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Originally published as JCO Early Release 10.1200/JCO.2007.11.9743 on August 20 2007 © 2007 American Society of Clinical Oncology.
Low-Dose Tamoxifen for Combination Hormone Replacement Therapy Users
University of Kansas Medical Center, Kansas City, KS Despite a dramatic reduction in postmenopausal hormone use after the initial publication of the Women's Health Initiative results,1-4 a substantial number of women continue to use some form of hormonal supplementation predominately to control menopausal symptoms. The conjugated equine estrogen Premarin (Wyeth Pharmaceuticals, Madison, NJ) is the 22nd most frequently prescribed brand name drug in the United States with more than 13 million prescriptions issued in 2006.5 Almost 3 million prescriptions were issued in 2006 for Prempo (Wyeth Pharmaceuticals) a combination of an androgenic progestin with conjugated equine estrogen.5 As the preponderance of clinical trial data indicating an increased risk of breast cancer and an unfavorable global health index has been for conjugated equine estrogens and progestins, interest in more physiologic types of hormone replacement has soared. These so-called bioidentical forms of hormone replacement include estradiol, estriol, testosterone, and progesterone, given as either single agents or compounded together and administered as pills, troches, transdermal patches, creams, or vaginal gels. More than 4 million brand name estradiol patches are currently sold annually.5 Change in risk of breast cancer by the use of postmenopausal hormones may be dependent on the type of drug(s) and dose, route of administration, prior oophorectomy, age at initiation, and duration of use. Women using standard dose oral or transdermal estrogen without a progestin might anticipate either no increase or a very small relative increase of up to 2% per year of current use.2,6 Women using estrogen plus a progestin can expect a more substantial 6% to 10% increase in relative risk per year of current use.1,6 Increased risk for breast cancer with progesterone may be somewhat less than for progestins.6 To date, there is no reported increase in risk associated with vaginal hormones, and the risks for very low-dose oral or transdermal formulations have not been assessed.6 Younger postmenopausal women who use estrogen alone for a moderate period may not face a greater risk. In fact, investigators from the Women's Health Initiative have reported that women between age 50 and 79 who have undergone a hysterectomy and were randomly assigned to estrogen alone for an average of 7 years enjoyed a 20% reduction in incidence of invasive breast cancer (P = .09).7 In addition, a nonsignificant 27% reduction in deaths from all causes was reported for women in the 50- to 59-year age range who were randomly assigned to estrogen alone compared with placebo.2 The effect of these modifying factors on risk associated with hormone replacement therapy is not well understood by many health care providers or their patients. Further, little effort is made to translate change in relative risk into change in absolute risk, which can be better appreciated by the patient. For example, an average risk woman in her early 50s who starts estrogen alone after a hysterectomy and is calculated to have a 5-year Gail risk of 1% may—at worst—exhibit an increase of 1.1% after 5 years of receiving the hormone, and at best actually enjoy a small reduction in risk for breast cancer. For a woman taking estrogen alone, even the worst case scenario seems a small price to pay for relief of symptoms. The same average risk woman in her 50s who has not undergone a hysterectomy might see her absolute 5-year risk increase from 1% to as much as 1.5% with hormone replacement therapy as a result of the need to add progesterone or a progestin to estrogen treatment. For the average to high-risk postmenopausal woman who has both a uterus and significant menopausal symptoms, some approach to risk reduction is needed that permits the simultaneous use of hormone replacement therapy. In this issue of the Journal of Clinical Oncology, Decensi et al8 report just such an approach using low-dose tamoxifen. Women on an estrogen plus a progestin were randomly assigned to three different reduced dose tamoxifen regimens or placebo for 12 months. The rationale for this study came from a prior primary prevention trial in which standard dose tamoxifen was associated with a reduced risk of breast cancer for individuals who were taking hormone replacement therapy9,10 and a short term study in women with newly diagnosed cancer that suggested that all tested levels of reduced dose tamoxifen were equivalent to the standard dose in reducing proliferation in cancer cells.11 Favorable modulation of the risk biomarkers insulin like growth factor 1 (IGF-1) and mammographic density was observed for women randomly assigned to