Managing the side effects of tamoxifen
- Suzanne D Conzen, MD
Suzanne D Conzen, MD
- Professor of Medicine
- The University of Chicago
- Section Editors
- Daniel F Hayes, MD
Daniel F Hayes, MD
- Section Editor — Breast Cancer
- Professor of Medicine
- University of Michigan School of Medicine
- William F Crowley, Jr, MD
William F Crowley, Jr, MD
- Section Editor — Female Reproductive Endocrinology
- Daniel K Podolsky Professor of Medicine
- Harvard Medical School
Tamoxifen and raloxifene are selective estrogen receptor modulators (SERMs) with both agonist and antagonist properties, depending on the individual target organ [1,2]. These differences are probably because of variable effects on gene expression in different cell types. (See "Mechanisms of action of selective estrogen receptor modulators and down-regulators".)
Both tamoxifen and raloxifene have antiestrogenic activity in breast tissue, reducing epithelial cell proliferation. This property has led to their clinical study as breast cancer chemopreventive agents. (See "Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention".)
However, an important difference between the two drugs is their effect on the uterus, where tamoxifen has an estrogen-like effect while raloxifene acts as an estrogen antagonist. In apparent contrast to raloxifene, tamoxifen has been associated with endometrial hyperplasia [3,4], fibroids, polyps [4-6], and endometrial tumors (estrogen agonist effects) [7,8]. Tamoxifen is also associated with other side effects, including hot flashes (an estrogen antagonist effect), vaginal discharge, menstrual irregularities, sexual dysfunction, and blood clots. Although longer treatment with tamoxifen increases the risk of adverse effects, the reduction in breast cancer mortality associated with longer treatment outweighs those risks.
This topic review will cover management of the major side effects of tamoxifen. The use of tamoxifen as a hormonal treatment for breast cancer, both in the adjuvant setting and for advanced disease, and the use of tamoxifen and raloxifene as chemopreventive agents in women at increased risk for breast cancer are discussed elsewhere. (See "Adjuvant endocrine therapy for non-metastatic, hormone receptor-positive breast cancer" and "Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention".)
Hot flashes are one of the most common and bothersome side effects of tamoxifen; they are believed to be due to a central nervous system antiestrogenic effect causing thermoregulatory dysfunction . Up to 80 percent of women prescribed tamoxifen complain of hot flashes, and about 30 percent rate them as severe . (See "Menopausal hot flashes".)
- Cosman F, Lindsay R. Selective estrogen receptor modulators: clinical spectrum. Endocr Rev 1999; 20:418.
- Riggs BL, Hartmann LC. Selective estrogen-receptor modulators -- mechanisms of action and application to clinical practice. N Engl J Med 2003; 348:618.
- Fisher B, Costantino JP, Redmond CK, et al. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 1994; 86:527.
- Chalas E, Costantino JP, Wickerham DL, et al. Benign gynecologic conditions among participants in the Breast Cancer Prevention Trial. Am J Obstet Gynecol 2005; 192:1230.
- Kedar RP, Bourne TH, Powles TJ, et al. Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomised breast cancer prevention trial. Lancet 1994; 343:1318.
- Lahti E, Blanco G, Kauppila A, et al. Endometrial changes in postmenopausal breast cancer patients receiving tamoxifen. Obstet Gynecol 1993; 81:660.
- Osborne CK. Tamoxifen in the treatment of breast cancer. N Engl J Med 1998; 339:1609.
- Braithwaite RS, Chlebowski RT, Lau J, et al. Meta-analysis of vascular and neoplastic events associated with tamoxifen. J Gen Intern Med 2003; 18:937.
- Stearns V, Ullmer L, López JF, et al. Hot flushes. Lancet 2002; 360:1851.
- Day R, National Surgical Adjuvant Breast and Bowel Projet P-1 study (NSABP-1). Quality of life and tamoxifen in a breast cancer prevention trial: a summary of findings from the NSABP P-1 study. National Surgical Adjuvant Breast and Bowel Project. Ann N Y Acad Sci 2001; 949:143.
- Jin Y, Hayes DF, Li L, et al. Estrogen receptor genotypes influence hot flash prevalence and composite score before and after tamoxifen therapy. J Clin Oncol 2008; 26:5849.
- Crandall C, Petersen L, Ganz PA, Greendale GA. Association of breast cancer and its therapy with menopause-related symptoms. Menopause 2004; 11:519.
