Skip to main content
SpringerLink
Log in

Advances in Endocrine Therapy for Postmenopausal Metastatic Breast Cancer

  • Chapter
  • First Online:
Optimizing Breast Cancer Management

Part of the book series: Cancer Treatment and Research ((CTAR,volume 173))

Abstract

A majority of breast cancers are hormone receptor (HR) positive and are responsive to various types of hormone manipulation. Endocrine therapy is the preferred first-line therapy for patients with advanced estrogen receptor (ER) positive, HER2-negative breast cancer who do not have symptomatic visceral disease. Endocrine therapy is often continued in the second- and third-line setting, with chemotherapy deferred until tumor becomes endocrine therapy refractory and/or a visceral crisis in imminent. Therapeutic options vary based on clinical presentation and include single-agent therapies such as tamoxifen, aromatase inhibitors and fulvestrant, and combination therapies options. Over the past few years, multiple trials have shown significant improvement in outcomes when endocrine therapy is combined with CDK 4/6 inhibitors or mTOR inhibitors. Improved efficacy comes at a cost of a modest increase in toxicity. Mechanisms of ER resistance have been defined leading to multiple strategies to improve efficacy and overcome resistance. These include the combination therapies options mentioned above and other novel drugs that are in development. This review will summarize the existing literature regarding endocrine therapy in postmenopausal metastatic breast cancer and outline treatment approaches in the first-line metastatic setting and beyond.

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

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
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. Beatson G (1895) On the treatment of inoperable cases of carcinoma of the mamma-suggestions for a new method of treatment with illustrative cases. Lancet 2:104–107

    Google Scholar 

  2. Morgan LR Jr, Schein PS, Woolley PV et al (1976) Therapeutic use of tamoxifen in advanced cancer, correlation with biochemical parameters. Cancer Treat Rep 60:1437–1443

    PubMed  Google Scholar 

  3. Rose C, Mouridsen HT (1984) Treatment of advanced breast cancer with tamoxifen. Recent Results Cancer Res 91:230–242

    Article  CAS  PubMed  Google Scholar 

  4. Muss HB, Case LD, Atkins JN et al (1994) Tamoxifen versus high dose oral medroxyprogesterone acetate as initial endocrine therapy for patients with metastatic breast cancer: a Piedmont Oncology Association study. J Clin Oncol 12:1630–1638

    Article  CAS  PubMed  Google Scholar 

  5. Buzdar A, Jonat W, Howell A et al (1996) Anastrozole, a potent and selective aromatase inhibitor versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two phase III trials. Arimidex Study Group. J Clin Oncol 14:2000–2011

    Article  CAS  Google Scholar 

  6. Kaufmann M, Bajetta E, Dirix LY et al (2000) Exemestane is superior to megesterol 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 18:1399–1411

    Article  CAS  PubMed  Google Scholar 

  7. Budzar A, Douma J, Davidson N et al (2001) Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate. J Clin Oncol 19:3357–3366

    Article  Google Scholar 

  8. Bonneterre J, Thurlimann B, Robertson JF et al (2000) 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 18:3748–3757

    Article  CAS  PubMed  Google Scholar 

  9. Nabholtz JM, Budzar A, Pollak M et al (2000) 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 18:3758–3767

    Article  CAS  Google Scholar 

  10. Mouridsen H, Gershanovich M, Sun Y et al (2001) Superior 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 19:2596–2606

    Article  CAS  PubMed  Google Scholar 

  11. Paridaens R, Dirix L, Beex L et al (2008) Phase III study comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal women: The European Organisation for Research and Treatment of Breast Cancer cooperative group. J Clin Oncol 28:4883–4890

    Article  Google Scholar 

  12. Mauri D, Pavlidis N, Polyzos NP, Ionnidis JP (2006) Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis. J Natl Cancer Inst 98:1285–1299

    Article  CAS  PubMed  Google Scholar 

  13. Campos SM, Guastall JP, Subar M et al (2009) A Comparative study of exemestane versus anastrozole in patient with postmenopausal breast cancer with visceral metastases. Clin Breast Cancer 9:39–44

    Article  CAS  PubMed  Google Scholar 

  14. Rose C, Vtoraya O, Pluzanska A et al (2003) An open randomized trial of second line endocrine therapy in advanced breast cancer. Comparison of the aromatase inhibitors letrozole and anastrozole. Eur J Cancer 39:2318–2327

    Article  CAS  PubMed  Google Scholar 

  15. Wakeling AE, Dukes M, Bowler J (1991) A potent pure antiestrogen with clinical potential. Cancer Res 15:3867–3873

    Google Scholar 

  16. Howell A, Robertson JF, Abram P et al (2004) 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 22:1605–1613

    Article  CAS  PubMed  Google Scholar 

  17. Howell A, Robertson JF, Quaresma Albano J et al (2002) Fulvestrant (ICI 182,780) is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol 20:3396–3403

