Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer.
Journal: 2007/April - Steroids
ISSN: 0039-128X
Abstract:
This article describes the origins and evolution of "antiestrogenic" medicines for the treatment and prevention of breast cancer. Developing drugs that target the estrogen receptor (ER) either directly (tamoxifen) or indirectly (aromatase inhibitors) has improved the prognosis of breast cancer and significantly advanced healthcare. The development of the principles for treatment and the success of the concept, in practice, has become a model for molecular medicine and presaged the current testing of numerous targeted therapies for all forms of cancer. The translational research with tamoxifen to target the ER with the appropriate duration (5 years) of adjuvant therapy has contributed to the falling national death rates from breast cancer. Additionally, exploration of the endocrine pharmacology of tamoxifen and related nonsteroidal antiestrogen (e.g. keoxifene now known as raloxifene) resulted in the laboratory recognition of selective ER modulation and the translation of the concept to use raloxifene for the prevention of osteoporosis and breast cancer. However, the extensive evaluation of tamoxifen treatment revealed small but significant side effects such as endometrial cancer, blood clots and the development of acquired resistance. The solution was to develop drugs that targeted the aromatase enzyme specifically to prevent the conversion of androstenedione to estrone and subsequently estradiol. The successful translational research with the suicide inhibitor 4-hydroxyandrostenedione (known as formestane) pioneered the development of a range of oral aromatase inhibitors that are either suicide inhibitors (exemestane) or competitive inhibitors (letrozole and anastrozole) of the aromatase enzyme. Treatment with aromatase inhibitors is proving effective and is associated with reduction in the incidence of endometrial cancer and blood clots when compared with tamoxifen and there is also limited cross resistance so treatment can be sequential. Current clinical trials are addressing the value of aromatase inhibitors as chemopreventive agents for postmenopausal women.
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Steroids 72(1): 7-25

Development and Evolution of Therapies Targeted to the Estrogen Receptor for the Treatment and Prevention of Breast Cancer

Fox Chase Cancer Center, Philadelphia, PA
Department of Pharmacology & Experimental Therapeutics, University of Maryland School of Medicine, University of Maryland Greenebaum Cancer Center, Baltimore, MD
Corresponding author.
V. Craig Jordan: ude.cccf@nadroj.giarc.v; Angela M. H. Brodie: ude.dnalyramu@eidorba
Present Address: Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497
V. Craig Jordan: ude.cccf@nadroj.giarc.v; Angela M. H. Brodie: ude.dnalyramu@eidorba
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The enthusiasm with which the clinical community has embraced the use of antiestrogenic therapy to treat breast cancer is based upon the proven record of success that first the nonsteroidal antiestrogen tamoxifen and then the aromatase inhibitor have demonstrated in clinical trial. The reasons for the enthusiasm are obvious. Antihormonal therapy, particularly aromatase inhibition to create a “no estrogen state” in the postmenopausal breast cancer patient is effective, saves women’s lives, is contributing successfully to reducing the national mortality from breast cancer, is relatively cheap and has fewer side effects and easy administration (oral) than any other anticancer strategy. However, the successful application of a therapeutic strategy to block the known growth stimulation property of estrogen in breast cancer was not greeted with such enthusiasm 40 years ago.

Estrogen is essential for life. Without the critical role of estrogenic steroids, reproduction would not be possible. Based on emerging knowledge from laboratory studies, the value of modulating the steroid environment during the menstrual cycle was advanced to clinical testing during the 1950’s as a means of oral contraception. The results of these studies were to change society forever.

The Worcester Foundation for Experimental Biology is the place where Gregory Pincus established the scientific principles necessary to propose clinical testing of the oral contraceptive and M.C. Chang subsequently established the first protocols to perform in vitro fertilization. Simply stated, the Worcester Foundation was, at that time, the world center for steroid endocrinology and reproductive biology. Over the years, hundreds of scientists have trained at the Foundation and subsequently spread their knowledge throughout the world [1]. However, fashions in research change and new opportunities emerge.

In 1971, President Nixon made a national commitment to seek a cure for cancer by signing the National Cancer Act. Mahlon Hoagland, the President of the Worcester Foundation, responded to the initiative by appointing Professor Elwood V. Jensen, Director of the Ben May Cancer Research Laboratory at the University of Chicago, to be a member of the Foundation’s Scientific Advisory Board. Jensen had discovered the estrogen receptor (ER) as the putative mechanism of estrogen action in its target tissues [2]. The known link between estrogen and breast cancer suggested that “antiestrogenic strategies” might have potential as therapeutic agents [3]. Jensen applied knowledge of ER action to breast cancer treatment by devising the ER assay to identify breast cancers that would respond to endocrine ablation [4] but not all breast cancers responded. Hoagland’s plan was to encourage the exploitation of the rich resources in endocrinology at the Foundation to be used for cancer research. The scene was set for independent investigators to work in cancer endocrinology but it is fair to say no one in academic medical oncology was interested in development of new antihormone therapies. Combination cytotoxic chemotherapy was king. Industry and clinical trial groups were respectively convinced that 1) developing anticancer drugs was a very risky business and 2) the right combination of cytotoxic agents applied at the right time would cure cancer. The principle was working in childhood leukemia, why not breast cancer?

The authors first met at the Worcester Foundation during the closing months of 1972. By coincidence, we were both English and grew up in the same county of Cheshire. One of us (VCJ) had conducted a PhD (1968–72) on the structure activity relationships of a group of failed contraceptives, the nonsteroidal antiestrogens, the other (AMHB) had worked on hormones and breast cancer at the Christie Hospital in Manchester where the first preliminary study of ICI 46,474 was subsequently completed [5]. This was before ICI 46,474 was renamed tamoxifen (Figure 1).

