Skip to main content

Advertisement

Log in

SERMs for the treatment and prevention of breast cancer

  • Published:
Reviews in Endocrine and Metabolic Disorders Aims and scope Submit manuscript

Abstract

Tamoxifen and raloxifene are both selective estrogen receptor modulators (SERMs). The medicines can block estrogen mediated breast cancer growth and development but will also maintain bone density in postmenopausal women and lower circulating cholesterol. Tamoxifen has remained the antihormonal therapy of choice for the treatment of ER positive breast cancer for the last 30 years. However, although adjuvant tamoxifen produces profound increases in disease-free and overall survival in patients with ER positive breast cancer, concerns about drug resistance, blood clots and endometrial cancer have resulted in a change to the use of aromatase inhibitors for the treatment of postmenopausal women. Nevertheless, tamoxifen remains the antihormonal treatment of choice for premenopausal women with ER positive breast cancer and for risk reduction in premenopausal women who are at high risk for developing breast cancer. The risk of endometrial cancer and thromboembolic disorders during tamoxifen therapy is not elevated in premenopausal women. It is important to note that aromatase inhibitors or raloxifene should not be used in premenopausal women. Raloxifene is used to prevent osteoporosis in postmenopausal women and, unlike tamoxifen, does not increase the risk of endometrial cancer. However, raloxifene does reduce breast cancer risk by 50–70% in both low risk and high risk postmenopausal women. Comparisons of raloxifene with tamoxifen show equal efficacy as a chemopreventive for breast cancer but there is a reduction in thromboembolic disorders, fewer endometrial cancers, hysterectomies, cataracts and cataract surgeries in women taking raloxifene. Overall, SERMs continue to fulfill their promise as appropriate medicines that target specific populations for the treatment and prevention of breast cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Schinzinger A. Ueber carcinoma mammae [abstract] 18th Congress of the German Society for Surgery. Beilage zum Centralblatt fur Chirurgie 1889;16:55–6.

    Google Scholar 

  2. Schinzinger A. Ueber carcinoma mammae [abstract].18th Kongress, Berlin, April 24–27, 1889. Berlin (Germany): Hirschwald. Verhandlungen der Deutschen Gesellschaft fur Chirurgie 1889;28.

  3. Beatson GT. On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment with illustrative cases. Lancet 1896;2:104–7.

    Article  Google Scholar 

  4. Beatson CT. On treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment with illustrative cases. Lancet 1896;2:162–5.

    Article  Google Scholar 

  5. Jensen EV, Jacobson HI. Basic guides to the mechanism of estrogen action. Recent Progr Hormone Res 1962;18:387–414.

    CAS  Google Scholar 

  6. Jordan VC, Brodie AMH. Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer. Steroids 2007;72:7–25.

    Article  PubMed  CAS  Google Scholar 

  7. Jordan VC. Tamoxifen: a most unlikely pioneering medicine. Nature Reviews Drug Discovery 2003;2:205–13.

    Article  PubMed  CAS  Google Scholar 

  8. Jordan VC. Biochemical pharmacology of antiestrogen action. Pharmacol Rev 1984;36:245–76.

    PubMed  CAS  Google Scholar 

  9. Jordan VC. Selective estrogen receptor modulation: a personal perspective. Cancer Res 2001;61:5683–7.

    PubMed  CAS  Google Scholar 

  10. EBCTCG. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;354:1451–67.

    Google Scholar 

  11. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, 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;90:1371–88.

    Article  PubMed  CAS  Google Scholar 

  12. Fisher B, Costantino JP, Wickerham DL, Cecchini RS, Cronin WM, Robidoux A, 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;97:1652–62.

    Article  PubMed  CAS  Google Scholar 

  13. Jordan VC. Chemosuppression of breast cancer with tamoxifen: laboratory evidence and future clinical investigations. Cancer Invest 1988;6:589–95.

    Article  PubMed  CAS  Google Scholar 

  14. Lerner LJ, Jordan VC. The development of antiestrogens for the treatment of breast cancer: Eighth Cain Memorial Award Lecture. Cancer Res 1990;50:4177–89.

    PubMed  CAS  Google Scholar 

  15. Hersh AL, Stefanick ML, Stafford RS. National use of postmenopausal hormone therapy. JAMA 2004;291:47–53.

    Article  PubMed  CAS  Google Scholar 

  16. Riggs BL, Hartmann LC. Selective Estrogen-Receptor Modulators—Mechanisms of Action and Application to Clinical Practice. N Engl J Med 2003;348:618–29.

