast cancer and was present in both users and non-users of tamoxifen.
Conclusion Among women with breast cancer, soy food consumption was significantly associated with decreased risk of death and recurrence.
From the Full-Text Article:
Estrogen is believed to play a central role in breast cancer development and progression. Blocking the effect of estrogen, either by inhibiting estrogen action or by reducing estrogen production, has been widely used in breast cancer treatment as an adjuvant therapy.  Soy foods are rich in phytoestrogens, mainly in the form of isoflavones, which are natural estrogen receptor modulators that possess both estrogen-like and anti-estrogenic properties. Soy constituents have also been shown to have other anti-cancer effects, including the inhibition of DNA topoisomerase I and II, proteases, tyrosine kinases, inositol phosphate, angiogenesis may also boost immune response, and possess antioxidative effects. [2, 3] Consumption of soy food has been inversely related to the risk of breast cancer in many epidemiological studies. [4–6] On the other hand, genistein, a major form of isoflavone, has been shown to enhance the proliferation of breast cancer cells in vitro and to promote estrogen-dependent mammary tumor growth in overiectomized rats. [3, 7] In addition, breast cancer treatments often lead to a decrease in the endogenous estrogen supply of survivors, and a concern has been raised as to whether soy isoflavones may exert their estrogenic effects, promote cancer recurrence, and thus negatively influence overall survival. [7, 8] Furthermore, both in vivo and in vitro studies have suggested that soy isoflavones may interact with tamoxifen, although both synergistic and antagonistic interactions have been reported. [3, 10–13] To our knowledge, only one epidemiological study, the Life After Cancer Epidemiology (LACE) study, has evaluated the association of post-diagnosis soy isoflavone intake with cancer recurrence. An inverse association was suggested for postmenopausal women who have used tamoxifen. 
Here, we report on a comprehensive evaluation of the association of soy food consumption after diagnosis with breast cancer prognosis using data from a longitudinal study of 5,042 breast cancer patients, with a particular focus on differences in the association according to the ER status of the cancer and tamoxifen use by patients.
Although soy food consumption among US women is substantially lower than among women in China (the average isoflavone intake among US women is 1–6 mg/day  compared with 47 grams/day in our study population), soy food consumption in the United States has been increasing rapidly. The proportion of people eating soy products at least once per week was 28% in 2003, up from 15% in 1997.  Although soy constituents have been shown to possess anti-cancer properties [1–7] and improve cardiovascular and bone health, [23–25] the estrogen-like effect of soy isoflavones [1, 3, 7, 8] and conflicting data from in vivo and in vitro studies regarding the role of soy constituents in stimulating cell proliferation [3, 7] have raised a concern about the safety of soy food consumption among breast cancer survivors. [7, 8, 26] Because concentrated soy isoflavones are increasingly being added to a wide variety of foods, including beverages, nutrition bars, yogurt, baked goods, meal replacements, and confections, exposure to isoflavones is becoming ubiquitous, which is heightening concern about soy food consumption among the rapidly growing population of breast cancer survivors. In our comprehensive evaluation of soy food consumption and breast cancer outcomes using data from a large, population-based cohort study, we found that soy food intake was inversely associated with mortality and recurrence. The inverse association did not appear to vary by menopausal status and was evident for women with both ER-positive and ER-negative cancer and early and late stage cancer.
Among the many constituents of soy food, soy isoflavones are the most intensively studied phytochemicals for their health-related effects. It has been shown that soy isoflavones compete with endogenous estrogens in the binding of estrogen receptors, increase the synthesis of sex-hormone-binding globulin (thus lowering the biological availability of sex hormones), inhibit 17ß-hydroxysteroid dehydrogenases (thus reducing estrogen synthesis), and increase clearance of steroids from the circulation. [2, 3] These anti-estrogenic effects may be one of the underlying mechanisms through which soy food consumption is associated with better breast cancer outcomes.
We did not find that risk estimates associated with soy isoflavone intake were stronger than risk estimates associated with soy protein intake. This may be due to the fact that measurement errors related to the assessment of isoflavone intake are larger than measurements errors related to soy protein intake. On the other hand, these results may also suggest that other known and unknown constituents of soy foods, such as folate, protein, protease inhibitor, calcium, or fiber, individually or in combination are responsible for the survival benefits of soy food consumption. It has been previously reported in some studies that the health effects of soy supplements and soy isoflavone supplements may differ. For example, soy milk supplements have been found to reduce circulating levels of estrogen, [27–29] while soy isoflavone supplements failed to do so.  Similarly, soy milk or soy protein supplements were found to relieve menopausal symptoms, [31–33] while soy isoflavone supplements showed no effect.  More studies are needed to replicate our findings and to disentangle whether the benefit of soy food consumption on breast cancer prognosis is the result of soy isoflavones or other soy constituents or is the result of a combination of the effects of multiple soy constituents.
In our study population, soy food intake was associated with other characteristics of a healthy lifestyle, including more exercise, high vegetable and fish intake, and low red meat intake. Earlier studies have shown that high vegetable intake may be related to an improved survival rate, although evidence is not entirely consistent. [35–37] We carefully adjusted for other dietary intake and lifestyle factors in our analyses. However, residual confounding resulting from measurement errors or unmeasured lifestyle factors could not be entirely ruled out, which would likely lead to an underestimation of the true association. Another concern is that reverse causation, i.e., poor health and appetite among breast cancer patients who had subclinical relapse, could lead to a reduction of soy food consumption. If this were true, we would expect to see that other dietary intakes were also inversely related to survival. However, in our study, meat consumption was not associated with breast cancer survival, which argues against reverse causation.
Because isoflavones and tamoxifen both bind to estrogen receptors and because of the conflicting results from in vivo and in vitro studies, which have reported both synergetic and antagonistic effects between isoflavones and tamoxifen use, there is a concern that soy isoflavones may affect the efficacy of this widely-used adjuvant treatment for breast cancer. In our study, we found that soy food intake was associated with improved survival regardless of tamoxifen use, while tamoxifen use was only related to improved survival among women who had low or moderate levels of soy isoflavone intake. Tamoxifen was not related to further improvement of survival rates among women who had the highest level of soy isoflavone intake. More importantly, women who had the highest level of soy food intake and who did not take tamoxifen had a lower risk of mortality and a lower recurrence rate than women who had the lowest level of soy food intake and used tamoxifen, suggesting that high soy food intake and tamoxifen use may have a comparable effect on breast cancer outcomes.
Our study is the largest population-based study of breast cancer survival to date and was specifically designed to evaluate the influence of soy food intake on breast cancer outcomes. Soy food intake was assessed using a validated dietary questionnaire and was updated during the course of follow-up. The high response rate and ability to adjust for other lifestyle factors also improved the quality of our study.
However, the follow-up period of our study is still relatively short, which prevented an evaluation of the long-term effects of soy intake on breast cancer outcomes. Continued follow-up of the cohort would overcome this limitation. Our study also has limited statistical power for sub-analyses (e.g. ER status, tamoxifen use status).
In summary, in this population-based prospective study, we found that soy food intake is safe and was associated with lower mortality and recurrence among breast cancer patients. The association of soy food intake with mortality and recurrence appears to follow a linear, dose-response pattern until soy food intake reached 11 grams of soy protein per day; no additional benefits on mortality and recurrence were observed with higher intakes of soy food. This study suggests that moderate soy food intake is safe and potentially beneficial for women with breast cancer.