Skip to main content

Treatment of Metastatic Breast Cancer: Endocrine Therapy

  • Chapter
  • First Online:
Breast Disease
  • 891 Accesses

Abstract

Estrogen plays a primary role in breast cancer carcinogenesis and functions similarly to growth factors in some subtypes of breast cancer cells, particularly hormone receptor-positive (HR+) cells. Reducing estrogen production and preventing estrogen from interacting with the estrogen receptor pathway have been the focus of several preclinical and clinical trials and are commonly used strategies for treating HR+ breast cancer. Because the ovaries are the main source of estrogen in premenopausal women, ovarian ablation or functional suppression is the primary means of decreasing circulating estrogen. In postmenopausal women, estrogen production by the ovaries is functionally inactive, and the peripheral conversion of androgens to estrogen is the predominant source of estrogen. Thus, the inhibition of the conversion of androgens by an aromatase inhibitor and of the interaction of estrogen with its receptor are the most frequently used approaches to treat postmenopausal women with HR+ breast cancer. Initial endocrine treatment is a relevant option for patients with locally advanced or metastatic HR+ breast cancer who have no or mild symptomatic disease. Patients in whom breast cancer has progressed during the adjuvant or first-line endocrine treatment or within 1 year after adjuvant endocrine treatment termination should be evaluated for a non-cross-resistant second-line endocrine agent. The concurrent administration of an endocrine agent with a human epidermal growth factor receptor (HER2)-directed agent is also widely accepted for breast cancer patients with both HR and HER2 receptor positivity.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 119.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.

    Article  PubMed  Google Scholar 

  2. Criscitiello C, Andre F, Thompson AM, De Laurentiis M, Esposito A, Gelao L, et al. Biopsy confirmation of metastatic sites in breast cancer patients: clinical impact and future perspectives. Breast Cancer Res. 2014;16(2):205.

    Article  PubMed  PubMed Central  Google Scholar 

  3. 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;365:1687–717.

    Article  CAS  Google Scholar 

  4. Lu J, Steeg PS, Price JE, Krishnamurthy S, Mani SA, Reuben J, et al. Breast cancer metastasis: challenges and opportunities. Cancer Res. 2009;69(12):4951–3.

    Article  CAS  PubMed  Google Scholar 

  5. Tsai MJ, O’Malley BW. Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu Rev Biochem. 1994;63:451–86.

    Article  CAS  PubMed  Google Scholar 

  6. Horwitz KB, Jackson TA, Bain DL, Richer JK, Takimoto GS, Tung L, et al. Nuclear receptor coactivators and corepressors. Mol Endocrinol. 1996;10(10):1167–77.

    CAS  PubMed  Google Scholar 

  7. Huet G, Mérot Y, Le Dily F, Kern L, Ferrière F, Saligaut C, et al. Loss of E-cadherin-mediated cell contacts reduces estrogen receptor alpha (ER alpha) transcriptional efficiency by affecting the respective contribution exerted by AF1 and AF2 transactivation functions. Biochem Biophys Res Commun. 2008;365(2):304–9.

    Article  CAS  PubMed  Google Scholar 

  8. Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, et al. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science. 1995;270(5241):1491–4.

    Article  CAS  PubMed  Google Scholar 

  9. Parikh PM, Gupta S, Dawood S, Rugo H, Bhattacharyya GS, Agarwal A, et al. ICON 2013: practical consensus recommendations for hormone receptor-positive HER2-negative advanced or metastatic breastcancer. Indian J Cancer. 2014;51(1):73–9.

    Article  CAS  PubMed  Google Scholar 

  10. Yang YF, Liao YY, Yang M, Peng NF, Xie SR, Xie YF, et al. Discordances in ER, PR and HER2 receptors between primary and recurrent/metastatic lesions and their impact on survival in breast cancer patients. Med Oncol. 2014;31(10):214.

    Article  PubMed  CAS  Google Scholar 

  11. Chang HJ, Han SW, Oh DY, Im SA, Jeon YK, Park IA, et al. Discordant human epidermal growth factor receptor 2 and HR status in primary and MBC and response to trastuzumab. Jpn J Clin Oncol. 2011;41(5):593–9.

    Article  PubMed  Google Scholar 

  12. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Breast Cancer, Version 1. 2019. http://www.nccn.org/professionals/physiciangls/pdf/breast.pdf.

  13. National Collaborating Centre for Cancer (UK). Advanced breast cancer: diagnosis and treatment. Cardiff: National Collaborating Centre for Cancer (UK); 2009. p. 90–332.

    Google Scholar 

  14. Wilcken N, Hornbuckle J, Ghersi D. Chemotherapy alone versus endocrine therapy alone for metastatic breast cancer. Cochrane Database Syst Rev. 2003;(2). Art. No.: CD002747. https://doi.org/10.1002/14651858.CD002747.

  15. Partridge AH, Rumble RB, Carey LA, Come SE, Davidson NE, Di Leo A, et al. Chemotherapy and targeted therapy for women with human epidermal growth factor receptor 2-negative (or unknown) advanced breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2014;32(29):3307–29.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Dutta U, Pant K. AIs: past, present and future in breast cancer therapy. Med Oncol. 2008;25:113–24.

    Article  CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

  18. Paterson R, Russel MH. Clinical trials in malignant disease. Part II-breast cancer: value of irradiation of the ovaries. J Fac Radiol. 1959;10:130–3.

    Article  CAS  PubMed  Google Scholar 

  19. Jensen EV, Greene GL, Closs LE, DeSombre ER, Nadji M. Receptors reconsidered: a 20-year perspective. Recent Prog Horm Res. 1982;38:1–40.

    CAS  PubMed  Google Scholar 

  20. Blamey RW, Jonat W, Kaufmann M, Bianco AR, Namer M. Goserelin depot in the treatment of premenopausal advanced breast cancer. Eur J Cancer. 1992;28:810–4.

    Article  Google Scholar 

  21. Foekens JA, Henkelman ME, Fukkink JF, Blankenstein MA, Klijn JG. Combined effects of buserelin, estradiol and tamoxifen on the growth of MCF-7 human breast cancer cells in vitro. Biochem Biophys Res Commun. 1986;140:550–6.

