A new rat study from Georgetown University provides intriguing findings regarding the effects of genistein on the efficacy of the breast cancer drug tamoxifen. But for breast cancer patients, this study does not clarify whether they should incorporate soyfoods into their diet.
Animal studies are obviously an important component of the scientific literature and often help to generate new hypotheses. But they often fall short of being able to predict human responses. 1,2 In 2004, the Food and Drug Administration estimated that 92% of drugs that pass preclinical tests, including “pivotal” animal tests, fail to proceed to the market.3 Consequently, they are a poor basis for making clinical decisions. Animal studies are near the bottom of the pyramid in the hierarchy of evidence. For this reason, this blog rarely, if ever, cites animal studies as evidence in support of the health effects of soyfoods. Instead, the emphasis is placed on prospective epidemiologic studies and clinical trials.
The research in question was conducted by a team of well-respected investigators who have studied isoflavones and breast cancer in rodents for 20 years. All of the rats in this study were given DMBA at postnatal day (PND) 48 to induce mammary tumors and consumed diets containing genistein at different time periods. In brief, the results showed that in rats who consumed genistein-containing diets early in life (PND 15 to 30), during adulthood (PND 55 to study end) or throughout life (PND 15 to 30 and 55 to end of study), the efficacy of tamoxifen was enhanced in comparison to rats not consuming genistein. In contrast, in rats given genistein only after tumors that had reached a very large size (1.3 cm in diameter), the efficacy of tamoxifen was modestly inhibited.
The authors of this research concluded that “although translation of findings from animal models to humans should always be done with caution, our results suggest that it is beneficial to continue to consume soy foods after diagnosis to reduce tamoxifen resistance and breast cancer recurrence.” There is some evidence from two U.S. prospective epidemiologic studies4,5 to suggest that soy consumption enhances the efficacy of tamoxifen, but the data overall are conflicting and limited.6-8 In fact, a meta-analysis by Chi et al.9of the prospective data “did not identify any good or bad effects on mortality and recurrence for those breast cancer patients who use tamoxifen.” Thus, it isn’t at all clear that the epidemiologic data support the Georgetown results.
It is also known from a cross-sectional study of 380 Asian breast cancer patients who were tamoxifen users that neither isoflavone intake (assessed at two time points) nor serum isoflavone levels were associated with circulating levels of tamoxifen or its metabolites.10 These findings suggest that it is unlikely that soy intake significantly affects internal exposures to tamoxifen and its metabolites although there could be an interaction between isoflavones and tamoxifen in ways that were not assessed.
The finding that raises concern from the Georgetown study is that in rats consuming diets containing genistein only after tumors had already developed, the efficacy of tamoxifen was inhibited. Tumor recurrence wasn’t statistically significantly greater in the post-diagnosis group compared to the controls, but the percentage of tumors that fully responded to tamoxifen was a bit lower in the post-diagnosis group (54 vs. 38%).
It isn’t clear that there are any clinical or epidemiologic data that directly relate to this finding. However, it is possible that the findings from two of the aforementioned prospective studies provide relevant insight.4,5
What is unknown about these two cohorts is when the soy-consumers actually began consuming soy. As these studies utilized a prospective design, women were enrolled into the studies only after a diagnosis of breast cancer and information on soy intake was only assessed thereafter at different time points. No retrospective assessment of soy intake was conducted. But almost certainly women were consuming soy prior to their diagnosis. An interesting question therefore is: “Were these women consuming soy prior to the initiation of their tumors?”
Tumors take many years to go from the initiation to the beginning stages of growth to the point at which they can be detected. It is certainly conceivable that for many women in these cohorts cancer was detected only after tumors were personally palpable.
With the exception of vegetarians, which were relatively few in number, the vast majority of Americans consumed little in the way of soyfoods until the 1990s when its popularity began to markedly increase. It was about this time when women were enrolled into the two U.S. cohorts. So unless they were very unusual, many of these women likely only started consuming soy around the time their cancers had already developed. If this is the case, the data from these two studies conflict from the Georgetown results. That is because in rats, genistein exposure after tumors were developed inhibited the efficacy of the drug, whereas in the prospective studies, efficacy wasn’t inhibited even though it appears many women began consuming soy only after tumors had already developed, although they were undetected. Unfortunately, we can only speculate about this possibility.
It is also worth noting that clinical studies show that isoflavone exposure does not adversely affect breast tissue. Although no clinical trials evaluating the effects of soy or isoflavones on breast cancer recurrence have been conducted, many studies have investigated effects on markers of breast cancer risk including mammographic density11,12 and in vivo breast cell proliferation.13-18 Some of the clinical studies involved women with breast cancer12,15,18 These studies provide no information on a possible interaction with tamoxifen, but they do show that soy is not acting on breast tissue like combination hormone therapy does,19,20 which increases breast cancer risk.21
Finally, the Georgetown study reported that serum genistein concentrations averaged 4.14 umol/l. Presumably, these levels represent steady state conditions. The authors suggest this serum level can be reached in humans by consuming two to four servings of soyfoods daily. However, the single reference cited in support of this statement is the USDA isoflavone database, which only lists the isoflavone content of foods.