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The activation of the pro drug tamoxifen to 4-hydroxytamoxifen which has a high binding affinity for ER [103]. This knowledge resulted in the development of numerous new agents for use as selective estrogen ER modulations (SERMs) for the prevention of breast cancer and osteoporosis or the pure antiestrogen fulvestrant used as a treatment for ER positive advanced breast cancer following the failure of either tamoxifen treatment or an aromatase inhibitor.

We have started this review with an account of our individual experiences that led to the development of tamoxifen and the aromatase inhibitors. Our perspective is followed by a description of the therapeutic target , the estrogen signal transduction system and we close with current clinical advances in antihormonal therapy.

Footnotes

The STAR trial compared and contrasted the efficacy of tamoxifen and raloxifene to reduce the incidence of breast cancer in postmenopausal women at high risk for breast cancer. Side effect profiles were a secondary endpoint. The RUTH trial is a placebo-controlled study to determine whether raloxifene would reduce the risk of coronary heart disease in high risk women.

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Footnotes

References

  • 1. Hoagland H The road to yesterday. Worcester MA: 1974. [PubMed][Google Scholar]
  • 2. Jensen EV, Jacobson HIBasic guides to the mechanism of estrogen action. Recent Progr Hormone Res. 1962;18:387–414.[PubMed][Google Scholar]
  • 3. Kennedy BJHormone therapy for advanced breast cancer. Cancer. 1965;18:1551–1557.[PubMed][Google Scholar]
  • 4. Jensen EV, Block GE, Smith S, Kyser K, DeSombre EREstrogen receptors and breast cancer response to adrenalectomy. Natl Cancer Inst Monogr. 1971;34:55–70.[PubMed][Google Scholar]
  • 5. 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;25:270–275.
  • 6. Harper MJ, Walpole ALA new derivative of triphenylethylene: effect on implantation and mode of action in rats. J Reprod Fertil. 1967;13:101–119.[PubMed][Google Scholar]
  • 7. Harper MJ, Walpole AL. Mode of action of I.C.I. 46,474 in preventing implantation in rats. J Endocrinol. 1967;37:83–92.[PubMed]
  • 8. Jordan VCThe development of tamoxifen for breast cancer therapy: a tribute to the late Arthur L. Walpole Breast Cancer Res Treat. 1988;11:197–209.[PubMed][Google Scholar]
  • 9. Huggins C, Grand LC, Brillantes FPMammary cancer induced by a single feeding of polynuclear hydrocarbons and their suppression. Nature. 1961;189:204.[PubMed][Google Scholar]
  • 10. Jordan VC, Koerner STamoxifen (ICI 46,474) and the human carcinoma 8S oestrogen receptor. Eur J Cancer. 1975;11:205–206.[PubMed][Google Scholar]
  • 11. Jordan VC. The antioestrogen tamoxifen (ICI 46,474) as an antitumour agent. Proceedings Eastern Cooperative Oncology Group Meeting; Miami, Florida. February 11–12 1974. [PubMed]
  • 12. Jordan VCAntiestrogenic and antitumor properties of tamoxifen in laboratory animals. Cancer Treat Rep. 1976;60:1409–19.[PubMed][Google Scholar]
  • 13. Jordan VCTamoxifen: a most unlikely pioneering medicine. Nature Reviews Drug Discovery. 2003;2:205–213.[PubMed][Google Scholar]
  • 14. Jordan VCTamoxifen (ICI 46,474) as a targeted therapy to treat and prevent breast cancer. Brit J Pharmacol. 2006;147:S269–S276.[Google Scholar]
  • 15. Jordan VC, Dowse LJTamoxifen as an anti-tumour agent: effect on oestrogen binding. J Endocrinol. 1976;68:297–303.[PubMed][Google Scholar]
  • 16. Jordan VC, Jaspan TTamoxifen as an antitumour agent: oestrogen binding as a predictive test for tumour response. J Endocrinol. 1976;68:453–460.[PubMed][Google Scholar]
  • 17. Jordan VCEffect of tamoxifen (ICI 46,474) on initiation and growth of DMBA- induced rat mammary carcinoma. Eur J Cancer. 1976;12:419–424.[PubMed][Google Scholar]
  • 18. Jordan VCUse of the DMBA-induced rat mammary carcinoma system for the evaluation of tamoxifen as a potential adjuvant therapy. Reviews on Endocrine-related Cancer. 1978:49–55. (October Supplement) [PubMed][Google Scholar]
  • 19. Jordan VC, Dix CJ, Allen KEThe effectiveness of long term tamoxifen treatment in a laboratory model for adjuvant hormone therapy of breast cancer. Adjuvant Therapy of Cancer. 1979;2:19–26.[PubMed][Google Scholar]
  • 20. Jordan VC, Allen KEEvaluation of the antitumour activity of the non-steroidal antioestrogen monohydroxytamoxifen in the DMBA-induced rat mammary carcinoma model. Eur J Cancer. 1980;16:239–251.[PubMed][Google Scholar]
  • 21. Tormey DC, Jordan VCLong-term tamoxifen adjuvant therapy in node-positive breast cancer: a metabolic and pilot clinical study. Breast Cancer Res Treat. 1984;4:297–302.[PubMed][Google Scholar]