    Article  CAS  PubMed  Google Scholar 

  22. Klijn JGM, Berns PM, Bontenbal M, Alexieva-Figusch J, Foekens JA. Clinical breast cancer, new developments in selection and endocrine treatment of patients. J Steroid Biochem Mol Biol. 1992;43:211–21.

    Article  CAS  PubMed  Google Scholar 

  23. Taylor CW, Green S, Dalton WS, Martino S, Rector D, Ingle JN, et al. Multicenter randomized clinical trial of goserelin versus surgical oophorectomy in premenopausal patients with receptor-positive MBC: an intergroup study. J Clin Oncol. 1998;16(3):994–9.

    Article  CAS  PubMed  Google Scholar 

  24. Jaiyesimi IA, Buzdar AU, Decker DA, Hortobagyi GN. Use of tamoxifen for breast cancer: twenty-eight years later. J Clin Oncol. 1995;13(2):513–29.

    Article  CAS  PubMed  Google Scholar 

  25. Klopper A, Hall M. New synthetic agent for the induction of ovulation: preliminary trial in women. Br Med J. 1971;2:152–4.

    Article  Google Scholar 

  26. Williamson JG, Ellis JD. The induction of ovulation by tamoxifen. J Obstet Gynaecol Br Commonw. 1973;80:844–7.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  28. Cole MP, Jones CTA, Todd IDH. A new antioestrogenic agent in late breast cancer: an early clinical appraisal of ICI 46,474. Br J Cancer. 1971;25:270–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Heel RC, Brogden RN, Speight TM, Avery GS. Tamoxifen: a review of its pharmacological properties and therapeutic use in the treatment of breast cancer. Drugs. 1978;16(1):1–24.

    Article  CAS  PubMed  Google Scholar 

  30. Imai Y, Leung CKH, Friesen HG, Shiu RP. Epidermal growth factor receptors and effect of epidermal growth factor on growth of human breast cancer cells in long term tissue culture. Cancer Res. 1982;42:4394–8.

    CAS  PubMed  Google Scholar 

  31. Osborne CK, Coronado EB, Kitten LJ, Arteaga CI, Fuqua SA, Ramasharma K, et al. Insulin like growth factor-II (IGF-II): a potential autocrine/paracrine growth factor for human breast cancer acting via IGF- 1 receptor. Mol Endocrinol. 1989;3:1701–9.

    Article  CAS  PubMed  Google Scholar 

  32. Sporn MB, Roberts AB. Transforming growth factor-beta. Multiple actions and potential clinical applications. JAMA. 1989;262:938–41.

    Article  CAS  PubMed  Google Scholar 

  33. Osborne CK, Boldt DH, Clark GM, Trent JM. Effects of tamoxifen on human breast cancer cell cycle kinetics: accumulation of cells in early G1 phase. Cancer Res. 1983;43(8):3583–5.

    CAS  PubMed  Google Scholar 

  34. Jordan VC. Long-term tamoxifen therapy to control or to prevent breast cancer: laboratory concept to clinical trials. Prog Clin Biol Res. 1988;262:105–23.

    CAS  PubMed  Google Scholar 

  35. Sutherland RL, Hall RE, Taylor IW. Cell proliferation kinetics of MCF-7 human mammary carcinoma cells in culture and effects of tamoxifen on exponentially growing and plateau-phase cells. Cancer Res. 1983;43(9):3998–4006.

    CAS  PubMed  Google Scholar 

  36. Lippman M, Bolan G, Huff K. The effects of estrogens and antiestrogens on hormone-responsive human breast cancer in long-term tissue culture. Cancer Res. 1976;36:4595–601.

    CAS  PubMed  Google Scholar 

  37. Darbre PD, Curtis S, King RJ. Effects of estradiol and tamoxifen on human breast cancer cells in serum-free culture. Cancer Res. 1984;44:2790–3.

    CAS  PubMed  Google Scholar 

  38. Sutherland RL, Murphy LC, Foo MS, Green MD, Whybourne AM, Krozowski ZS. High affinity antioestrogen binding site distinct from the oestrogen receptor. Nature. 1980;288:273–5.

    Article  CAS  PubMed  Google Scholar 

  39. Horgan K, Cooke E, Hallett MB, Mansel RE. Inhibition of protein kinase C mediated signal transduction by tamoxifen. Importance for antitumour activity. Biochem Pharmacol. 1986;35(24):4463–5.

    Article  CAS  PubMed  Google Scholar 

  40. Gulino A, Barrera G, Vacca A, Farina A, Ferretti C, Screpanti I, et al. Calmodulin antagonism and growth-inhibiting activity of triphenylethylene antiestrogens in MCF-7 human breast cancer cells. Cancer Res. 1986;46(1):6274–8.

    CAS  PubMed  Google Scholar 

  41. Berry J, Green BJ, Matheson DS. Modulation of natural killer cell activity by tamoxifen in stage I post-menopausal breast cancer. Eur J Cancer Clin Oncol. 1987;23(5):517–20.

    Article  CAS  PubMed  Google Scholar 

  42. Love RR, Mazess RB, Barden HS, Epstein S, Newcomb PA, Jordan VC, et al. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med. 1992;326(13):852–6.

    Article  CAS  PubMed  Google Scholar 

  43. Reddel RR, Murphy LC, Hall RE, Sutherland RL. Differential sensitivity of human breast cancer cell lines to the growth-inhibitory effects of tamoxifen. Cancer Res. 1985;45(4):1525–31.

    CAS  PubMed  Google Scholar 

  44. Margreiter R, Wiegle J. Tamoxifen (Nolvadex) for premenopausal patients with advanced breast cancer. Breast Cancer Res Treat. 1984;4:45–84.

    Article  CAS  PubMed  Google Scholar 

  45. Sawka CA, Pritchard KI, Paterson AHG, Sutherland DJ, Thomson DB, Shelley WE, et al. Role and mechanism of action of tamoxifen in premenopausal women with metastatic breast carcinoma. Cancer Res. 1986;46:3152–6.

    CAS  PubMed  Google Scholar 

  46. Sawka CA, Pritchard KI, Shelley W, DeBoer G, Paterson AH, Meakin JW, et al. A randomized crossover trial of tamoxifen versus ovarian ablation for MBC in premenopausal women: a report of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial MA.1. Breast Cancer Res Treat. 1997;44(3):211–5.