More relevant data come from Setchell et al.,22 who reported in 2011 that steady state serum genistein concentrations 3.5 days after consuming 500 ml of soymilk per day that provided approximately 50 mg isoflavones, were only about 0.6 umol/l. Furthermore, rats poorly conjugate isoflavones such that the percentage of total genistein that is unconjugated (the biologically active form) is likely at least 2-3 times higher than the percentage of total genistein that is unconjugated in the serum of humans consuming soyfoods.22 Thus, the rats in the Georgetown study were likely continuously exposed to much more genistein than would be a person consuming a couple of servings of soyfoods per day.
The Georgetown study will likely fuel additional research into the effects of genistein and soyfoods on the efficacy of tamoxifen. But only clinical data can form the basis for definitive recommendations for breast cancer patients and survivors.
- Shanks N, Greek R, Greek J. Are animal models predictive for humans? Philos Ethics Humanit Med. 2009;4:2.
- Akhtar A. The flaws and human harms of animal experimentation. Camb Q Healthc Ethics. 2015;24:407-19.
- Harding A. More compounds failing phase I. The Scientist [Internet]. 2004 Feburary 1, 2017. Available from: http://www.the-scientist.com/?articles.view/articleNo/23003/title/More-compounds-failing-Phase-I.
- Caan BJ, Natarajan L, Parker B, et al. Soy food consumption and breast cancer prognosis. Cancer Epidemiol Biomarkers Prev. 2011;20:854-8.
- Guha N, Kwan ML, Quesenberry CP, Jr., Weltzien EK, Castillo AL, Caan BJ. Soy isoflavones and risk of cancer recurrence in a cohort of breast cancer survivors: the Life After Cancer Epidemiology study. Breast Cancer Res Treat. 2009;118:395-405.
- Shu XO, Zheng Y, Cai H, et al. Soy food intake and breast cancer survival. JAMA. 2009;302:2437-43.
- Kang X, Zhang Q, Wang S, Huang X, Jin S. Effect of soy isoflavones on breast cancer recurrence and death for patients receiving adjuvant endocrine therapy. CMAJ. 2010;182:1857-62.
- Zhang YF, Kang HB, Li BL, Zhang RM. Positive effects of soy isoflavone food on survival of breast cancer patients in China. Asian Pacific journal of cancer prevention : APJCP. 2012;13:479-82.
- Chi F, Wu R, Zeng YC, Xing R, Liu Y, Xu ZG. Post-diagnosis soy food intake and breast cancer survival: A meta-analysis of cohort studies. Asian Pacific journal of cancer prevention : APJCP. 2013;14:2407-12.
- Wu AH, Pike MC, Williams LD, et al. Tamoxifen, soy, and lifestyle factors in Asian American women with breast cancer. J Clin Oncol. 2007;25:3024-30.
- Hooper L, Madhavan G, Tice JA, Leinster SJ, Cassidy A. Effects of isoflavones on breast density in pre- and post-menopausal women: a systematic review and meta-analysis of randomized controlled trials. Hum Reprod Update. 2010;16:745-60.
- Wu AH, Spicer D, Garcia A, et al. Double-blind randomized 12-month soy intervention had no effects on breast MRI fibroglandular tissue density or mammographic density. Cancer Prev Res (Phila). 2015;8:942-51.
- Hargreaves DF, Potten CS, Harding C, et al. Two-week dietary soy supplementation has an estrogenic effect on normal premenopausal breast. J Clin Endocrinol Metab. 1999;84:4017-24.
- Sartippour MR, Rao JY, Apple S, et al. A pilot clinical study of short-term isoflavone supplements in breast cancer patients. Nutr Cancer. 2004;49:59-65.
- Palomares MR, Hopper L, Goldstein L, Lehman CD, Storer BE, Gralow JR. Effect of soy isoflavones on breast proliferation in postmenopausal breast cancer survivors. Breast Cancer Res Treatment. 2004;88 (Suppl 1):4002 (Abstract).
- Cheng G, Wilczek B, Warner M, Gustafsson JA, Landgren BM. Isoflavone treatment for acute menopausal symptoms. Menopause. 2007;14:468-73.
- Khan SA, Chatterton RT, Michel N, et al. Soy isoflavone supplementation for breast cancer risk reduction: A randomized phase II trial. Cancer Prev Res (Phila). 2012;5:309-19.
- Shike M, Doane AS, Russo L, et al. The effects of soy supplementation on gene expression in breast cancer: a randomized placebo-controlled study. J Natl Cancer Inst. 2014;106.
- Boyd NF, Lockwood GA, Martin LJ, Byng JW, Yaffe MJ, Tritchler DL. Mammographic density as a marker of susceptibility to breast cancer: a hypothesis. IARC Sci Publ. 2001;154:163-9.
- Boyd NF, Martin LJ, Li Q, et al. Mammographic density as a surrogate marker for the effects of hormone therapy on risk of breast cancer. Cancer Epidemiol Biomarkers Prev. 2006;15:961-6.
- Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321-33.
- Setchell KD, Brown NM, Zhao X, et al. Soy isoflavone phase II metabolism differs between rodents and humans: implications for the effect on breast cancer risk. Am J Clin Nutr. 2011;94:1284-94.