    Article  PubMed  CAS  Google Scholar 

  17. Writing Group for the Women’s Health Initiative Investigators, Rossouw JEAG, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288:321–32.

    Article  PubMed  CAS  Google Scholar 

  18. Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003;362:419–27.

    Article  CAS  Google Scholar 

  19. Faber A, Bouvy ML, Loskamp L, van de Berg PB, Egberts ACG, de Jong-van den Berg LTW. Dramatic change in prescribing of hormonal replacement therapy in the Netherlands after publication of the Million Women Study: a follow-up study. Br J Clin Pharmacol 2005;60:641–7.

    Article  PubMed  Google Scholar 

  20. Ravdin PM, Cronin KA, Howlander N, Chlebowski RT, Berry DA. A sharp decrease in breast cancer incidence in the United States in 2003. Breast Cancer Res and Treatment Breast Cancer Research & Treatment 100 Supplement 1,S6:59, 2003.

  21. Jordan VC. The science of selective estrogen receptor modulators: concept to clinical practice. Clin Cancer Res 2006;12:5010–3.

    Article  PubMed  CAS  Google Scholar 

  22. Jordan VC. SERMs: meeting the promise of multifunctional medicines. (Commentary). J Natl Cancer Inst 2007;99:350–6.

    Article  PubMed  CAS  Google Scholar 

  23. Harper MJ, Walpole AL. A new derivative of triphenylethylene: effect on implantation and mode of action in rats. J Reprod Fertil 1967;13:101–19.

    Article  PubMed  CAS  Google Scholar 

  24. Cole MP, Jones CT, Todd ID. A new anti-oestrogenic agent in late breast cancer. an early clinical appraisal of ICI 46474. Br J Cancer 1971;25:270–5.

    PubMed  CAS  Google Scholar 

  25. Jordan VC, Koerner S. Tamoxifen (ICI 46,474) and the human carcinoma 8S oestrogen receptor. Eur J Cancer 1975;11:205–6.

    PubMed  CAS  Google Scholar 

  26. Nicholson RI, Golder MP. The effect of synthetic anti-oestrogens on the growth and biochemistry of rat mammary tumours. Eur J Cancer 1975;11:571–9.

    PubMed  CAS  Google Scholar 

  27. Jordan VC, Jaspan T. Tamoxifen as an antitumour agent: oestrogen binding as a predictive test for tumour response. J Endocrinol 1976;68:453–60.

    Article  PubMed  CAS  Google Scholar 

  28. Skidmore J, Walpole AL, Woodburn J. Effect of some triphenylethylenes on oestradiol binding in vitro to macromolecules from uterus and anterior pituitary. J Endocrinol 1972;52:289–98.

    Article  PubMed  CAS  Google Scholar 

  29. Jordan VC, Collins MM, Rowsby L, Prestwich G. A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J Endocrinol 1977;75:305–16.

    Article  PubMed  CAS  Google Scholar 

  30. Langan-Fahey SM, Tormey DC, Jordan VC. Tamoxifen metabolites in patients on long-term adjuvant therapy for breast cancer. Eur J Cancer 1990;26:883–8.

    Article  PubMed  CAS  Google Scholar 

  31. Jordan VC, Dix CJ, Allen KE. The effectiveness of long term tamoxifen treatment in a laboratory model for adjuvant hormone therapy of breast cancer. Adjuv Ther Cancer 1979;2:19–26.

    Google Scholar 

  32. Jordan VC, Allen KE. Evaluation of the antitumour activity of the non-steroidal antioestrogen monohydroxytamoxifen in the DMBA-induced rat mammary carcinoma model. Eur J Cancer 1980;16:239–51.

    PubMed  CAS  Google Scholar 

  33. Jordan VC, Allen KE, Dix CJ. Pharmacology of tamoxifen in laboratory animals. Cancer Treat Rep 1980;64:745–59.

    PubMed  CAS  Google Scholar 

  34. EBCTCG. Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer. An overview of 61 randomized trials among 28,896 women. N Engl J Med 1988;319:1681–92.

    Article  Google Scholar 

  35. EBCTCG. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 1992;339:1–15.

    Google Scholar 

  36. 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;365:1687–717.

    Article  CAS  Google Scholar 

  37. Jordan VC. Antitumour activity of the antioestrogen ICI 46,474 (tamoxifen) in the dimethylbenzanthracene (DMBA)-induced rat mammary carcinoma model. J Steroid Biochem 1974;5:354.