    Article  CAS  PubMed  Google Scholar 

  47. Crump M, Sawka CA, DeBoer G, Buchanan RB, Ingle JN, Forbes J, et al. An individual patient-based meta-analysis of tamoxifen versus ovarian ablation as first line endocrine therapy for premenopausal women with MBC. Breast Cancer Res Treat. 1997;44(3):201–10.

    Article  CAS  PubMed  Google Scholar 

  48. Klijn JG, Blamey RW, Boccardo F, Tominaga T, Duchateau L, Sylvester R, Combined Hormone Agents Trialists’ Group and the European Organization for Research and Treatment of Cancer. Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. J Clin Oncol. 2001;19(2):343–53.

    Article  CAS  PubMed  Google Scholar 

  49. Adjuvant Breast Cancer Trials Collaborative Group. Ovarian ablation or suppression in premenopausal early breast cancer: results from the international adjuvant breast cancer ovarian ablation or suppression randomized trial. J Natl Cancer Inst. 2007;99(7):516–25.

    Article  Google Scholar 

  50. Francis PA, Regan MM, Fleming GF, Láng I, Ciruelos E, Bellet M, et al. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 2015;372:436–46.

    Article  PubMed  CAS  Google Scholar 

  51. Jonat W, Kaufmann M, Blamey RW, Howell A, Collins JP, Coates A, et al. A randomised study to compare the effect of the luteinising hormone releasing hormone (LHRH) analogue goserelin with or without tamoxifen in pre- and perimenopausal patients with advanced breast cancer. Eur J Cancer. 1995;31(2):137–42.

    Article  Google Scholar 

  52. Lerner LJ, Holthaus FJ, Thompson CR. A non-steroidal estrogen antiagonist 1- (p-2-diethylaminoethoxyphenyl)- phenyl-2-p-methoxyphenyl ethanol. Endocrinology. 1958;63(3):295–318.

    Article  CAS  PubMed  Google Scholar 

  53. Harper MJ, Walpole AL. A new derivative of triphenylethylene: effect on implantation and mode of action in rats. J Reprod Fertil. 1967;13(1):101–19.

    Article  CAS  PubMed  Google Scholar 

  54. Harper MJ, Walpole AL. Mode of action of I.C.I. 46,474 in preventing implantation in rats. J Endocrinol. 1967;37(1):83–92.

    Article  CAS  PubMed  Google Scholar 

  55. 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(18):1371–88.

    Article  CAS  PubMed  Google Scholar 

  56. Bryant HU, Dere WH. Selective estrogen receptor modulators: an alternative to hormone replacement therapy. Proc Soc Exp Biol Med. 1998;217(1):45–52.

    Article  CAS  PubMed  Google Scholar 

  57. Szamel I, Vincze B, Hindy I, Kerpel-Fronius S, Eckhardt S, Mäenpää J, et al. Hormonal effects of toremifene in breast cancer patients. J Steroid Biochem. 1990;36(3):243–7.

    Article  CAS  PubMed  Google Scholar 

  58. Coombes RC, Haynes BP, Dowsett M, Quigley M, English J, Judson IR, et al. Idoxifene: report of a phase I study in patients with MBC. Cancer Res. 1995;55(5):1070–4.

    CAS  PubMed  Google Scholar 

  59. Bruning PF. Droloxifene, a new anti-oestrogen in postmenopausal advanced breast cancer: preliminary results of a double-blind dose-finding phase II trial. Eur J Cancer. 1992;28(8–9):1404–7.

    Article  Google Scholar 

  60. Wakeling AE. Chapter 7: Pure antiestrogens. In: Jordan VC, BJA F, editors. Hormone therapy in breast and prostate cancer. Totowa: Humana Press; 2002. p. 162.

    Google Scholar 

  61. Mustonen MV, Pyrhönen S, Kellokumpu-Lehtinen PL. Toremifene in the treatment of breast cancer. World J Clin Oncol. 2014;5(3):393–405.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Mao C, Yang ZY, He BF, Liu S, Zhou JH, Luo RC, et al. Toremifene versus tamoxifen for advanced breast cancer. Cochrane Database Syst Rev. 2012;(7). Art. No.: CD008926. https://doi.org/10.1002/14651858.CD008926.pub2.

  63. Schwarzel WC, Kruggel W, Brodie HJ, Liu S, Zhou JH, Luo RC. Studies on the mechanism of estrogen biosynthesis. VII. The development of inhibitors of the enzyme system in the human placenta. Endocrinology. 1973;92:866–80.

    Article  CAS  PubMed  Google Scholar 

  64. Brodie AMH, Schwarzel WC, Shaikh AA, Brodie HJ. The effect of an AI, 4-hydroxy-4-androstene-3, 17-dione, on estrogen dependent processes in reproduction and breast cancer. Endocrinology. 1977;100:1684–94.

    Article  CAS  PubMed  Google Scholar 

  65. Lombardi P. Exemestane, a new steroidal AI of clinical relevance. Biochim Biophys Acta. 2002;1587(2–3):326–37.

    Article  CAS  PubMed  Google Scholar 

  66. Santen RJ. Potential clinical role of new AIs. Steroids. 1977;50:575–93.

    Article  Google Scholar 

  67. Yue W, Zhou DJ, Chen S, Brodie A. A new nude mouse model for postmenopausal breast cancer using MCF-7 cells transfected with the human aromatase gene. Cancer Res. 1994;54:5092–5.

    CAS  PubMed  Google Scholar 

  68. Yue W, Wang J, Savinov A, Brodie A. Effect of AIs on the growth of mammary tumors in a nude mouse model. Cancer Res. 1995;55:3073–7.

    CAS  PubMed  Google Scholar 

  69. Various Authors. Proceedings of the conference aromatase: new perspectives for breast cancer. Cancer Res. 1982;42S.

    Google Scholar 

  70. Barone RM, Shamonki IM, Siiteri PK, Judd HL. Inhibition of peripheral aromatization of androstenedione to estrone in postmenopausal women with breast cancer using D1-testololactone. J Clin Endocrinol Metab. 1979;49:672–6.

    Article  CAS  PubMed  Google Scholar 

  71. Griffiths CT, Hall TC, Saba Z, Barlow JJ, Nevinny HB. Preliminary trial of aminoglutethimide in breast cancer. Cancer. 1973;32:31–7.