    Article  CAS  PubMed  Google Scholar 

  18. Osborne CK, Pippen J, Jones SE et al (2002) A double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant with anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol 29:3386–3395

    Article  Google Scholar 

  19. Chia S, Gradishar W, Mauriac J (2008) 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 EFFECT. J Clin Oncol 26:1664–1670

    Article  CAS  PubMed  Google Scholar 

  20. Howell A, Pippen J, Elledge RM (2005) Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma: a prospective planned combined survival analysis of two multicenter trials. Cancer 104:236–239

    Article  CAS  PubMed  Google Scholar 

  21. Di Leo A, Jerusalem G, Petruzelka L et al (2010) Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor positive advanced breast cancer. J Clin Oncol 28:4594–4600

    Article  PubMed  Google Scholar 

  22. Di Leo A, Jerusalem G, Petruzelka L et al. (2014) Final overall survival: fulvestrant 500 vs 250 mg in the randomized CONFIRM trial. J Natl Cancer Inst 106: djt337

    Google Scholar 

  23. Robertson J, Llombart-Cussac A, Rolski J et al (2009) Activity of fulvestrant 500 mg versus anastrozole 1 mg as first-line treatment for advanced breast cancer: results from the FIRST study. J Clin Oncol 27:4530–4534

    Article  CAS  PubMed  Google Scholar 

  24. Robertson J, Lindemann J, Llombart-Cussac A et al (2012) Activity of fulvestrant 500 versus anastrozole 1 m as first-line treatment for advanced breast cancer-follow-up analysis from the randomized FIRST study. Breast Cancer Res Treat 136:503–511

    Article  CAS  PubMed  Google Scholar 

  25. Ellis M, Llombart-Cussac A, Feltl D et al (2015) Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: overall survival analysis from the phase II FIRST study. J Clin Oncol 33:3781–3786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Robertson JF, Bondarenko I, Trishkina E et al (2016) Fulvestrant 500 mg versus anastrazole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomized, double-blind, phase 3 trial. Lancet 388:2997–3005

    Article  CAS  PubMed  Google Scholar 

  27. Bergh J, Jonsson PE, Lidbrink EK et al (2012) FACT: an open label randomized phase III study of fulvestrant and anastrozole in combination compared to anastrozole alone as first line therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol 30:1919–1925

    Article  CAS  PubMed  Google Scholar 

  28. Mehta RS, Barlow WE, Albain KS et al (2012) Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med 367:435–444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Johnstom SR, Kilburn LS, Ellis P et al (2013) Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicenter, phase 3 randomised trial. Lancet Oncol 14:989–998

    Article  Google Scholar 

  30. Finn RS, Crown JP, Lang I et al (2015) The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of estrogen receptor positive, HER-2 negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomized phase 2 study. Lancet Oncol 16:25–35

    Article  CAS  PubMed  Google Scholar 

  31. Finn RS, Martin M, Rugo S (2016) Palbociclib and letrozole in advanced breast cancer. N Engl J Med 375:1925–1936

    Article  CAS  PubMed  Google Scholar 

  32. Turner NC, Ro J, Andre F et al (2015) Palbociclib in hormone receptor positive advanced breast cancer. N Engl J Med 373:209–219

    Article  CAS  PubMed  Google Scholar 

  33. Cristofanilli M, Turner NC, Bondarenko I et al (2016) Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicenter, double blind, phase 3 randomised controlled trial. Lancet Oncol 17:425–439

    Article  CAS  PubMed  Google Scholar 

  34. Phase III Study of Palbociclib (PD-0332991) in Combination With Endocrine Therapy (Exemestane or Fulvestrant) Versus Chemotherapy (Capecitabine) in Hormonal Receptor (HR) Positive/HER2 Negative Metastatic Breast Cancer (MBC) Patients With Resistance to Non-steroidal Aromatase Inhibitors (PEARL) (ClinicalTrials.gov Identifier: NCT02028507)

    Google Scholar 

  35. Hortobagyi GN, Stemmer SM, Burris HA et al (2016) Ribociclib as First-Line Therapy for HR-positive, advanced breast cancer. N Engl J Med 375:1738–1748

    Article  CAS  PubMed  Google Scholar 

  36. A Randomized Double-blind, Placebo-controlled Study of Ribociclib in Combination With Fulvestrant for the Treatment of Men and Postmenopausal Women With Hormone Receptor Positive, HER2-negative, Advanced Breast Cancer Who Have Received no or Only One Line of Prior Endocrine Treatment MONALEESA 3 (ClinicalTrials.gov Identifier: NCT02422615)