low-dose tamoxifen compared with placebo and this was accomplished without a significant increase in endometrial proliferation or hot flashes.8 Importantly, no one in the combined tamoxifen hormone replacement groups had clinical evidence of a thromboembolic event. The magnitude of risk biomarker modulation appeared greatest for the highest of the low-dose regimens tested (5 mg tamoxifen per day). Although mammographic density was employed as a secondary response biomarker, its favorable modulation provided perhaps more convincing proof of efficacy for low-dose tamoxifen as mammographic density is likely to be more directly reflective of changes in the breast than a serum marker. Further, both oral and transdermal hormones were used by study participants and blood IGF-1 is differentially modulated by oral versus transdermal estrogen preparations.12 Combined estrogen plus progestin hormone replacement therapy is known to both increase epithelial proliferation and retard breast involution; and thus increase postmenopausal breast density.13,14 Tamoxifen administration is associated with reduction in breast proliferation and mammographic density, particularly in a high estrogen environment.15 The lack of a significant increase in endometrial proliferation, which may be observed in women treated with standard dose tamoxifen, might be due to the reduced dose or to the progestational component of the combined hormone replacement therapy taken by all women in this trial.16 Failure to observe favorable modulation of markers of bone turnover by adding tamoxifen to the hormone replacement therapy regimen might be due to the failure of low-dose tamoxifen to reduce bone turnover markers to a greater extent than that produced by hormone replacement therapy alone or the antiestrogenic effects of tamoxifen on bone in an estrogen rich environment.17 The finding that low-dose tamoxifen favorably modulates both IGF-1 and mammographic breast density in women receiving combined hormone replacement therapy without significantly increasing hot flashes or endometrial proliferation is exciting and is grounds for further clinical study. Given limited resources, what type of study, if any, is needed before tamoxifen should routinely be used for risk reduction in women taking hormone replacement? Currently, tamoxifen may be considered for primary risk reduction therapy for any woman with a Gail risk of higher than 1.66% or those with prior atypical hyperplasia or in situ cancer.18 Hormone replacement may be considered for most women having moderate to severe climacteric symptoms.19 The safety of the two given together has been demonstrated in large European trials.9,20,21 There is really little to impede the use of low-dose tamoxifen in women taking hormone replacement therapy except for concerns that low-dose tamoxifen may be less effective than standard dose or the use of both together may negate the therapeutic benefits of the two drugs used separately. The large primary prevention trials with extended follow-up have provided somewhat conflicting results on whether tamoxifen does reduce the incidence of breast cancer in women taking concomitant hormones. The results appeared to be favorable in the Italian prevention trial, but all participants had had a hysterectomy and most presumably were on estrogen without a progestin. In the Royal Marsden trial, tamoxifen appeared to reduce risk whether or not women received concomitant hormone replacement therapy.20 In International Breast Cancer Intervention Study 1, women who used hormone replacement therapy during the trial (usually for study-induced hot flashes) and were randomly assigned to tamoxifen did not have a significant reduction in breast cancer events.21 Hormone replacement was also not effective in alleviating menopausal symptoms in this study.22 The reasons for these differences can probably be traced to differences in cohort and trial conduct. We do not know if the majority of International Breast Cancer Intervention Study 1 participants who received hormones for menopausal symptoms during the trial were estrogen deficient (tamoxifen actually increases estrogen levels in pre- and perimenopausal women with functioning ovaries) or if they were less compliant than their counterparts who did not find it necessary to use hormones for hot flashes. A phase III study of placebo versus 5 mg of tamoxifen for women taking hormone replacement (the HOT trial), is underway.23 This study, with cancer development as a primary end point, has been ongoing for 4 years but has accrued less than one third of the 4,000 subject goal (B. Bonanni, personal communication, April 2007). Even if the investigators are able to complete accrual in a timely fashion, is it likely that a sufficient number of women taking hormones will embrace concomitant low-dose tamoxifen so as to justify the time and expense of such an effort? Tamoxifen for primary prevention might be predicted to enjoy an increase in popularity given its affordability and the demonstration of lasting risk reduction benefits beyond the active treatment phase when risk of adverse effects diminishes.19,21,24 If completion of a cancer end point trial comparing low-dose tamoxifen to placebo for women on combined hormone replacement therapy is not realistic for whatever reason, perhaps the time has come for use of tissue-based surrogate markers. End points such as reduction in precancerous breast disease or need for breast biopsy could be accomplished with fewer patients than are usually required for a cancer incidence study, yet would still provide a measure of clinical benefit. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. NOTES published online ahead of print at www.jco.org on August 20, 2007. REFERENCES
1. Rossouw JE, Anderson GL, Prentice RL, et al: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results From the Women's Health Initiative randomized controlled trial. JAMA 288:321-333, 2002 2. Anderson GL, Limacher M, Assaf AR, et al: Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women's Health Initiative randomized controlled trial. JAMA 291:1701-1712, 2004 3. Buist DS, Newton KM, Miglioretti DL, et al: Hormone therapy prescribing patterns in the United States. Obstet Gynecol 104:1042-1050, 2004 4. Ravdin PM, Cronin KA, Howlader N, et al: The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med 356:1670-1674, 2007 5. DrugTopics: Top 200 brand-name drugs by units in 2006. March 5, 2007. http://www.drugtopics.com/drugtopics/data/articlestandard/drugtopics/092007/407649/article.pdf 6. Beral V: Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362:419-427, 2003[CrossRef][Medline] 7. Stefanick ML, Anderson GL, Margolis KL, et al: Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 295:1647-1657, 2006 8. Decensi A, Gandini S, Serrano D, et al: A randomized dose-ranging trial of tamoxifen at low doses in hormone replacement therapy users. J Clin Oncol 25:4201-4209, 2007 9. Veronesi U, Maisonneuve P, Costa A, et al: Prevention of breast cancer with tamoxifen: Preliminary findings from the Italian randomised trial among hysterectomised women. Lancet 352:93-97, 1998[Medline] 10. Veronesi U, Maisonneuve P, Rotmensz N, et al: Italian randomized trial among women with hysterectomy: Tamoxifen and hormone-dependent breast cancer in high-risk women. J Natl Cancer Inst 95:160-165, 2003 11. Decensi A, Robertson C, Viale G, et al: A randomized trial of low-dose tamoxifen on breast cancer proliferation and blood estrogenic biomarkers. J Natl Cancer Inst 95:779-790, 2003 12. Boyd NF, Jensen HM, Cooke G, et al: Relationship between mammographic and histological risk factors for breast cancer. J Natl Cancer Inst 84:1170-1179, 1992 13. Greendale GA, Reboussin BA, Slone S, et al: Postmenopausal hormone therapy and change in mammographic density. J Natl Cancer Inst 95:30-37, 2003 14. McTiernan A, Martin CF, Peck JD, et al: Estrogen-plus-progestin use and mammographic density in postmenopausal women: Women's Health Initiative randomized trial. J Natl Cancer Inst 97:1366-1376, 2005 15. Cuzick J, Warwick J, Pinney E, et al: Tamoxifen and breast density in women at increased risk of breast cancer. J Natl Cancer Inst 96:621-628, 2004 16. Gardner FJ, Konje JC, Abrams KR, et al: Endometrial protection from tamoxifen-stimulated changes by a levonorgestrel-releasing intrauterine system: A randomised controlled trial. Lancet 356:1711-1717, 2000[CrossRef][Medline] 17. Powles TJ, Hickish T, Kanis JA, et al: Effect of tamoxifen on bone mineral density measured by dual energy x-ray absorptionmetry in health premenopausal and postmenopausal women. J Clin Oncol 14:78-84, 1996[Abstract] 18. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 90:1371-1388, 1998 19. National Institutes of Health: National Institutes of Health State-of-the-Science Conference statement: Management of menopause-related symptoms. Ann Intern Med 142:1003-1013, 2005[Medline] 20. Powles TJ, Ashley S, Tidy A, et al: Twenty-year follow-up of the Royal Marsden randomized, double-blinded tamoxifen breast cancer prevention trial. J Natl Cancer Inst 99:283-290, 2007 21. Cuzick J, Forbes JF, Sestak I, et al: Long-term results of tamoxifen prophylaxis for breast cancer–96-month follow-up of the randomized IBIS-I trial. J Natl Cancer Inst 99:272-282, 2007 22. Sestak I, Kealy R, Edwards R, et al: Influence of hormone replacement therapy on tamoxifen-induced vasomotor symptoms. J Clin Oncol 24:3991-3996, 2006 23. Decensi A, Galli A, Veronesi U: HRT opposed to low-dose tamoxifen (HOT study): Rationale and design. Recent Results Cancer Res 163:104-111, 2003[Medline] 24. Veronesi U, Maisonneuve P, Decensi A: Tamoxifen: An enduring star. J Natl Cancer Inst 99:258-260, 2007 Related Article
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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