    Article  CAS  PubMed  Google Scholar 

  72. Harvey HA. AIs in clinical practice: current status and a look to the future. Semin Oncol. 1996;23:33–8.

    CAS  PubMed  Google Scholar 

  73. De Jong PC, Blijham GH. New AIs for the treatment of advanced breast cancer in postmenopausal women. Neth J Med. 1999;55:50–8.

    Article  PubMed  Google Scholar 

  74. Carlson RW, Theriault R, Schurman CM, Rivera E, Chung CT, Phan SC, et al. Phase II trial of anastrozole plus goserelin in the treatment of HR+, metastatic carcinoma of the breast in premenopausal women. J Clin Oncol. 2010;28(25):3917–21.

    Article  CAS  PubMed  Google Scholar 

  75. Park IH, Ro J, Lee KS, Kim EA, Kwon Y, Nam BH, et al. Phase II parallel group study showing comparable efficacy between premenopausal MBC patients treated with letrozole plus goserelin and postmenopausal patients treated with letrozole alone as first-line hormone therapy. J Clin Oncol. 2010;28(16):2705–11.

    Article  CAS  PubMed  Google Scholar 

  76. Ellis M, Naughton MJ, Ma CX. Treatment approach to metastatic hormone receptor-positive breast cancer: endocrine therapy. Uptodate. Section Editor: Hayes DF, Deputy Editor: Dizon DS. 2014; p. 1–17.

    Google Scholar 

  77. Espie M. Megestrol acetate in advanced breast carcinoma. Oncology. 1994;51(1):8–12.

    Article  PubMed  Google Scholar 

  78. Abrams J, Aisner J, Cirrincione C, Berry DA, Muss HB, Cooper MR, et al. Dose- response trial of megestrol acetate in advanced breast cancer: cancer and leukemia group B phase III study 8741. J Clin Oncol. 1999;17:64–73.

    Article  CAS  PubMed  Google Scholar 

  79. Petru E, Schmähl D. On the role of additive hormone monotherapy with tamoxifen, medroxyprogesterone acetate and aminoglutethimide, in advanced breast cancer. Klin Wochenschr. 1987;65(20):959–66.

    Article  CAS  PubMed  Google Scholar 

  80. Cardoso F, Bischoff J, Brain E, Zotano ÁG, Lück HJ, Tjan-Heijnen VC, et al. A review of the treatment of endocrine responsive MBC in postmenopausal women. Cancer Treat Rev. 2013;39(5):457–65.

    Article  CAS  PubMed  Google Scholar 

  81. Ingle JN, Mailliard JA, Schaid DJ, Krook JE, Gesme DH Jr, Windschitl HE, et al. A double-blind trial of tamoxifen plus prednisolone versus tamoxifen plus placebo in postmenopausal women with MBC. A collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic. Cancer. 1991;68(1):34–9.

    Article  CAS  PubMed  Google Scholar 

  82. Tormey DC, Lippman ME, Edwards BK, Cassidy JG. Evaluation of tamoxifen doses with and without fluoxymesterone in advanced breast cancer. Ann Intern Med. 1983;98:139–44.

    Article  CAS  PubMed  Google Scholar 

  83. Ingle JN, Twito DI, Schaid DJ, Cullinan SA, Krook JE, Mailliard JA, et al. Randomized clinical trial of tamoxifen alone or combined with fluoxymesterone in postmenopausal women with MBC. J Clin Oncol. 1988;6:825–31.

    Article  CAS  PubMed  Google Scholar 

  84. Cavalli F, Beer M, Martz G, Jungi WF, Alberto P, Obrecht JP, et al. Concurrent or sequential use of cytotoxic chemotherapy and hormone treatment in advanced breast cancer: report of the Swiss Group for Clinical Cancer Research. Br Med J. 1983;286:5–8.

    Article  CAS  Google Scholar 

  85. Australian and New Zealand Breast Cancer Trials Group. A randomized trial in postmenopausal patients with advanced breast cancer comparing endocrine and cytotoxic therapy given sequentially or in combination. J Clin Oncol. 1986;4:186–93.

    Article  Google Scholar 

  86. Glick JH, Creech RH, Torri S, Holroyde C, Brodovsky H, Catalano RB, et al. Tamoxifen plus sequential CMF chemotherapy versus tamoxifen alone in postmenopausal patients with advanced breast cancer: a randomized trial. Cancer. 1980;45:735–41.

    Article  CAS  PubMed  Google Scholar 

  87. Bezwoda WR, Derman D, DeMoor NG, Lange M, Levin J. Treatment of MBC in estrogen receptor positive patients: a randomized trial comparing tamoxifen alone versus tamoxifen plus CMF. Cancer. 1982;50:2747–50.

    Article  CAS  PubMed  Google Scholar 

  88. Mouridsen HT, Rose C, Engelsman E, Sylvester R, Rotmensz N. Combined cytotoxic and endocrine therapy in postmenopausal patients with advanced breast cancer. A randomized study of CMF vs CMF plus tamoxifen. Eur J Cancer Clin Oncol. 1985;21:291–9.

    Article  CAS  PubMed  Google Scholar 

  89. Cocconi G, Delisi V, Boni C, Mori P, Malacarne P, Amadori D, et al. Chemotherapy versus combination of chemotherapy and endocrine therapy in advanced breast cancer. A prospective randomized study. Cancer. 1983;51:581–8.

    Article  CAS  PubMed  Google Scholar 

  90. Bocccardo F, Rubagotti A, Rosso R, Santi L. Chemotherapy with or without tamoxifen in postmenopausal patients with late breast cancer: a randomized study. J Steroid Biochem. 1985;23:1123–7.

    Article  Google Scholar 

  91. Lønning PE, Dowsett M, Powles TJ. Postmenopausal estrogen synthesis and metabolism: alterations caused by AIs used for the treatment of breast cancer. J Steroid Biochem. 1990;35:355–66.

    Article  PubMed  Google Scholar 

  92. Luft R, Olivecrona H, Sjögren B. Hypophysectomy in man. Nord Med. 1952;14:351–4.

    Google Scholar 

  93. Huggins C, Dao TLY. Adrenalectomy and oophorectomy in treatment of advanced carcinoma of the breast. J Am Med Assoc. 1953;151:1388–94.