    Google Scholar 

  37. Dickler MN, Tolaney SM, Rugo HS (2016) MONARCH 1: Results from a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR +/HER-2-breast cancer after chemotherapy for advanced disease. J Clin Oncol 34, suppl; abstr 510

    Google Scholar 

  38. MONARCH 2: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Fulvestrant With or Without Abemaciclib, a CDK4/6 Inhibitor, for Women With Hormone Receptor Positive, HER2 Negative Locally Advanced or Metastatic Breast CancerA Study of Abemaciclib (LY2835219) ClinicalTrials.gov Identifier: NCT02107703

    Google Scholar 

  39. A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Nonsteroidal Aromatase Inhibitors (Anastrozole or Letrozole) Plus LY2835219, a CDK4/6 Inhibitor, or Placebo in Postmenopausal Women With Hormone Receptor-Positive, HER2-Negative Locoregionally Recurrent or Metastatic Breast Cancer With No Prior Systemic Therapy in This Disease Setting. A Study of Nonsteroidal Aromatase Inhibitors Plus Abemaciclib (LY2835219) in Postmenopausal Women With Breast Cancer (MONARCH 3) ClinicalTrials.gov Identifier: NCT02246621

    Google Scholar 

  40. Baselga J, Campone M, Piccart M et al (2012) Everolimus in postmenopausal hormone-receptor positive advanced breast cancer. N Engl J Med 366:520–529

    Article  CAS  PubMed  Google Scholar 

  41. Yardley DA, Noguchi S, Pritchard KI et al (2013) Everolimus plus exemestane in postmenopausal patients with HR-positive breast cancer: BOLERO-2 final progression free survival analysis. Adv Ther 30:870–884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Piccart M, Hortobagyi GN, Campone M (2014) Everolimus plus exemestane for hormone receptor positive, HER-2 negative advanced breast cancer: overall survival results from BOLERO-2. Ann Oncol 25:2357–2362

    Article  CAS  PubMed  Google Scholar 

  43. Toy W, Shen Y, Won H et al. (2013) ESR1 ligand binding domain mutations in hormone resistant breast cancer. Nat Genet 45: 1439–1445

    Google Scholar 

  44. Turner et al. (2016) Efficacy of palbociclib plus fulvestrant in patients with metastatic breast cancer and ESR1 mutations in circulating tumor DNA. J Clin Oncol 34 (suppl; abstr 512)

    Google Scholar 

  45. Fribbens C, O’Leary B, Kilburn L (2016) Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer 34: 2961–2968

    Google Scholar 

  46. Krop I, Johnston S, Mayer IA (2014) The FERGI phase II study of the PI3 K inhibitor pictilisib (GDC-0941) plus fulvestrant vs fulvestrant plus placebo in patients with ER+, AI resistant advanced or metastatic breast cancer-Part I results. SABCS, Abstract S2-02

    Google Scholar 

  47. Baselga J, Im S-A, Iwata H et al. (2015) PIK3CA status in circulating tumor DNA predicts efficacy of buparlisib plus fulvestrant in postmenopausal women with endocrine-resistant HER+/HER2− advanced breast cancer: first results from the randomized, phase III BELLE-2 trial. SABCS, Abstract S6-01

    Google Scholar 

  48. Di Leo A, Lee K, Ciuelos E et al. (2016) BELLE-3: a phase III study of buparlisib and fulvestrant in postmenopausal women with HR+, HER2-, AI-treated, locally advanced or metastatic breast cancer, who progressed on or after mTOR inhibitor-based treatment. SABCS, Abstract S4-07

    Google Scholar 

  49. Yardley DA, Ismail-Khan R, Klein P (2011) Results of ENCORE 301, a 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 a nonsteroidal AI. J Clin Oncol suppl 27, abstr 268

    Google Scholar 

  50. Thurlimann B, Robertson JF, Nabholtz JM et al (2003) Efficacy of tamoxifen following anastrozole compared to anastrozole following tamoxifen as first-line treatment for advanced breast cancer in postmenopausal women. Eur J Cancer 39:2310

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA

    Lisa E. Flaum & William J. Gradishar

Authors
  1. Lisa E. Flaum
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William J. Gradishar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to William J. Gradishar .

Editor information

Editors and Affiliations

  1. Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

    William J. Gradishar

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Flaum, L.E., Gradishar, W.J. (2018). Advances in Endocrine Therapy for Postmenopausal Metastatic Breast Cancer. In: Gradishar, W. (eds) Optimizing Breast Cancer Management. Cancer Treatment and Research, vol 173. Springer, Cham. https://doi.org/10.1007/978-3-319-70197-4_9

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-70197-4_9

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-70195-0

  • Online ISBN: 978-3-319-70197-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation