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© 2002 American Society for Clinical Oncology
Safety Issues of Soy Phytoestrogens in Breast Cancer PatientsVancouver, British Columbia, Canada To the Editor:The results of Van Patten et al1 confirmed previous findings2 that soy phytoestrogens have minimal efficacy for menopausal symptoms in breast cancer patients. However, I am concerned that patients in neither study were apparently informed of the potential stimulatory effects of phytoestrogens on breast tumor.3 Similar omission would have raised ethical concerns if pharmaceutical drugs were involved. At concentrations below 10 µmol/L, phytoestrogens can stimulate breast tumor growth4-15 and antagonize the antitumor effects of tamoxifen,7,9 particularly in an environment of low endogenous estrogen.3,11 In contrast, phytoestrogens inhibit breast tumor growth and enhance the antitumor effects of tamoxifen at concentrations above 10 µmol/L.5,6,8,9,11 In humans, serum phytoestrogen concentrations attained after acute or chronic intake of phytoestrogens were much lower than 10 µmol/L.1,16,17 Without long-term human data, cancer risk assessments need to be cautious and assume that substances that promote tumor growth in preclinical studies may pose similar risks clinically.18 Hence, to weigh the potential risks versus benefits before using phytoestrogens for unproven indications, breast cancer patients should be informed that phytoestrogens have the potential to stimulate tumor growth. REFERENCES
1.
Van Patten CL, Olivotto IA, Chambers GK, et al: Effect of soy phytoestrogens on hot flashes in postmenopausal women with breast cancer: A randomized, controlled clinical trial. J Clin Oncol 20: 1449-1455, 2002
2.
Quella SK, Loprinzi CL, Barton DL, et al: Evaluation of soy phytoestrogens for the treatment of hot flashes in breast cancer survivors: A North Central Cancer Treatment Group Trial. J Clin Oncol 18: 1068-1074, 2000 3. de Lemos ML: Effects of soy phytoestrogens genistein and daidzein on breast cancer growth. Ann Pharmacother 35: 1118-1121, 2001[Abstract]
4.
Sathyamoorthy N, Wang TT, Phang JM: Stimulation of pS2 expression by diet-derived compounds. Cancer Res 54: 957-961, 1994
5.
Wang TT, Sathyamoorthy N, Phang JM: Molecular effects of genistein on estrogen receptor mediated pathways. Carcinogenesis 17: 271-275, 1996 6. Dees C, Foster JS, Ahamed S, et al: Dietary estrogens stimulate human breast cells to enter the cell cycle. Environ Health Perspect 105: 633-636, 1997 7. Sathyamoorthy N, Wang TT: Differential effects of dietary phyto-oestrogens daidzein and equol on human breast cancer MCF-7 cells. Eur J Cancer 33: 2384-2389, 1997[CrossRef][Medline] 8. Wang C, Kurzer MS: Phytoestrogen concentration determines effects on DNA synthesis in human breast cancer cells. Nutr Cancer 28: 236-247, 1997[Medline] 9. Zava DT, Duwe G: Estrogenic and antiproliferative properties of genistein and other flavonoids in human breast cancer cells in vitro. Nutr Cancer 27: 31-40, 1997[Medline]
10.
Hsieh CY, Santell RC, Haslam SZ, et al: Estrogenic effects of genistein on the growth of estrogen receptor-positive human breast cancer (MCF-7) cells in vitro and in vivo. Cancer Res 58: 3833-3838, 1998 11. Wang C, Kurzer MS: Effects of phytoestrogens on DNA synthesis in MCF-7 cells in the presence of estradiol or growth factors. Nutr Cancer 31: 90-100, 1998[Medline] 12. Miodini P, Fioravanti L, Di Fronzo G, et al: The two phyto-oestrogens genistein and quercetin exert different effects on oestrogen receptor function. Br J Cancer 80: 1150-1155, 1999[CrossRef][Medline] 13. Balabhadrapathruni S, Thomas TJ, Yurkow EJ, et al: Effects of genistein and structurally related phytoestrogens on cell cycle kinetics and apoptosis in MDA-MB-468 human breast cancer cells. Oncol Rep 7: 3-12, 2000[Medline] 14. Nakagawa H, Yamamoto D, Kiyozuka Y, et al: Effects of genistein and synergistic action in combination with eicosapentaenoic acid on the growth of breast cancer cell lines. J Cancer Res Clin Oncol 126: 448-454, 2000[CrossRef][Medline]
15.