    CAS  PubMed  Google Scholar 

  94. Fracchia AA, Randall HT, Farrow JH. The results of adrenalectomy in advanced breast cancer in 500 consecutive patients. Surg Gynecol Obstet. 1967;125:747–56.

    CAS  PubMed  Google Scholar 

  95. Fracchia AA, Farrow JH, Miller TR, Tollefsen RH, Greenberg EJ, Knapper WH. Hypophysectomy as compared with adrenalectomy in the treatment of advanced carcinoma of the breast. Surg Gynecol Obstet. 1971;133:241–6.

    CAS  PubMed  Google Scholar 

  96. Kofman S, Nagamani D, Buenger RF, Taylor SG. The use of prednisolone in the treatment of disseminated breast carcinoma. Cancer. 1958;11:226–32.

    Article  CAS  PubMed  Google Scholar 

  97. Lemon HM. Prednisone therapy of advanced mammary cancer. Cancer. 1959;12:93–107.

    Article  CAS  PubMed  Google Scholar 

  98. Harris AL, Cantwell BMJ, Dowsett M. High dose ketoconazole: endocrine and therapeutic effects in postmenopausal breast cancer. Br J Cancer. 1998;58:493–6.

    Article  Google Scholar 

  99. Geisler J, Lonning PE. Aromatase inhibition: translation into a successful therapeutic approach. Clin Cancer Res. 2005;11:2809–21.

    Article  CAS  PubMed  Google Scholar 

  100. Bulun SE, Sebastian S, Takayama K, Suzuki T, Sasano H, Shozu M. The human CYP19 (aromatase P450) gene: update on physiologic roles and genomic organization of promoters. J Steroid Biochem Mol Biol. 2003;86:219–24.

    Article  CAS  PubMed  Google Scholar 

  101. Agarwal VR, Bulun SE, Leitch M, Rohrich R, Simpson ER. Use of alternative promoters to express the aromatase cytochrome p450 (CYP19) gene in breast adipose tissues of cancer-free and breast cancer patients. J Clin Endocrinol Metab. 1996;81:3843–9.

    CAS  PubMed  Google Scholar 

  102. Mendelson CR, Jiang B, Shelton JM, Richardson JA, Hinshelwood MM. Transcriptional regulation of aromatase in placenta and ovary. J Steroid Biochem Mol Biol. 2005;95:25–33.

    Article  CAS  PubMed  Google Scholar 

  103. Dowsett M, Cantwell B, Lal A, Jeffcoate SL, Harris AL. Suppression of postmenopausal ovarian steroidogenesis with the luteinizing hormone- releasing hormone agonist goserelin. J Clin Endocrinol Metab. 1988;66:672–7.

    Article  CAS  PubMed  Google Scholar 

  104. Couzinet B, Meduri G, Lecce M, Young J, Brailly S, Loosfelt H, et al. The postmenopausal ovary is not a major androgen-producing gland. J Clin Endocrinol Metab. 2001;86:5060–6.

    Article  CAS  PubMed  Google Scholar 

  105. Johnson PE, Buzdar A. Are differences in the available AIs and inactivators significant? Clin Cancer Res. 2001;7(12):4360–8.

    Google Scholar 

  106. Van Asten K, Neven P, Lintermans A, Wildiers H, Paridaens R. AIs in the breast cancer clinic: focus on exemestane. Endocr Relat Cancer. 2014;21(1):31–49.

    Article  CAS  Google Scholar 

  107. Lønning PE, Eikesdal HP. Aromatase inhibition 2013: clinical state of the art and questions that remain to be solved. Endocr Relat Cancer. 2013;20(4):183–201.

    Article  CAS  Google Scholar 

  108. Folkerd EJ, Dixon JM, Renshaw L, A’Hern RP, Dowsett M. Suppression of plasma estrogen levels by letrozole and anastrozole is related to body mass index in patients with breast cancer. J Clin Oncol. 2012;30:2977–80.

    Article  CAS  PubMed  Google Scholar 

  109. Buzdar AU, Jonat W, Howell A, Jones SE, Blomqvist CP, Vogel CL, et al. Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from two mature phase III trials. Arimidex Study Group. Cancer. 1998;83(6):1142–52.

    Article  CAS  PubMed  Google Scholar 

  110. Buzdar A, Douma J, Davidson N, Elledge R, Morgan M, Smith R, et al. Phase III, multicenter, double-blind, randomized study of letrozole, an AI, for advanced breast cancer versus megestrol acetate. J Clin Oncol. 2001;19(14):3357–66.

    Article  CAS  PubMed  Google Scholar 

  111. Bonneterre J, Thurlimann B, Robertson JF, Krzakowski M, Mauriac L, Koralewski P, et al. Anastrozole 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.

    Article  CAS  PubMed  Google Scholar 

  112. Nabholtz JM, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A, et al. Anastrozole 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. 2001;18:3758–67.

    Article  Google Scholar 

  113. Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol. 2003;21:2101–9.

    Article  CAS  PubMed  Google Scholar 

  114. Paridaens RJ, Dirix LY, Beex LV, Nooij M, Cameron DA, Cufer T, et al. Phase III study comparing exemestane with tamoxifen as first-line hormonal treatment of MBC in postmenopausal women: the European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group. J Clin Oncol. 2008;26:4883–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Johannessen DC, Engan T, Di Salle E, Zurlo MG, Paolini J, Ornati G, et al. Endocrine and clinical effects of exemestane (PNU 155971), a novel steroidal AI, in postmenopausal breast cancer patients: a phase I study. Clin Cancer Res. 1997;3(7):1101–8.

    CAS  PubMed  Google Scholar 

  116. Evans TR, Di Salle E, Ornati G, Lassus M, Benedetti MS, Pianezzola E, et al. Phase I and endocrine study of exemestane (FCE 24304), a new AI, in postmenopausal women. Cancer Res. 1992;52(21):5933–9.

    CAS  PubMed  Google Scholar 

  117. Geisler J, King N, Anker G, Ornati G, Di Salle E, Lønning PE, et al. In vivo inhibition of aromatization by exemestane, a novel irreversible AI, in postmenopausal breast cancer patients. Clin Cancer Res. 1998;4(9):2089–93.

    CAS  PubMed  Google Scholar 

  118. Kaufmann M, Bajetta E, Dirix LY, Fein LE, Jones SE, Zilembo N, et al. Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group. J Clin Oncol. 2000;18(7):1399–411.