    Article  Google Scholar 

  38. Jordan VC. Effect of tamoxifen (ICI 46,474) on initiation and growth of DMBA-induced rat mammary carcinoma. Eur J Cancer 1976;12:419–24.

    PubMed  CAS  Google Scholar 

  39. Cuzick J, Baum M. Tamoxifen and contralateral breast cancer [letter]. Lancet 1985;2:282.

    Article  PubMed  CAS  Google Scholar 

  40. Cuzick J, Powles T, Veronesi U, Forbes J, Edwards R, Ashley S, et al. Overview of the main outcomes in breast-cancer prevention trials. Lancet 2003;361:296–300.

    Article  PubMed  CAS  Google Scholar 

  41. Gail MH, Brinton LA, Byar DP, Corle DK, Green SB, Schairer C, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 1989;81:1879–86.

    Article  PubMed  CAS  Google Scholar 

  42. IBIS Investigators. First results from the International Breast Study: a randomized prevention trial. Lancet 2002;360:817–24.

    Article  Google Scholar 

  43. Jordan VC. Optimising endocrine approaches for the chemoprevention of breast cancer. Beyond the Study of Tamoxifen and Raloxifene (STAR) Trial. Eur J Cancer 2006;42:2909–13.

    Article  PubMed  CAS  Google Scholar 

  44. Furr BJ, Jordan VC. The pharmacology and clinical uses of tamoxifen. Pharmacol Ther 1984;25:127–205.

    Article  PubMed  CAS  Google Scholar 

  45. Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, et al. Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 2003;95:1758–64.

    PubMed  CAS  Google Scholar 

  46. Johnson MD, Zuo H, Lee KH, Trebley JP, Rae JM, Weatherman RV, et al. Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat 2004;85:151–9.

    Article  PubMed  CAS  Google Scholar 

  47. Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. JNCI 2005;97:30–9.

    PubMed  CAS  Google Scholar 

  48. Goetz MP, Rae JM, Suman VJ, Safgren SL, Ames MM, Visscher DW, et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 2005;23:9312–8.

    Article  PubMed  CAS  Google Scholar 

  49. Goetz MP, Knox SK, Suman VJ, Rae JM, Safgren SL, Ames MM, et al. The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res Treat 2007;101:113–21.

    Article  PubMed  CAS  Google Scholar 

  50. Garber K. Tamoxifen pharmacogenetics moves closer to reality. J Natl Cancer Inst 2005;97:412–3.

    Article  PubMed  Google Scholar 

  51. Jordan VC, Phelps E, Lindgren JU. Effects of anti-estrogens on bone in castrated and intact female rats. Breast Cancer Res Treat 1987;10:31–5.

    Article  PubMed  CAS  Google Scholar 

  52. Turner RT, Wakley GK, Hannon KS, Bell NH. Tamoxifen prevents the skeletal effects of ovarian hormone deficiency in rats. J Bone Miner Res 1987;2:449–56.

    Article  PubMed  CAS  Google Scholar 

  53. Turner RT, Wakley GK, Hannon KS, Bell NH. Tamoxifen inhibits osteoclast-mediated resorption of trabecular bone in ovarian hormone-deficient rats. Endocrinology 1988;122:1146–50.

    Article  PubMed  CAS  Google Scholar 

  54. Gottardis MM, Jordan VC. Antitumor actions of keoxifene and tamoxifen in the N-nitrosomethylurea-induced rat mammary carcinoma model. Cancer Res 1987;47:4020–4.

    PubMed  CAS  Google Scholar 

  55. Jordan VC, Robinson SP. Species-specific pharmacology of antiestrogens: role of metabolism. Fed Proc 1987;46:1870–4.

    PubMed  CAS  Google Scholar 

  56. Gottardis MM, Robinson SP, Satyaswaroop PG, Jordan VC. Contrasting actions of tamoxifen on endometrial and breast tumor growth in the athymic mouse. Cancer Res 1988;48:812–5.

    PubMed  CAS  Google Scholar 

  57. Fornander T, Rutqvist LE, Cedermark B, Glas U, Mattsson A, Silfversward C, et al. Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1989;1:117–20.

    Article  PubMed  CAS  Google Scholar 

  58. Fisher B, Costantino JP, Redmond CK, Fisher ER, Wickerham DL, Cronin WM. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 [see comments]. J Natl Cancer Inst 1994;86:527–37.

    Article  PubMed  CAS  Google Scholar 

  59. Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA 1999;281:2189–97.

    Article  PubMed  CAS  Google Scholar 

  60. Martino S, Cauley JA, Barrett-Connor E, Powles TJ, Mershon J, Disch D, et al. For the CORE investigators continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst 2004;96:1751–61.

    Article  PubMed  CAS  Google Scholar 

  61. Cauley JA, Norton L, Lippman ME, Eckert S, Krueger KA, Purdie DW, et al. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Multiple outcomes of raloxifene evaluation. Breast Cancer Res Treat 2001;65:125–34.

    Article  PubMed  CAS  Google Scholar 

  62. Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators [see comments] [published erratum appears in JAMA 1999 Dec 8;282(22):2124]. JAMA 1999;282:637–45.

    Article  PubMed  CAS  Google Scholar 

  63. Barrett-Connor E, Mosca L, Collins P, Geiger MJ, Grady D, Kornitzer M, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 2006;355:125–37.

    Article  PubMed  CAS  Google Scholar 

  64. Gottardis MM, Ricchio ME, Satyaswaroop PG, Jordan VC. Effect of steroidal and nonsteroidal antiestrogens on the growth of a tamoxifen-stimulated human endometrial carcinoma (EnCa101) in athymic mice. Cancer Res 1990;50:3189–92.

    PubMed  CAS  Google Scholar 

  65. Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, et al. The Study of Tamoxifen and Raloxifene (STAR): Report of the National Surgical Adjuvant Breast and Bowel Project P-2 Trial. JAMA 2006;295:2727–41.

    Article  PubMed  CAS  Google Scholar 

  66. Jordan VC. Chemoprevention of breast cancer with selective estrogen-receptor modulators. Nat Rev, Cancer 2007;7:46–53.

    Article  CAS  Google Scholar 

  67. Jordan VC. Beyond raloxifene for the prevention of osteoporosis and breast cancer. Br J Pharmacol. 2007;150:3–4.

    Article  PubMed  CAS  Google Scholar 

  68. Jordan VC. Antiestrogens and selective estrogen receptor modulators as multifunctional medicines. 2. Clinical considerations and new agents. J Med Chem 2003;46:1081–111.

    Article  PubMed  CAS  Google Scholar 

  69. Espeland MA, Rapp SR, Shumaker SA, Brunner R, Manson JE, Sherwin BB, et al. Conjugated equine estrogens and global cognitive function in postmenopausal women: Women’s Health Initiative Memory Study. JAMA 2004;291:2959–68.

    Article  PubMed  CAS  Google Scholar 

  70. Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, Lane DS, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study. JAMA 2004;291:2947–58.

    Article  PubMed  CAS  Google Scholar 

  71. Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the women’s health initiative memory study: a randomized controlled trial. JAMA 2003;289:2651–62.

    Article  PubMed  CAS  Google Scholar 

  72. Wassertheil-Smoller S, Hendrix SL, Limacher M, Heiss G, Kooperberg C, Baird A, et al. Effect of estrogen plus progestin on stroke in postmenopausal women: the Women’s Health Initiative: a randomized trial. JAMA 2003;289:2673–84.

    Article  PubMed  CAS  Google Scholar 

  73. Licata AA. Discovery, clinical development, and therapeutic uses of bisphosphonates. Ann Pharmacother 2005;39:668–77.

    Article  PubMed  CAS  Google Scholar 

  74. Miller CP, Collini MD, Tran BD, Harris HA, Kharode YP, Marzolf JT, et al. Design, synthesis, and preclinical characterization of novel, highly selective indole estrogens. J Med Chem 2001;44:1654–7.

    Article  PubMed  CAS  Google Scholar 

  75. Rosati RL, Da Silva Jardine P, Cameron KO, Thompson DD, Ke HZ, Toler SM, et al. Discovery and preclinical pharmacology of a novel, potent, nonsteroidal estrogen receptor agonist/antagonist, CP-336156, a diaryltetrahydronaphthalene. J Med Chem 1998;41:2928–31.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This manuscript is supported by the Department of Defense Breast Program under award number BC050277 Center of Excellence(VCJ) (Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense), SPORE in Breast Cancer CA 89018(VCJ), R01 GM067156(VCJ), FCCC Core Grant NIH P30 CA006927, the Avon Foundation(VCJ) and the Weg Fund of Fox Chase Cancer Center(VCJ). Dr. Swaby is also supported by the Fox Chase Intramural Translational Research Award.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to V. Craig Jordan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Swaby, R.F., Sharma, C.G.N. & Jordan, V.C. SERMs for the treatment and prevention of breast cancer. Rev Endocr Metab Disord 8, 229–239 (2007). https://doi.org/10.1007/s11154-007-9034-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11154-007-9034-4

Keywords

Navigation