  • 22. Tormey DC, Rasmussen P, Jordan VCLong-term adjuvant tamoxifen study: clinical update. Breast Cancer Res Treat. 1987;9:157–8.[PubMed][Google Scholar]
  • 23. AnonymousReview of mortality results in randomized trials in early breast cancer. Lancet. 1984;ii:1205.[PubMed][Google Scholar]
  • 24. 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.[PubMed]
  • 25. Consensus ConferenceAdjuvant chemotherapy for breast cancer. Journal of the American Medical Association. 1985;254:3461–3463.[PubMed][Google Scholar]
  • 26. Schwarzel WC, Kruggel WG, Brodie HJ. Studies on the mechanism of estrogen biosynthesis. 8 The development of inhibitors of the enzyme system in human placenta . Endocrinology. 1973;92:866–80.[PubMed]
  • 27. Brodie AMH, Schwarzel WC, Shaikh AA, Brodie HJThe effect of an aromatase inhibitor, 4-hydroxy-4-androstene-3,17-dione, on estrogen dependent processes in reproduction and breast cancer. Endocrinology. 1977;100:1684–1695.[PubMed][Google Scholar]
  • 28. Brodie AM, Garrett WM, Hendrickson JR, Tsai-Morris CH, Marcotte PA, Robinson CHInactivation of aromatase in vitro by 4-hydroxy-4-androstene-3,17-dione and 4-acetoxy-4-androstene-3,17-dione and sustained effects in vivo. Steroids. 1981;38:693–702.[PubMed][Google Scholar]
  • 29. Brodie AM, Longcope CInhibition of peripheral aromatization by aromatase inhibitors, 4-hydroxy- and 4-acetoxy-androstene-3,17-dione. Endocrinology. 1980;106:19–21.[PubMed][Google Scholar]
  • 30. Samojlik E, Santen RJ, Wells SA. Adrenal suppression with aminoglutethimide. II Differential effects of aminoglutethimide on plasma androstenedione and estrogen levels. J Clin Endocrinol Metab. 1977;45:480–7.[PubMed]
  • 31. Lipton A, Santen RJMedical adrenalectomy using aminoglutethimide and dexamethasone in advanced breast cancer. Cancer. 1974;33:503–512.[PubMed][Google Scholar]
  • 32. Santen RJ, Worgul TJ, Samojlik E, Interrante A, Boucher AE, Lipton A, Harvey HA, White DS, Smart E, Cox C, Wells SAA randomized trial comparing surgical adrenalectomy with aminoglutethimide plus hydrocortisone in women with advanced breast cancer. N Engl J Med. 1981;305:545–51.[PubMed][Google Scholar]
  • 33. Santen RJ, Wells SAThe use of aminoglutethimide in the treatment of patients with metastatic carcinoma of the breast. Cancer. 1980;46:1066–1074.[PubMed][Google Scholar]
  • 34. Jensen EV, Jordan VC. The estrogen receptor: a model for molecular medicine. The Dorothy P Landon AACR Prize for Translational Research . Clin Cancer Res. 2003;9:1980–1989.[PubMed]
  • 35. Inkster SE, Brodie AMExpression of aromatase cytochrome P-450 in premenopausal and postmenopausal human ovaries: an immunocytochemical study. J Clin Endocrinol Metab. 1991;73:717–26.[PubMed][Google Scholar]
  • 36. MacClusky NJ, Naftolin FSexual differentiation of the central nervous system. Science. 1981;211:1294–1303.[PubMed][Google Scholar]
  • 37. Balthazart J Advances in Comparative and Environmental Phvsiology. 1989. Steroid metabolism, and the activation of social behavior. [PubMed][Google Scholar]
  • 38. Longcope C, Pratt JH, Schneider SH, Fineberg SEAromatization of androgens by muscle and adipose tissue in vivo. J Clin Endocrinol Metab. 1978;46:146–52.[PubMed][Google Scholar]
  • 39. Hemsell DL, Grodin JM, Brenner PF, Siiteri PK, MacDonald PC. Plasma precursors of estrogen. II Correlation of the extent of conversion of plasma androstenedione to estrone with age. J Clin Endocrinol Metab. 1974;38:476–9.[PubMed]
  • 40. van Landeghem AA, Poortman J, Nabuurs M, Thijssen JHEndogenous concentration and subcellular distribution of estrogens in normal and malignant human breast tissue. Cancer Res. 1985;45:2900–6.[PubMed][Google Scholar]
  • 41. Blankenstein MA, Szymczak J, Daroszewski J, Milewicz A, Thijssen JHEstrogens in plasma and fatty tissue from breast cancer patients and women undergoing surgery for non-oncological reasons. Gynecol Endocrinol. 1992;6:13–7.[PubMed][Google Scholar]
  • 42. Covey DF, Hood WF, Beusen DD, Carrell HLHydroperoxides as inactivators of aromatase: 10 beta-hydroperoxy-4-estrene-3,17-dione, crystal structure and inactivation characteristics. Biochemistry. 1984;23:5398–406.[PubMed][Google Scholar]
  • 43. Hahn EF, Fishman J. Immunological probe of estrogen biosynthesis. Evidence for the 2 beta-hydroxylative pathway in aromatization of androgens. J Biol Chem. 1984;259:1689–94.[PubMed]
  • 44. Cole PA, Bean JM, Robinson CHConversion of a 3-desoxysteroid to 3-desoxyestrogen by human placental aromatase. Proc Natl Acad Sci U S A. 1990;87:2999–3003.[Google Scholar]
  • 45. Kao YC, Korzekwa KR, Laughton CA, Chen S. Evaluation of the mechanism of aromatase cytochrome P450. A site-directed mutagenesis study. Eur J Biochem. 2001;268:243–51.[PubMed]