    Article  CAS  PubMed  Google Scholar 

  119. Mauri D, Pavlidis N, Polyzos NP, Ioannidis JP. Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis. J Natl Cancer Inst. 2006;98(18):1285–91.

    Article  CAS  PubMed  Google Scholar 

  120. Walker G, Xenophontos M, Chen L, Cheung K. Long-term efficacy and safety of exemestane in the treatment of breast cancer. Patient Prefer Adherence. 2013;7:245–58.

    PubMed  PubMed Central  Google Scholar 

  121. Lønning PE, Geisler J. Evaluation of plasma and tissue estrogen suppression with third-generation AIs: of relevance to clinical understanding? J Steroid Biochem Mol Biol. 2010;118(4–5):288–93.

    Article  PubMed  CAS  Google Scholar 

  122. Geisler J, Haynes B, Anker G, Dowsett M, Lønning PE. Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study. J Clin Oncol. 2002;20(3):751–7.

    Article  CAS  PubMed  Google Scholar 

  123. Pauwels S, Antonio L, Jans I, Lintermans A, Neven P, Claessens F, et al. Sensitive routine liquid chromatography-tandem mass spectrometry method for serum estradiol and estrone without derivatization. Anal Bioanal Chem. 2013;405(26):8569–77.

    Article  CAS  PubMed  Google Scholar 

  124. Campos SM, Guastalla JP, Subar M, Abreu P, Winer EP, Cameron DA. A comparative study of exemestane versus anastrozole in patients with postmenopausal breast cancer with visceral metastases. Clin Breast Cancer. 2009;9(1):39–44.

    Article  CAS  PubMed  Google Scholar 

  125. Llombart-Cussac A, Ruiz A, Antón A, Barnadas A, Antolín S, Alés-Martínez JE, et al. Exemestane versus anastrozole as front-line endocrine therapy in postmenopausal patients with HR+, advanced breast cancer: final results from the Spanish Breast Cancer Group 2001-03 phase 2 randomized trial. Cancer. 2012;118(1):241–7.

    Article  CAS  PubMed  Google Scholar 

  126. Riemsma R, Forbes CA, Kessels A, Lykopoulos K, Amonkar MM, Rea DW, et al. Systematic review of AIs in the first-line treatment for hormone sensitive advanced or MBC. Breast Cancer Res Treat. 2010;123(1):9–24.

    Article  CAS  PubMed  Google Scholar 

  127. Lønning PE. Clinico-pharmacological aspects of different hormone treatments. Eur J Cancer. 2010;36(4):81–2.

    Google Scholar 

  128. Kim SH, Park IH, Lee H, Lee KS, Nam BH, Ro J. Efficacy of exemestane after nonsteroidal aromatase inhibitor use in metastatic breast cancer patients. Asian Pac J Cancer Prev. 2012;13(3):979–83.

    Article  PubMed  Google Scholar 

  129. Bertelli G, Garrone O, Merlano M, Occelli M, Bertolotti L, Castiglione F, et al. Sequential treatment with exemestane and non-steroidal aromatase inhibitors in advanced breast cancer. Oncology. 2005;69(6):471–7.

    Article  PubMed  CAS  Google Scholar 

  130. Steele N, Zekri J, Coleman R, Leonard R, Dunn K, Bowman A, et al. Exemestane in metastatic breast cancer: effective therapy after third-generation non-steroidal aromatase inhibitor failure. Breast. 2006;15(3):430–6.

    Article  CAS  PubMed  Google Scholar 

  131. Gennatas C, Michalaki V, Carvounis E, Psychogios J, Poulakaki N, Katsiamis G, et al. Third-line hormonal treatment with exemestane in postmenopausal patients with advanced breast cancer progressing on letrozole or anastrozole. A phase II trial conducted by the Hellenic Group of Oncology (HELGO). Tumori. 2006;92(1):13–7.

    Article  CAS  PubMed  Google Scholar 

  132. Chin YS, Beresford MJ, Ravichandran D, Makris A. Exemestane after non-steroidal aromatase inhibitors for post-menopausal women with advanced breast cancer. Breast. 2007;16(4):436–9.

    Article  CAS  PubMed  Google Scholar 

  133. Chia S, Gradishar W, Mauriac L, Bines J, Amant F, Federico M, et al. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol. 2008;26(10):1664–70.

    Article  CAS  PubMed  Google Scholar 

  134. Mauriac L, Romieu G, Bines J. Activity of fulvestrant versus exemestane in advanced breast cancer patients with or without visceral metastases: data from the EFECT trial. Breast Cancer Res Treat. 2009;117(1):69–75.

    Article  CAS  PubMed  Google Scholar 

  135. Iaffaioli RV, Formato R, Tortoriello A, Del Prete S, Caraglia M, Pappagallo G, et al. Phase II study of sequential hormonal therapy with anastrozole/exemestane in advanced and metastatic breast cancer. Br J Cancer. 2005;92(9):1621–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Beresford M, Tumur I, Chakrabarti J, Barden J, Rao N, Makris A. A qualitative systematic review of the evidence base for non-cross-resistance between steroidal and non-steroidal aromatase inhibitors in metastatic breast cancer. Clin Oncol (R Coll Radiol). 2011;23(3):209–15.

    Article  CAS  Google Scholar 

  137. Howell A, Osborne CK, Morris C, Wakeling AE. ICI 182,780 (Faslodex): development of a novel, “pure” antiestrogen. Cancer. 2000;89(4):817–25.

    Article  CAS  PubMed  Google Scholar 

  138. Al-Mubarak M, Sacher AG, Ocana A, Vera-Badillo F, Seruga B, Amir E. Fulvestrant for advanced breast cancer: a meta-analysis. Cancer Treat Rev. 2013;39(7):753–8.

    Article  CAS  PubMed  Google Scholar 

  139. Robertson JF, Nicholson RI, Bundred NJ, Anderson E, Rayter Z, Dowsett M, et al. Comparison of the short-term biological effects of 7alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]estra-1,3,5, (10)-triene-3,17beta-diol (Faslodex) versus tamoxifen in postmenopausal women with primary breast cancer. Cancer Res. 2001;61(18):6739–46.

