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© 2000 American Society for Clinical Oncology
Phytoestrogens and Adjuvant Endocrine Treatment of Breast CancerInstitut Curie Paris, France To the Editor:The study of the treatment of hot flashes in breast cancer survivors presented by Quella et al1 in the March 2000 issue of the Journal of Clinical Oncology, testing 150 mg of isoflavones daily versus placebo in a double-blind randomized cross-over trial, is interesting in that it shows that there is no difference between treatment groups. Nevertheless, we would like to draw the attention to the following point: in this study, the concurrent use of tamoxifen or raloxifene was permitted, provided it had started at least 4 weeks before inclusion of patients in the study. Thus 68% of patients in each group were receiving concurrently an adjuvant endocrine therapy regimen. What is the rationale for treating patients who are receiving adjuvant endocrine treatment with phytoestrogens? Genistein, which is the principal isoflavone in the tablets prescribed, is considered a weak estrogen, with binding affinity to the receptor and activity 20-fold less than that of estradiol. At the doses given in the study by Quella et al, genistein concentrations in the plasma would be between 0.1 to 3 µmol/L.2 Given alone at these concentrations, genistein has an estrogen-agonist effect on breast cancer cells. Adjuvant endocrine treatment of breast cancer with tamoxifen leads to similar plasma concentrations2 of this drug. Given the high affinities of tamoxifen and of its 4-OH metabolite to the estrogen receptor,3 the individual effects of genistein and tamoxifen would be minimized if they were administered simultaneously. Today, we know that there are two types of estrogen receptors, estrogen receptor alpha and estrogen receptor beta (ERß), with overlapping but distinct distribution in different tissues. According to Kuiper et al,3 genistein has a higher binding affinity to ERß than to estrogen receptor alpha, whereas tamoxifen has an equivalent affinity to each of these receptors. There are no reliable data on the actual concentrations of both targets receptors and administered compounds in the various target tissues. Finally, genistein seems to be only a partial agonist for ERß.4 The prescription of phytoestrogens together with adjuvant endocrine treatment poses, in our opinion, two problems: (1) in the breast, by competing with tamoxifen or raloxifene as it does in vitro,2 it could diminish the efficacy of the adjuvant treatment, and (2) in the CNS, tamoxifen or raloxifene could diminish the binding of genistein to estrogen receptors and its estrogen-agonist activity, which could explain the negative results of the study by Quella et al. Considering the present knowledge of the molecular mechanisms underlying the effects of phytoestrogens and tamoxifen (or raloxifene), their simultaneous administration after breast cancer should be envisaged only in randomized trials testing the in vivo impact of the association not only on climacteric symptoms but also on the efficacy of adjuvant breast cancer treatment. REFERENCES
1.
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 2. 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]
3.
Kuiper G, Carlsson B, Grandien K, et al: Comparison of the ligand binding specificity and transcript tissue distribution of ER-alpha and ER-beta. Endocrinology 138:863-870, 1997 4. Pike AC, Brzozowski AM, Hubbard RE, et al: Structure of the ligand-binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist. EMBO 18:4608-4618, 1999[Medline]
ResponseDivision of Medical Oncology Mayo Clinic Rochester, MN In Reply:To address the first question posed by This and Magdelenat, the rationale for testing soy phytoestrogens in patients receiving tamoxifen1 was based on the following assertions: (1) hot flashes are a major problem in women receiving tamoxifen, (2) soy phytoestrogens have been widely touted as being helpful for alleviating hot flashes, and (3) previous experience has revealed that the eventual effects of various drugs on hot flashes are not dependent on whether a patient is taking tamoxifen.2-5 For these reasons, patients receiving tamoxifen were included in our study. This and Magdelenat describe that phytoestrogens, such as genistein, have estrogen-agonist properties. We agree and feel that phytoestrogens might readily be classified as selective estrogen receptor modu- lators (SERMs). We accept that soy phytoestrogens might affect the activity of tamoxifen and/or raloxifene. What we do not know, however, is if this effect is clinically favorable, unfavorable, or neutral. Clinical studies would be necessary to adequately answer such a question. Given the possibility that soy phytoestrogens might be detrimental in terms of breast cancer itself or tamoxifen’s antitumor activity, why did we proceed to study them? There are several reasons. First, epidemiologic and other preclinical data suggest that soy phytoestrogens have cancer chemopreventive properties and thus might be protective.6 Second, physicians do not generally proscribe diets rich in soy and other vegetable products (many of which also contain phytoestrogens), but, rather, we generally favor such a diet over a more meat-based diet. Third, there has been intense interest in the use of soy-based products for the treatment of hot flashes, supported by noting that 182 patients entered our clinical trial in approximately 2 months. These factors led us to conclude that it seemed both safe and appropriate for soy phytoestrogens to be tested in breast cancer survivors, including those receiving tamoxifen. Although our trial did not try to test the effects of soy phytoestrogens on breast cancer pathophysiology (knowing that such a study might require the investment of thousands of patients), it did conclusively determine that the chosen soy phytoestrogen product does not alleviate hot flashes to any substantial degree. Notably, the bulk of available preliminary information from other randomized placebo-controlled clinical trials, testing other soy phytoestrogen products, arrive at the same conclusion.7 Information from these randomized trials allows patients, and their physicians, to make more informed decisions about whether to utilize soy phytoestrogens for treating hot flashes. REFERENCES 1. 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
2.
Loprinzi CL, Michalak JC, Quella SK, et al: Megestrol acetate for the prevention of hot flashes. N Engl J Med 331:347-352, 1994 3. Goldberg RM, Loprinzi CL, O’Fallon JR, et al: Transdermal clonidine for ameliorating tamoxifen-induced hot flashes. J Clin Oncol 12:155-158, 1993[Abstract] 4. Barton DL, Loprinzi CL, Quella SK, et al: Prospective evaluation of vitamin E for hot flashes in breast cancer survivors. J Clin Oncol 16:495-500, 1998[Abstract] 5. Loprinzi CL, Pisansky TM, Fonseca R, et al: Pilot evaluation of venlafaxine hydrochloride for the therapy of hot flashes in cancer survivors. J Clin Oncol 16:2377-2381, 1998[Abstract] 6. Kelloff GJ, Boone CW, Steele VE, et al: Mechanistic considerations in chemopreventive drug development. J Cell Biochem 20:1-24, 1994 7. Patterson AG: Menopause. The Soy Connection 8:4-6, Spring 2000
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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