  • 46. Hackett JC, Brueggemeier RW, Hadad CMThe final catalytic step of cytochrome p450 aromatase: a density functional theory study. J Am Chem Soc. 2005;127:5224–37.[PubMed][Google Scholar]
  • 47. Brodie A, Garrett W, Hendrickson JM, Marsh DA, Brodie HJThe effect of 1,4,6-androstatriene-3,17-dione (ATD) on DMBA-induced mammary tumors in the rat and its mechanism of action in vivo. Biochem Pharmacol. 1982;31:2017–2023.[PubMed][Google Scholar]
  • 48. Brodie AMH, Schwarzel WC, Brodie HJStudies on the mechanism of estrogen biosynthesis in the rat ovary-1. J Steroid Biochem. 1976;7:787–793.[PubMed][Google Scholar]
  • 49. Brodie AMH, Marsh DA, Brodie HJ. Aromatase inhibitors IV. Regression of estrogen-dependent mammary tumors in the rat with 4-acetoxy-4-androstene-3, 17-dione. J Steroid Biochem. 1979;10:423–429.[PubMed]
  • 50. Sjoerdsma ASuicide inhibitors as potential drugs. Clin Pharmac Ther. 1981;30:3–22.[PubMed][Google Scholar]
  • 51. Hong Y, Yu B, Yuan Y-C, Zhou D, Chen SMolecular basis for the aromatization reaction and exemestane-mediated irreversible inhibition of human aromatase. Molecular Endocrinoloogy. 2006 (in press) [[PubMed][Google Scholar]
  • 52. Favia AD, Cavalli A, Masetti M, Carotti A, Recanatini MThree-dimensional model of the human aromatase enzyme and density functional parameterization of the iron-containing protoporphyrin IX for a molecular dynamics study of heme-cysteinato cytochromes. Proteins. 2006;62:1074–87.[PubMed][Google Scholar]
  • 53. Brueggemeier R, Li P-K, Snider CE, Darby MV, Katlic NE7α-Substituted androstenediones as effective in vitro and in vivo inhibitors of aromatase. Steroids. 1987;50:163–178.[PubMed][Google Scholar]
  • 54. Brueggemeier R, Li P-K, Chen HH, Moh PP, Katlic NEBiochemical pharmacology of new 7-substituted androstenediones as inhibitors of aromatase. J Steroid Biochem Molec Biol. 1990;37:379–385.[PubMed][Google Scholar]
  • 55. Henderson D, Norbirath G, Kerb U1-Methyl-1,4-androstadiene-3,17-dione (SH 489):Characterization of an irreversible inhibitor of estrogen biosynthesis. J Steroid Biochem Molec Biol. 1986;24:303–306.[PubMed][Google Scholar]
  • 56. Metcalf BW, Wright CL, Burkhart JP, Johnston JOSubstrate-induced inactivation of aromatase by allenic and acetylenic steroids. Journal of American Chem Society. 1981;103:3221–3222.[PubMed][Google Scholar]
  • 57. Zaccheo T, Giudici D, Ornati G, Panzeri A, DiSalle EComparison of the effects of the irreversible aromatase inhibitor exemestane with atamestane and MDL-18962 in rats with DMBA-induced mammary tumors. Eur J Cancer. 1991;27:1145–1150.[PubMed][Google Scholar]
  • 58. Evans T, DiSalle E, Ornati G, et al Phase I and endocrine study of exemestane (FCE 24304), a new aromatase inhibitor, in postmenopausal women. Cancer Res. 1992;52:5933–5939.[PubMed][Google Scholar]
  • 59. Bajetta EZN, Noberasco C, et al The minimal effective exemestane dose for endocrine activity in advanced breast cancer. Eur J Cancer. 1997;33:587–591.[PubMed][Google Scholar]
  • 60. Geisler JKN, Anker G, et al In vivo inhibition of aromatization by exemestane, a novel irreversible aromatase inhibitor, in postmenopausal breast cancer patients. Clin Cancer Res. 1998;4:29–2093.[PubMed][Google Scholar]
  • 61. Lonning P, Bajetta E, Murray R, et al Activity of exemestane in metastatic breast cancer after failure of nonsteroidal aromatase inhibitors: a phase II trial. J Clin Oncol. 2000;18:2234–2244.[PubMed][Google Scholar]
  • 62. Jefcoate CRMeasurement of substrate and inhibitor binding to microsomal cytochrome P-450 by optical-difference spectroscopy. Methods Enzymol. 1978;52:258–79.[PubMed][Google Scholar]
  • 63. Dawson JH, Andersson LA, Sono M. Spectroscopic investigations of ferric cytochrome P-450-CAM ligand complexes. Identification of the ligand trans to cysteinate in the native enzyme. J Biol Chem. 1982;257:3606–17.[PubMed]
  • 64. Cash R, Brough AJ, Cohen MNP, Satoh PS. Aminoglutethimide (Elipten-CIBA) as an inhibitor of adrenal steroidogenesis. Mechanism of action and therapeutic trial. J Clin Endocrinol Metab. 1967;27:1239–1248.[PubMed]
  • 65. Simpson E, Mahendroo MS, Means GD, et al Tissue-specific promoters regulate aromatase cytochrome P450 expression. J Steroid Biochem Mol Biol. 1993;44:321–330.[PubMed][Google Scholar]
  • 66. Zhao Y, Agarwal VR, Mendelson CR, et al Transcriptional regulation of CYP19 gene (aromatase) expression in adipose stromal cells in primary culture. J Steroid Biochem Mol Biol. 1997;61:203–210.[PubMed][Google Scholar]
  • 67. Simpson E, Clyne C, Rubin G, et al Aromatase--a brief overview. Annu Rev Physiol. 2002;64:93–127.[PubMed][Google Scholar]