Santell RC, Kieu N, Helferich WG: Genistein inhibits growth of estrogen-independent human breast cancer cells in culture but not in athymic mice. J Nutr 130: 1665-1669, 2000 16. King RA, Bursill DB: Plasma and urinary kinetics of the isoflavones daidzein and genistein after a single soy meal in humans. Am J Clin Nutr 67: 867-872, 1998[Abstract]
17.
Lu LJ, Anderson KE, Grady JJ, et al: Decreased ovarian hormones during a soya diet: Implications for breast cancer prevention. Cancer Res 60: 4112-4121, 2000 18. National Research Council: Strategies for improving risk assessment: Science and judgment in risk assessment. Washington, DC, National Academy Press, 1994
Response
British Columbia Cancer Agency, Vancouver, British Columbia, Canada In Reply:The safety of phytoestrogens in women with breast cancer is controversial, and this issue was specifically addressed in the consent form for our study.1 The potential risk was discussed with women. Thirteen eligible women declined randomization as indicated in our article in Figure 1. At least some of these women who declined did so because of their concerns about phytoestrogen risks. At the time the study was designed in 1997, there were limited data on the risk of phytoestrogens, and even today, most studies have been based on the effects of genistein alone rather than soy foods. Additionally, soy foods contain a number of nonhormonal compounds with potential anticancer activity.2,3 Our clinical trial was designed to test the very intervention that many women in our practice were beginning to adopt in the hopes of achieving relief from hot flushes, a complete soy beverage at a dose similar to traditional Asian diets. Furthermore, our intervention with soy was short-term and thus unlikely to pose an important risk, as even with prolonged use of estrogen therapy, the increase in incidence of breast cancer is modest and declines when hormones are stopped.4,5 It remains speculative if a short course of weak phytoestrogens, with no clinical evidence of an estrogenic effect greater than placebo as measured by hot flush relief, would result in a significant increase in risk of breast cancer. However, we are continuing long-term follow-up of the cohort of women who participated in this study to determine if soy beverage is associated with any excess risk of breast cancer recurrence or second breast primaries. The correspondent and others concerned about breast cancer risks from phytoestrogens are recommended to read a recent review article on the subject.3 The authors of that review conclude, "Overall, the data are not impressive that the adult consumption of soy affects the risk of developing breast cancer or that soy consumption affects the survival of breast cancer patients." REFERENCES
1.
Van Patten CL, Olivotto IA, Chambers K, et al: Effect of soy phytoestrogens on hot flashes in postmenopausal women with breast cancer: A randomized, controlled clinical trial. J Clin Oncol 20: 1449-1455, 2002 2. Tham DM, Gardner CD, Haskell WL: Potential health benefits of dietary phytoestrogens: A review of the clinical, epidemiological, and mechanistic evidence. J Clin Endocrin Met 33: 2223-2235, 1998
3.
Messina MJ, Loprinzi CL: Soy for breast cancer survivors: A critical review of the literature. J Nutr 131: 3095S-3108S, 2001 4. Collaborative Group on Hormonal Factors in Breast Cancer: Breast cancer and hormone replacement therapy: Collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 350: 1047-1059, 1997[CrossRef][Medline] 5. Collaborative Group on Hormonal Factors in Breast Cancer: Breast Cancer and hormonal contraceptives: Collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies. Lancet 347: 1713-1727, 1996[CrossRef][Medline]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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