- Biglia N, Cozzarella M, Cacciari F, et al. Menopause after breast cancer: a survey on breast cancer survivors. Maturitas 2003; 45:29.
- Goetz MP, Rae JM, Suman VJ, et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 2005; 23:9312.
- Bonanni B, Macis D, Maisonneuve P, et al. Polymorphism in the CYP2D6 tamoxifen-metabolizing gene influences clinical effect but not hot flashes: data from the Italian Tamoxifen Trial. J Clin Oncol 2006; 24:3708.
- 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 1998; 90:1371.
- Cuzick J, Forbes J, Edwards R, et al. First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial. Lancet 2002; 360:817.
- Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Davies C, Godwin J, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 2011; 378:771.
- Davies C, Pan H, Godwin J, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 2013; 381:805.
- Garber JE, Halabi S, Tolaney SM, et al. Factor V Leiden mutation and thromboembolism risk in women receiving adjuvant tamoxifen for breast cancer. J Natl Cancer Inst 2010; 102:942.
- Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 2005; 97:1652.
- Runowicz CD. Gynecologic surveillance of women on tamoxifen: first do no harm. J Clin Oncol 2000; 18:3457.
- Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 365:1687.
- Swerdlow AJ, Jones ME, British Tamoxifen Second Cancer Study Group. Tamoxifen treatment for breast cancer and risk of endometrial cancer: a case-control study. J Natl Cancer Inst 2005; 97:375.
- 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 2007; 99:272.
- National Prescription Audit and National Prescription Audit Plus. Plymouth meeting, Pa. IMS Health, 1978-2001 (database).
- Bernstein L, Deapen D, Cerhan JR, et al. Tamoxifen therapy for breast cancer and endometrial cancer risk. J Natl Cancer Inst 1999; 91:1654.
- Wickerham DL, Fisher B, Wolmark N, et al. Association of tamoxifen and uterine sarcoma. J Clin Oncol 2002; 20:2758.
- Wysowski DK, Honig SF, Beitz J. Uterine sarcoma associated with tamoxifen use. N Engl J Med 2002; 346:1832.
- Bergman L, Beelen ML, Gallee MP, et al. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Comprehensive Cancer Centres' ALERT Group. Assessment of Liver and Endometrial cancer Risk following Tamoxifen. Lancet 2000; 356:881.
- Curtis RE, Freedman DM, Sherman ME, Fraumeni JF Jr. Risk of malignant mixed mullerian tumors after tamoxifen therapy for breast cancer. J Natl Cancer Inst 2004; 96:70.
- Saadat M, Truong PT, Kader HA, et al. Outcomes in patients with primary breast cancer and a subsequent diagnosis of endometrial cancer : comparison of cohorts treated with and without tamoxifen. Cancer 2007; 110:31.
- Committee on Practice Bulletins-Gynecology. ACOG Practice Bulletin No. 126: Management of gynecologic issues in women with breast cancer. Obstet Gynecol 2012; 119:666.
- Gerber B, Krause A, Müller H, et al. Effects of adjuvant tamoxifen on the endometrium in postmenopausal women with breast cancer: a prospective long-term study using transvaginal ultrasound. J Clin Oncol 2000; 18:3464.
- Dijkhuizen FP, Brölmann HA, Oddens BJ, et al. Transvaginal ultrasonography and endometrial changes in postmenopausal breast cancer patients receiving tamoxifen. Maturitas 1996; 25:45.
- Bertelli G, Venturini M, Del Mastro L, et al. Tamoxifen and the endometrium: findings of pelvic ultrasound examination and endometrial biopsy in asymptomatic breast cancer patients. Breast Cancer Res Treat 1998; 47:41.
- Cecchini S, Ciatto S, Bonardi R, et al. Screening by ultrasonography for endometrial carcinoma in postmenopausal breast cancer patients under adjuvant tamoxifen. Gynecol Oncol 1996; 60:409.
- Fung MF, Reid A, Faught W, et al. Prospective longitudinal study of ultrasound screening for endometrial abnormalities in women with breast cancer receiving tamoxifen. Gynecol Oncol 2003; 91:154.
- Cohen I. Endometrial pathologies associated with postmenopausal tamoxifen treatment. Gynecol Oncol 2004; 94:256.