    CAS  PubMed  Google Scholar 

  140. Howell A, Robertson JF, Abram P, Lichinitser MR, Elledge R, Bajetta E, et al. Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: a multinational, double-blind, randomized trial. J Clin Oncol. 2004;22(9):1605–13.

    Article  CAS  PubMed  Google Scholar 

  141. Howell A, Robertson JF, Quaresma Albano J, Aschermannova A, Mauriac L, Kleeberg UR, et al. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol. 2002;20(16):3396–403.

    Article  CAS  PubMed  Google Scholar 

  142. Osborne CK, Pippen J, Jones SE, Parker LM, Ellis M, Come S, et al. Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol. 2002;20(16):3386–95.

    Article  CAS  PubMed  Google Scholar 

  143. Robertson JF, Osborne CK, Howell A, Jones SE, Mauriac L, Ellis M, et al. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal women: a prospective combined analysis of two multicenter trials. Cancer. 2003;98(2):229–38.

    Article  CAS  PubMed  Google Scholar 

  144. Bergh J, Jönsson PE, Lidbrink EK, Trudeau M, Eiermann W, Brattström D, et al. FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol. 2012;30(16):1919–25.

    Article  CAS  PubMed  Google Scholar 

  145. Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, et al. Combination anastrozole and fulvestrant in MBC. N Engl J Med. 2012;367(5):435–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Tan PS, Haaland B, Montero AJ, Lopes G. A meta-analysis of anastrozole in combination with fulvestrant in the first line treatment of HR+ advanced breast cancer. Breast Cancer Res Treat. 2013;138(3):961–5.

    Article  CAS  PubMed  Google Scholar 

  147. Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, et al. Overall survival with fulvestrant plus anastrozole in metastatic breast cancer. N Eng J Med. 2019;380(13):1226–34.

    Article  CAS  PubMed  Google Scholar 

  148. Ma CX, Ellis MJ. The Cancer Genome Atlas: clinical applications for breast cancer. Oncology (Williston Park). 2013;27(12):1263–9, 1274–9.

    Google Scholar 

  149. Thangavel C, Dean JL, Ertel A, Knudsen KE, Aldaz CM, Witkiewicz AK, et al. Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocr Relat Cancer. 2011;18(3):333–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009;11(5):77.

    Article  CAS  Google Scholar 

  151. Beaver JA, Amiri-Kordestani L, Charlab R, Chen W, Palmby T, Tilley A, et al. FDA approval: palbociclib for the treatment of postmenopausal patients with estrogen receptor-positive, HER2-negative metastatic breast cancer. Clin Cancer Res. 2015;21(21):4760–6.

    Article  CAS  PubMed  Google Scholar 

  152. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16(1):25–35.

    Article  CAS  PubMed  Google Scholar 

  153. Kim ES, Scott LJ. Palbociclib: a review in HR-positive, HER2-negative, advanced or metastatic breast cancer. Target Oncol. 2017;12(3):373–83.

    Article  PubMed  Google Scholar 

  154. Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375(20):1925–36.

    Article  CAS  PubMed  Google Scholar 

  155. Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 2018;29(7):1541–7. https://doi.org/10.1093/annonc/mdy155.

    Article  CAS  PubMed  Google Scholar 

  156. Tripathy D, Im SA, Colleoni M, Franke F, Bardia A, Harbeck N, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018. pii: S1470-2045(18)30292-4. https://doi.org/10.1016/S1470-2045(18)30292-4.

    Article  CAS  PubMed  Google Scholar 

  157. Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J, et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017;35(32):3638–46.

    Article  CAS  PubMed  Google Scholar 

  158. Reinert T, Barrios CH. Optimal management of hormone receptor positive metastatic breast cancer in 2016. Ther Adv Med Oncol. 2015;7(6):304–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Kümler I, Christiansen OG, Nielsen DL. A systematic review of bevacizumab efficacy in breast cancer. Cancer Treat Rev. 2014;40(8):960–73.

    Article  PubMed  CAS  Google Scholar 

  160. Martín M, Loibl S, von Minckwitz G, Morales S, Martinez N, Guerrero A, et al. Phase III trial evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for advanced breast cancer: the letrozole/fulvestrant and avastin (LEA) study. J Clin Oncol. 2015;33(9):1045–52.

    Article  PubMed  CAS  Google Scholar 

  161. Dickler MN, Barry WT, Cirrincione CT, Ellis MJ, Moynahan ME, Innocenti F, et al. Phase III trial evaluating the addition of bevacizumab to letrozole as first-line endocrine therapy for treatment of hormone-receptor positive advanced breast cancer: CALGB 40503 (Alliance). J Clin Oncol. 2015;33:(suppl; abstr 501).

    Article  Google Scholar 

  162. Turner NC, Ro J, André F, Loi S, Verma S, Iwata H, PALOMA3 Study Group, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015;373(3):209–19.

    Article  CAS  PubMed  Google Scholar 

  163. Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X, et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2− advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35(25):2875–2884.

    Article  CAS  PubMed  Google Scholar 

  164. Dickler MN, Tolaney SM, Rugo HS, Cortés J, Diéras V, Patt D, et al. MONARCH 1, a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2− metastatic breast cancer. Clin Cancer Res. 2017;23(17):5218–5224.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Creighton CJ, Fu X, Hennessy BT, Casa AJ, Zhang Y, Gonzalez-Angulo AM, et al. Proteomic and transcriptomic profiling reveals a link between the PI3K pathway and lower estrogen-receptor (ER) levels and activity in ER+ breast cancer. Breast Cancer Res. 2010;12(3):R40. https://doi.org/10.1186/bcr2594. Epub 2010 Jun 22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Keegan NM, Gleeson JP, Hennessy BT, Morris PG. PI3K inhibition to overcome endocrine resistance in breast cancer. Expert Opin Investig Drugs. 2018;27(1):1–15. https://doi.org/10.1080/13543784.2018.1417384. Epub 2018 Jan 6.

    Article  CAS  PubMed  Google Scholar 

  167. Toska E, Osmanbeyoglu HU, Castel P, Chan C, Hendrickson RC, Elkabets M, et al. PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D. Science. 2017;355(6331):1324–30. https://doi.org/10.1126/science.aah6893.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Weir HM, Bradbury RH, Lawson M, Rabow AA, Buttar D, Callis RJ, et al. AZD9496: an oral estrogen receptor inhibitor that blocks the growth of ER-positive and ESR1-mutant breast tumors in preclinical models. Cancer Res. 2016;76(11):3307–18. https://doi.org/10.1158/0008-5472.CAN-15-2357. Epub 2016 Mar 28.