  • 68. Safi R, Kovacic A, Gaillard S, Murata Y, Simpson ER, McDonnell DP, Clyne CDCoactivation of liver receptor homologue-1 by peroxisome proliferator-activated receptor gamma coactivator-1alpha on aromatase promoter II and its inhibition by activated retinoid X receptor suggest a novel target for breast-specific antiestrogen therapy. Cancer Res. 2005;65:11762–70.[PubMed][Google Scholar]
  • 69. Su B, Diaz-Cr ES, Landini S, Brueggemeier RWNovel sulfonanilide analogues suppress aromatase expression and activity in breast cancer cells independent of COX-2 inhibition. J Med Chem. 2006;49:1413–1419.[PubMed][Google Scholar]
  • 70. Jordan VCSelective estrogen receptor modulation: a personal perspective. Cancer Res. 2001;61:5683–5687.[PubMed][Google Scholar]
  • 71. Smith CL, O'Malley BWCoregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocrine Reviews. 2004;25:45–71.[PubMed][Google Scholar]
  • 72. Wakeling AE, Dukes M, Bowler JA potent specific pure antiestrogen with clinical potential. Cancer Res. 1991;51:3867–73.[PubMed][Google Scholar]
  • 73. Pike AC, Brzozowski AM, Walton J, Hubbard RE, Thorsell A, Li Y, Gustafsson J, Carlquist MStructural insights into the mode of action of a pure antiestrogen. Structure. 2001 Feb;9:145–153.[PubMed][Google Scholar]
  • 74. Wijayaratne AL, McDonnell DPThe human estrogen receptor-alpha is a ubiquitinated protein whose stability is affected differentially by agonists, antagonists, and selective estrogen receptor modulators. J Biol Chem. 2001;276:35684–35692.[PubMed][Google Scholar]
  • 75. EBCTCGSystemic 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.[PubMed][Google Scholar]
  • 76. EBCTCGTamoxifen for early breast cancer: an overview of the randomised trials. Lancet. 1998;354:1451–1467.[PubMed][Google Scholar]
  • 77. EBCTCGEffects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365:1687–1717.[PubMed][Google Scholar]
  • 78. Ravdin PM, Fritz NF, Tormey DC, Jordan VCEndocrine status of premenopausal node-positive breast cancer patients following adjuvant chemotherapy and long-term tamoxifen. Cancer Res. 1988;48:1026–9.[PubMed][Google Scholar]
  • 79. Jordan VC, Fritz NF, Langan-Fahey S, Thompson M, Tormey DCAlteration of endocrine parameters in premenopausal women with breast cancer during long-term adjuvant therapy with tamoxifen as the single agent. J Natl Cancer Inst. 1991;83:1488–1491.[PubMed][Google Scholar]
  • 80. Colleoni M, Gelber S, Goldhirsch A, Aebi S, Castiglione-Gertsch M, Price KN, Coates AS, Gelber RDTamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13–93. J Clin Oncol. 2006;24:1332–41.[PubMed][Google Scholar]
  • 81. Fisher B, Dignam J, Bryant J, Wolmark NFive versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst. 2001;93:684–690.[PubMed][Google Scholar]
  • 82. Perez-Carrion R, Alberola V, Calabresi F, Michel R-T, Santos R, Fehling M, Royce CM, Trunet PFRandomized trial of the selective aromatase inhibitor formestane (Lentaron) versus tamoxifen as first-line hormonal therapy in postmenopausal patients with advanced breast cancer. The Breast. 1993;3:198–199.[PubMed][Google Scholar]
  • 83. Demers LM, Lipton A, Harvey HA, Kambic KB, Grossberg H, Brady C, Santen RJThe efficacy of CGS 20267 in suppressing estrogen biosynthesis in patients with advanced stage breast cancer. J Steroid Biochem Mol Biol. 1993;44:687–91.[PubMed][Google Scholar]
  • 84. Bonneterre J, Thurlimann B, Robertson JF, Krzakowski M, Mauriac L, Koralewski P, Vergote I, Webster A, Steinberg M, von Euler MAnastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol. 2000;18:3748–57.[PubMed][Google Scholar]
  • 85. Nabholtz JM, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A, Steinberg M, Webster A, von Euler MAnastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group J Clin Oncol. 2000;18:3758–67.[PubMed][Google Scholar]
  • 86. Bonneterre J, Buzdar A, Nabholtz JM, Robertson JF, Thurlimann B, von Euler M, Sahmoud T, Webster A, Steinberg MAnastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma. Cancer. 2001;92:2247–58.[PubMed][Google Scholar]
  • 87. Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, Apffelstaedt J, Smith R, Sleeboom HP, Janicke F, Pluzanska A, Dank M, Becquart D, Bapsy PP, Salminen E, Snyder R, Lassus M, Verbeek JA, Staffler B, Chaudri-Ross HA, Dugan MSuperior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol. 2001;19:2596–606.[PubMed][Google Scholar]
  • 88. Paridaens R, Dirix L, Lohrisch C, Beex L, Nooij M, Cameron D, Biganzoli L, Cufer T, Duchateau L, Hamilton A, Lobelle JP, Piccart MMature results of a randomized phase II multicenter study of exemestane versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer. Ann Oncol. 2003;14:1391–8.[PubMed][Google Scholar]
  • 89. Paridaens R, Therasse P, Dirix LFirst-line hormonal treatment (HT) for metastatic breast cancer (MBC) with exemestane (E) or tamoxifen (T) in postmenopausal patients (pts) - a randomized phase III trial of the EORTC Group. J Clinical Oncology. 2004;22[PubMed][Google Scholar]
  • 90. Pritchard KIEndocrine therapy of advanced disease: analysis and implications of the existing data. Clin Cancer Res. 2003;9:460S–7S.[PubMed][Google Scholar]
  • 91. Brodie A, Lu Q, Long BAromatase and its inhibitors. J Steroid Biochem Mol Biol. 1999;69:205–10.[PubMed][Google Scholar]
  • 92. Santen RJ, Harvey HAUse of aromatase inhibitors in breast carcinoma. Endocr Relat Cancer. 1999;6:75–92.[PubMed][Google Scholar]
  • 93. Long BJ, Jelovac D, Handratta V, Thiantanawat A, MacPherson N, Ragaz J, Goloubeva OG, Brodie AMTherapeutic strategies using the aromatase inhibitor letrozole and tamoxifen in a breast cancer model. JNCI. 2004;96:456–65.[PubMed][Google Scholar]
  • 94. Baum M, Budzar AU, Cuzick J, Forbes J, Houghton JH, Klijn JG, Sahmoud TAnastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomized trial. Lancet. 2002;359:2131–2139.[PubMed][Google Scholar]
  • 95. Goss PE, Ingle JN, Marino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JLA randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003;349:1–10.[PubMed][Google Scholar]
  • 96. Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, Jones SE, Alvarez I, Bertelli G, Ortmann O, Coates AS, Bajetta E, Dodwell D, Coleman RE, Fallowfield LJ, Mickiewicz E, Andersen J, Lonning PE, Cocconi G, Stewart A, Stuart N, Snowdon CF, Carpentieri M, Massimini G, Bliss JMA randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004;350:1081–92.[PubMed][Google Scholar]
  • 97. Winer EP, Hudis C, Burstein HJ, Wolff AC, Pritchard KI, Ingle JN, Chlebowski RT, Gelber R, Edge SB, Gralow J, Cobleigh MA, Mamounas EP, Goldstein LJ, Whelan TJ, Powles TJ, Bryant J, Perkins C, Perotti J, Braun S, Langer AS, Browman GP, Somerfield MRAmerican Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol. 2005;23:619–29.[PubMed][Google Scholar]
  • 98. Baum M, Buzdar A, Cuzick J, Forbes J, Houghton J, Howell A, Sahmoud TAnastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer. 2003;98:1802–10.[PubMed][Google Scholar]
  • 99. Ingle JAromatase inhibition and antiestrogen therapy in early breast cancer treatmen and chemoprevention. Oncology (Huntingt) 2001;15:28–34.[PubMed][Google Scholar]
  • 100. Wasan KM, Goss PE, Pritchard PH, Shepherd L, Palmer MJ, Liu S, Tu D, Ingle JN, Heath M, Deangelis D, Perez EAThe influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG MA 17L) Ann Oncol. 2005;16:707–15.[PubMed][Google Scholar]
  • 101. Thurlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Rabaglio M, Smith I, Wardly A, Price KN, Goldhirsch A BIG Group IC (Breast International Group) A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005;353:2747–57.[PubMed]
  • 102. Jordan VCBiochemical pharmacology of antiestrogen action. Pharmacol Rev. 1984;36:245–76.[PubMed][Google Scholar]
  • 103. Jordan VC, Collins MM, Rowsby L, Prestwich GA monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J Endocrinol. 1977;75:305–16.[PubMed][Google Scholar]
  • 104. Allen KE, Clark ER, Jordan VCEvidence for the metabolic activation of non-steroidal antioestrogens: a study of structure-activity relationships. Br J Pharmacol. 1980;71:83–91.[Google Scholar]
  • 105. Beall PT, Misra KL, Young RL, Spiut HJ, Evan HJ, LeBlanc AClomiphene protects against osteoporosis in the mature ovariectomized rat. Calcif Tissue Int. 1985;36:123–125.[PubMed][Google Scholar]
  • 106. Jordan VC, Phelps E, Lindgren JUEffects of anti-estrogens on bone in castrated and intact female rats. Breast Cancer Res Treat. 1987;10:31–5.[PubMed][Google Scholar]
  • 107. Turner RT, Wakley GK, Hannon KS, Bell NHTamoxifen prevents the skeletal effects of ovarian hormone deficiency in rats. J Bone Miner Res. 1987;2:449–56.[PubMed][Google Scholar]
  • 108. Turner RT, Wakley GK, Hannon KS, Bell NHTamoxifen inhibits osteoclast-mediated resorption of trabecular bone in ovarian hormone-deficient rats. Endocrinology. 1988;122:1146–50.[PubMed][Google Scholar]
  • 109. Turken S, Siris E, Seldin D, Flaster E, Hyman G, Lindsay REffects of tamoxifen on spinal bone density in women with breast cancer. J Natl Cancer Inst. 1989;81:1086–8.[PubMed][Google Scholar]
  • 110. Love RR, Mazess RB, Barden HS, Epstein S, Newcomb PA, Jordan VC, Carbone PP, DeMets DLEffects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med. 1992;326:852–6.[PubMed][Google Scholar]
  • 111. Love RR, Newcomb PA, Wiebe DA, Surawicz TS, Jordan VC, Carbone PP, DeMets DLEffects of tamoxifen therapy on lipid and lipoprotein levels in postmenopausal patients with node-negative breast cancer. J Natl Cancer Inst. 1990;82:1327–32.[PubMed][Google Scholar]
  • 112. Love RR, Wiebe DA, Newcomb PA, Cameron L, Leventhal H, Jordan VC, Feyzi J, DeMets DLEffects of tamoxifen on cardiovascular risk factors in postmenopausal women. Ann Intern Med. 1991;115:860–4.[PubMed][Google Scholar]
  • 113. Gottardis MM, Robinson SP, Satyaswaroop PG, Jordan VCContrasting actions of tamoxifen on endometrial and breast tumor growth in the athymic mouse. Cancer Res. 1988;48:812–815.[PubMed][Google Scholar]
  • 114. Hardell LTamoxifen as risk factor for carcinoma of corpus uterus. Lancet. 1988;ii:563.[PubMed][Google Scholar]
  • 115. Jordan VCTamoxifen and endometrial cancer [letter] Lancet. 1988;2:1019.[PubMed][Google Scholar]
  • 116. Fornander T, Rutqvist LE, Cedermark B, Glas U, Mattsson A, Silfversward C, Skoog L, Somell A, Theve T, Wilking N, Hjalmar MLAdjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet. 1989;1:117–20.[PubMed][Google Scholar]
  • 117. Neven P, DeMylder X, VanBelle Y, Vanderick G, DeMylder ETamoxifen and the uterus and endometrium. Lancet. 1989:375.[PubMed][Google Scholar]
  • 118. Stewart HJ, Knight GMTamoxifen and the uterus and endometrium. Lancet. 1989;i:375–376.[PubMed][Google Scholar]
  • 119. Fisher B, Costantino JP, Redmond CK, Fisher ER, Wickerham DL, Cronin WMEndometrial 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.[PubMed][Google Scholar]
  • 120. Magriples U, Naftolin F, Schwartz PE, Carcangui MLHigh grade endometrial carcinoma in tamoxifen treated breast cancer patients. Journal of Clinical Oncology. 1993;11:485–490.[PubMed][Google Scholar]
  • 121. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark NTamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90:1371–1388.[PubMed][Google Scholar]
  • 122. Fisher B, Costantino JP, Wickerham DL, Cecchini RS, Cronin WM, Robidoux A, Bevers TB, Kavanah MT, Atkins JN, Margolese RG, Runowicz CD, James JM, Ford LG, Wolmark NTamoxifen 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.[PubMed][Google Scholar]
  • 123. Buzdar A, Marcus C, Holmes F, Hug V, Hortobagyi GPhase II evaluation of Ly156758 in metastatic breast cancer. Oncology. 1988;45:344–5.[PubMed][Google Scholar]
  • 124. Gottardis MM, Jordan VCAntitumor actions of keoxifene and tamoxifen in the N-nitrosomethylurea-induced rat mammary carcinoma model. Cancer Res. 1987;47:4020–4.[PubMed][Google Scholar]
  • 125. Jordan VCChemosuppression of breast cancer with tamoxifen: laboratory evidence and future clinical investigations. Cancer Invest. 1988;6:589–95.[PubMed][Google Scholar]
  • 126. Lerner LJ, Jordan VCThe development of antiestrogens for the treatment of breast cancer: Eighth Cain Memorial Award Lecture. Cancer Res. 1990;50:4177–4189.[PubMed][Google Scholar]
  • 127. Black LJ, Jones CD, Falcone JFAntagonism of estrogen action with a new benzothiophene derived antiestrogen. Life Sci. 1983;32:1031–1036.[PubMed][Google Scholar]
  • 128. Jordan VC, Gosden BInhibition of the uterotropic activity of estrogens and antiestrogens by the short acting antiestrogen LY117018. Endocrinology. 1983;113:463–8.[PubMed][Google Scholar]
  • 129. Gottardis MM, Ricchio ME, Satyaswaroop PG, Jordan VCEffect 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][Google Scholar]
  • 130. Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, Christiansen C, Delmas PD, Zanchetta JR, Stakkestad J, Gluer CC, Krueger K, Cohen FJ, Eckert S, Ensrud KE, Avioli LV, Lips P, Cummings SRReduction 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.[PubMed][Google Scholar]
  • 131. Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, Norton L, Nickelsen T, Bjarnason NH, Morrow M, Lippman ME, Black D, Glusman JE, Costa A, Jordan VC. 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;281:2189–2197.[PubMed]
  • 132. Cauley JA, Norton L, Lippman ME, Eckert S, Krueger KA, Purdie DW, Farrerons J, Karasik A, Mellstrom D, Ng KW, Stepan JJ, Powles TJ, Morrow M, Costa A, Silfen SL, Walls EL, Schmitt H, Muchmore DB, Jordan VC, Ste-Marie LG. 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.[PubMed]
  • 133. Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, Bevers TB, Fehrenbacher L, Pajon ER, jr, Wade IJL, Robidoux A, Margolese RG, James J, Lippman SM, Runowicz CD, Ganz PA, Reis SE, McCaskill-Stevens W, Ford LG, Jordan VC, Wolmark NThe Study of Tamoxifen and Raloxifene (STAR): Report of the National Surgical Adjuvant Breast and Bowel Project P-2 Trial. JAMA. 2006;295:2727–2741.[PubMed][Google Scholar]
  • 134. Walsh BW, Kuller LH, Wild RA, Paul S, Farmer M, Lawrence JB, Shah AS, Anderson PWEffects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA. 1998;279:1445–1451.[PubMed][Google Scholar]
  • 135. Barrett-Connor E, Mosca L, Collins P, Geiger MJ, Grady D, Kornitzer M, McNabb MA, Wenger NKEffects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;355:125–37.[PubMed][Google Scholar]
  • 136. Jordan VC. Antiestrogens and selective estrogen receptor modulators as multifunctional medicines. 2 Clinical considerations and new agents. J Med Chem. 2003;46:1081–111.[PubMed]
  • 137. Ariazi EA, Ariazi JL, Cordera F, Jordan VCEstrogen receptors as therapeutic targets in breast cancer. Current Topics in Medicinal Chemistry. 2006;6:195–216.[PubMed][Google Scholar]
  • 138. Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY, Tobias JS, Group ATResults of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet. 2005;365:60–62.[PubMed][Google Scholar]
  • 139. Goss PEBreast cancer prevention--clinical trials strategies involving aromatase inhibitors. J Steroid Biochem Mol Biol. 2003;86:487–93.[PubMed][Google Scholar]
  • 140. Cavalieri E, Chakravarti D, Guttenplan J, Hart E, Ingle J, Jankowiak R, Muti P, Rogan E, Russo J, Santen R, Sutter TCatechol estrogen quinones as initiators of breast and other human cancers: implications for biomarkers of susceptibility and cancer prevention. Biochim Biophys Acta. 2006;1766:63–78.[PubMed][Google Scholar]
  • 141. Russo J, Fernandez SV, Russo PA, Fernbaugh R, Sheriff FS, Lareef HM, Garber J, Russo IH17-Beta-estradiol induces transformation and tumorigenesis in human breast epithelial cells. Faseb J. 2006;20:1622–34.[PubMed][Google Scholar]
  • 142. Jelovac D, Sabnis G, Long BJ, Goloubeva OG, Brodie AMHActivation of MAPK in xenografts and cells during prolonged treatment with aromatase inhibitor letrozole. Cancer Res. 2005;65:5380–5389.[PubMed][Google Scholar]
  • 143. Jelovac D, Macedo L, Goloubeva OG, Handratta V, Brodie AMHAdditive antitumor effect of aromatase inhibitor letrozole and antiestrogen fulvestrant in a postmenopausal breast cancer model. Cancer Res. 2005;65:5439–5444.[PubMed][Google Scholar]
  • 144. Pink JJ, Jordan VCModels of estrogen receptor regulation by estrogens and antiestrogens in breast cancer cell lines. Cancer Res. 1996;56:2321–30.[PubMed][Google Scholar]
  • 145. Welshons WV, Jordan VCAdaptation of estrogen-dependent MCF-7 cells to low estrogen (phenol red-free) culture. Eur J Cancer. 1987;232:1935–1939.[PubMed][Google Scholar]
  • 146. Jiang SY, Wolf DM, Yingling JM, Chang C, Jordan VCAn estrogen receptor positive MCF-7 clone that is resistant to antiestrogens and estradiol. Mol and Cell Endo. 1992;90:77–80.[PubMed][Google Scholar]
  • 147. Pink JJ, Bilimoria MM, Assikis J, Jordan VCIrreversible loss of the oestrogen receptor in T47D breast cancer cells following prolonged oestrogen deprivation. Br J Cancer. 1996;74:1227–36.[Google Scholar]
  • 148. Jordan VCSelective estrogen receptor modulation: concept and consequences in cancer. Cancer Cell. 2004;5:207–213.[PubMed][Google Scholar]
  • 149. Lewis JS, Osipo C, Meeke K, Jordan VCEstrogen induced apoptosis in breast cancer model resistant to long-term estrogen withdrawal. J Steroid Biochem Mol Biol. 2005;94:131–141.[PubMed][Google Scholar]
  • 150. Lewis JS, Meeke K, Osipo C, Bell E, Kidawi N, Chandel NS, Jordan VCIntrinsic mechanism of estradiol-induced apoptosis in breast cancer cells resistant to estrogen deprivation. JNCI. 2005;97:1746–59.[PubMed][Google Scholar]
  • 151. Yao K, Lee ES, Bentrem DJ, England G, Schafer JI, O'Regan RM, Jordan VCAntitumor action of physiological estradiol on tamoxifen-stimulated breast tumors grown in athymic mice. Clin Cancer Res. 2000;6:2028–36.[PubMed][Google Scholar]
  • 152. Liu H, Lee ES, Gajdos C, Pearce ST, Chen B, Osipo C, Loweth J, McKian K, De Los Reyes A, Wing L, Jordan VCApoptotic action of 17beta-estradiol in raloxifene-resistant MCF-7 cells in vitro and in vivo. J Natl Cancer Inst. 2003;95:1586–97.[PubMed][Google Scholar]
  • 153. Osipo C, Gajdos C, Liu H, Chen B, Jordan VCParadoxical action of fulvestrant on estradiol-induced regression of tamoxifen-stimulated breast cancer. J Natl Cancer Inst. 2003;95:1597–1607.[PubMed][Google Scholar]
  • 154. Lonning PE, Taylor PD, Anker G, Iddon J, Wie L, Jorgensen LM, Mella O, Howell AHigh-dose estrogen treatment in postmenopausal breast cancer patients heavily exposed to endocrine therapy. Breast Cancer Res Treat. 2001;67:111–116.[PubMed][Google Scholar]
  • 155. Jordan VC, Lewis JS, Osipo C, Cheng DThe apoptotic action of estrogen following exhaustive antihormonal therapy: a new clinical treatment strategy. The Breast. 2005;14:624–630.[PubMed][Google Scholar]
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