- Love CD, Muir BB, Scrimgeour JB, et al. Investigation of endometrial abnormalities in asymptomatic women treated with tamoxifen and an evaluation of the role of endometrial screening. J Clin Oncol 1999; 17:2050.
- Seoud M, Shamseddine A, Khalil A, et al. Tamoxifen and endometrial pathologies: a prospective study. Gynecol Oncol 1999; 75:15.
- Barakat RR, Gilewski TA, Almadrones L, et al. Effect of adjuvant tamoxifen on the endometrium in women with breast cancer: a prospective study using office endometrial biopsy. J Clin Oncol 2000; 18:3459.
- Chin J, Konje JC, Hickey M. Levonorgestrel intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen. Cochrane Database Syst Rev 2009; :CD007245.
- Trinh XB, Tjalma WA, Makar AP, et al. Use of the levonorgestrel-releasing intrauterine system in breast cancer patients. Fertil Steril 2008; 90:17.
- McGonigle KF, Vasilev SA, Odom-Maryon T, Simpson JF. Ovarian histopathology in breast cancer patients receiving tamoxifen. Gynecol Oncol 1999; 73:402.
- Grey AB, Stapleton JP, Evans MC, Reid IR. The effect of the anti-estrogen tamoxifen on cardiovascular risk factors in normal postmenopausal women. J Clin Endocrinol Metab 1995; 80:3191.
- Williams JK, Wagner JD, Li Z, et al. Tamoxifen inhibits arterial accumulation of LDL degradation products and progression of coronary artery atherosclerosis in monkeys. Arterioscler Thromb Vasc Biol 1997; 17:403.
- Guetta V, Lush RM, Figg WD, et al. Effects of the antiestrogen tamoxifen on low-density lipoprotein concentrations and oxidation in postmenopausal women. Am J Cardiol 1995; 76:1072.
- Williams JK, Honoré EK, Adams MR. Contrasting effects of conjugated estrogens and tamoxifen on dilator responses of atherosclerotic epicardial coronary arteries in nonhuman primates. Circulation 1997; 96:1970.
- Hozumi Y, Kawano M, Saito T, Miyata M. Effect of tamoxifen on serum lipid metabolism. J Clin Endocrinol Metab 1998; 83:1633.
- Hayes DF, Skaar TC, Rae JM, et al. Estrogen receptor genotypes, menopausal status, and the effects of tamoxifen on lipid levels: revised and updated results. Clin Pharmacol Ther 2010; 88:626.
- Hozumi Y, Suemasu K, Takei H, et al. The effect of exemestane, anastrozole, and tamoxifen on lipid profiles in Japanese postmenopausal early breast cancer patients: final results of National Surgical Adjuvant Study BC 04, the TEAM Japan sub-study. Ann Oncol 2011; 22:1777.
- Costantino JP, Kuller LH, Ives DG, et al. Coronary heart disease mortality and adjuvant tamoxifen therapy. J Natl Cancer Inst 1997; 89:776.
- McDonald CC, Stewart HJ. Fatal myocardial infarction in the Scottish adjuvant tamoxifen trial. The Scottish Breast Cancer Committee. BMJ 1991; 303:435.
- Rutqvist LE, Mattsson A. Cardiac and thromboembolic morbidity among postmenopausal women with early-stage breast cancer in a randomized trial of adjuvant tamoxifen. The Stockholm Breast Cancer Study Group. J Natl Cancer Inst 1993; 85:1398.
- Nordenskjöld B, Rosell J, Rutqvist LE, et al. Coronary heart disease mortality after 5 years of adjuvant tamoxifen therapy: results from a randomized trial. J Natl Cancer Inst 2005; 97:1609.
- Hackshaw A, Roughton M, Forsyth S, et al. Long-term benefits of 5 years of tamoxifen: 10-year follow-up of a large randomized trial in women at least 50 years of age with early breast cancer. J Clin Oncol 2011; 29:1657.
- Reis SE, Costantino JP, Wickerham DL, et al. Cardiovascular effects of tamoxifen in women with and without heart disease: breast cancer prevention trial. National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial Investigators. J Natl Cancer Inst 2001; 93:16.
- Pritchard KI, Sousa B. Long-term follow-up of women in trials of adjuvant therapy for breast cancer: is it still important? J Clin Oncol 2011; 29:1651.
- Geiger AM, Chen W, Bernstein L. Myocardial infarction risk and tamoxifen therapy for breast cancer. Br J Cancer 2005; 92:1614.