    Article  CAS  PubMed  Google Scholar 

  169. Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/Akt pathway for cancer drug discovery. Nat Rev Drug Discov. 2005;4(12):988–1004.

    Article  CAS  PubMed  Google Scholar 

  170. Creighton CJ. A gene transcription signature of the Akt/mTOR pathway in clinical breast tumors. Oncogene. 2007;26:4648–55.

    Article  CAS  PubMed  Google Scholar 

  171. Shi W, Zhang X, Pintilie M, Ma N, Miller N, Banerjee D, et al. Dysregulated PTEN-PKB and negative receptor status in human breast cancer. Int J Cancer. 2003;104:195–203.

    Article  CAS  PubMed  Google Scholar 

  172. Generali D, Fox S, Brizzi M, Allevi G, Bonardi S, Aguggini S, et al. Down-regulation of phosphatidylinositol 3′-kinase/Akt/molecular target of rapamycin metabolic pathway by primary letrozole-based therapy in human breast cancer. Clin Cancer Res. 2008;14:2673–80.

    Article  CAS  PubMed  Google Scholar 

  173. Boulay A, Rudloff J, Ye J, Zumstein-Mecker S, O’Reilly T, Evans DB, et al. Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer. Clin Cancer Res. 2005;11(14):5319–28.

    Article  CAS  PubMed  Google Scholar 

  174. Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520–9.

    Article  CAS  PubMed  Google Scholar 

  175. Piccart M, Hortobagyi GN, Campone M, Pritchard KI, Lebrun F, Ito Y, et al. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2†. Ann Oncol. 2014;25(12):2357–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Tancredi R, Furlanetto J, Loibl S. Endocrine therapy in premenopausal hormone receptor positive/human epidermal growth receptor 2 negative metastatic breast cancer: between guidelines and literature. Oncologist. 2018. pii: theoncologist.2018-0077. https://doi.org/10.1634/theoncologist.2018-0077.

    Article  PubMed  PubMed Central  Google Scholar 

  177. Wolff AC, Lazar AA, Bondarenko I, Garin AM, Brincat S, Chow L, et al. Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer. J Clin Oncol. 2013;31(2):195–202.

    Article  CAS  PubMed  Google Scholar 

  178. Baselga J, Semiglazov V, van Dam P, Manikhas A, Bellet M, Mayordomo J, et al. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol. 2009;27:2630–7.

    Article  CAS  PubMed  Google Scholar 

  179. Hortobagyi GN, Chen D, Piccart M, Rugo HS, Burris HA 3rd, Pritchard KI, et al. Correlative analysis of genetic alterations and everolimus benefit in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from BOLERO-2. J Clin Oncol. 2016;34(5):419–26.

    Article  CAS  PubMed  Google Scholar 

  180. Dhillon S. Everolimus in combination with exemestane: a review of its use in the treatment of patients with postmenopausal hormone receptor-positive, HER2-negative advanced breast cancer. Drugs. 2013;73(5):475–85.

    Article  CAS  PubMed  Google Scholar 

  181. Bachelot T, McCool R, Duffy S, Glanville J, Varley D, Fleetwood K, et al. Comparative efficacy of everolimus plus exemestane versus fulvestrant for hormone-receptor-positive advanced breast cancer following progression/recurrence after endocrine therapy: a network meta-analysis. Breast Cancer Res Treat. 2014;143(1):125–33.

    Article  CAS  PubMed  Google Scholar 

  182. Yardley DA, Ismail-Khan RR, Melichar B, Lichinitser M, Munster PN, Klein PM, et al. Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. J Clin Oncol. 2013;31(17):2128–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Knowlden JM, Hutcheson IR, Jones HE. Elevated levels of epidermal growth factor receptor/cerbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells. Endocrinology. 2013;144:1032–44.

    Article  CAS  Google Scholar 

  184. Massarweh S, Osborne CK, Jiang S, Wakeling AE, Rimawi M, Mohsin SK, et al. Mechanisms of tumor regression and resistance to estrogen deprivation and fulvestrant in a model of estrogen receptor-positive, HER-2/neu-positive breast cancer. Cancer Res. 2006;66:8266–77.

    Article  CAS  PubMed  Google Scholar 

  185. Mackey JR, Kaufman B, Clemens MR, Bapsy PP, Vaid A, Wardley A, et al. Trastuzumab prolongs progression-free survival in hormone-dependent and HER2+ MBC. Breast Cancer Res Treat. 2006;100:5.

    Google Scholar 

  186. Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A, et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2- positive, HR+ MBC: results from the randomized phase III TAnDEM study. J Clin Oncol. 2009;27:5529–37.

    Article  CAS  PubMed  Google Scholar 

  187. Johnston S, Pippen JJ, Pivot X, Lichinitser M, Sadeghi S, Dieras V, et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal HR+ MBC. J Clin Oncol. 2009;27:5538–46.

    Article  CAS  PubMed  Google Scholar 

  188. Riemsma R, Forbes CA, Amonkar MM, Lykopoulos K, Diaz JR, Kleijnen J, et al. Systematic review of lapatinib in combination with letrozole compared with other first-line treatments for HR+(HR+) and HER2+ advanced or MBC (MBC). Curr Med Res Opin. 2012;28(8):1263–79.

    Article  CAS  PubMed  Google Scholar 

  189. Burstein HJ, Cirrincione CT, Barry WT, Chew HK, Tolaney SM, Lake DE, et al. Endocrine therapy with or without inhibition of epidermal growth factor receptor and human epidermal growth factor receptor 2: a randomized, double-blind, placebo-controlled phase III trial of fulvestrant with or without lapatinib for postmenopausal women with HR+ advanced breast cancer-CALGB 40302 (Alliance). J Clin Oncol. 2014;32(35):3959–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Sen, F., Aydiner, A. (2019). Treatment of Metastatic Breast Cancer: Endocrine Therapy. In: Aydiner, A., Igci, A., Soran, A. (eds) Breast Disease. Springer, Cham. https://doi.org/10.1007/978-3-030-16792-9_30

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-16792-9_30

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-16791-2

  • Online ISBN: 978-3-030-16792-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics