Current Breast Cancer Reports

, Volume 5, Issue 4, pp 309–320 | Cite as

New Approaches for Hormone-Receptor Positive Metastatic Breast Cancer

  • Eirini Thanopoulou
  • Stephen R. D. Johnston
Clinical Trials (MN Dickler, Section Editor)


Overcoming endocrine resistance remains critical to further enhancing the benefit of existing endocrine therapies in estrogen receptor (ER) positive metastatic breast cancer. Preclinical research has significantly improved our understanding of molecular mechanisms associated with endocrine resistance. In turn, clinical research is focusing on designing trials that combine endocrine therapies with targeted inhibitors of specific signalling pathways that have been implicated in endocrine resistance. To date, first line studies have largely been disappointing, with many phase III trials failing to demonstrate a significant delay in endocrine resistance by the addition of a given targeted therapy. In contrast, the more successful trials have been performed in selected populations with acquired endocrine resistance. Numerous therapeutic agents are currently being tested in combination with endocrine therapies based on varying levels of preclinical data to support their use. In this review we provide the most recent advances in ER+ breast cancer, giving emphasis to recently concluded or ongoing trials with the potential to change current clinical practice.


Metastatic breast cancer ER+ breast cancer Targeted therapy Clinical trials 


Compliance with Ethics Guidelines

Conflict of Interest

Eirini Thanopoulou has received payment for a speaking engagement from Novartis. Stephen R.D. Johnston has received payment for consulting from Novartis, GlaxoSmithKline, Roche, and Genentech; research support from Pfizer, GlaxoSmithKline, and AstraZeneca; and payment for speaking engagements from Novartis and Roche.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Anderson WF, Katki HA, Rosenberg PS. Incidence of breast cancer in the United States: current and future trends. J Natl Cancer Inst. 2011;103(18):1397–402. doi: 10.1093/jnci/djr257.PubMedCrossRefGoogle Scholar
  2. 2.
    Ring A, Dowsett M. Mechanisms of tamoxifen resistance. Endocr Relat Cancer. 2004;11(4):643–58. doi: 10.1677/erc.1.00776.PubMedCrossRefGoogle Scholar
  3. 3.
    Miller TW, Balko JM, Arteaga CL. Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J Clin Oncol. 2011;29(33):4452–61. doi: 10.1200/JCO.2010.34.4879.PubMedCrossRefGoogle Scholar
  4. 4.
    Di Leo A, Malorni L. Polyendocrine treatment in estrogen receptor-positive breast cancer: a “FACT” yet to be proven. J Clin Oncol. 2012;30(16):1897–900. doi: 10.1200/JCO.2012.41.7394.PubMedCrossRefGoogle Scholar
  5. 5.
    •• Baselga J, Campone M, Piccart M, Burris 3rd HA, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520–9. doi: 10.1056/NEJMoa1109653. Pivotal registration trial of the addition of everolimus to exemestane as second-line treatment in ER+ advanced breast cancer. This trial showed substantial clinical benefit, especially in patients with acquired endocrine resistance following prior hormonal responsiveness.PubMedCrossRefGoogle Scholar
  6. 6.
    Robertson JF, Ferrero JM, Bourgeois H, Kennecke H, de Boer RH, Jacot W, et al. Ganitumab with either exemestane or fulvestrant for postmenopausal women with advanced, hormone-receptor-positive breast cancer: a randomised, controlled, double-blind, phase 2 trial. Lancet Oncol. 2013;14(3):228–35. doi: 10.1016/S1470-2045(13)70026-3.PubMedCrossRefGoogle Scholar
  7. 7.
    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. doi: 10.1093/jnci/djj357.PubMedCrossRefGoogle Scholar
  8. 8.
    • Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, et al. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med. 2012;367(5):435–44. doi: 10.1056/NEJMoa1201622. First line trial that suggested benefit for the combination of fulvestrant 250 mg plus anastrozole, especially in endocrine therapy naïve MBC.PubMedCrossRefGoogle Scholar
  9. 9.
    Bergh J, Jonsson PE, Lidbrink EK, Trudeau M, Eiermann W, Brattstrom 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. doi: 10.1200/JCO.2011.38.1095.PubMedCrossRefGoogle Scholar
  10. 10.
    Tan PS, Haaland B, Montero AJ, Lopes G. A meta-analysis of anastrozole in combination with fulvestrant in the first line treatment of hormone receptor positive advanced breast cancer. Breast Cancer Res Treat. 2013;138(3):961–5. doi: 10.1007/s10549-013-2495-0.PubMedCrossRefGoogle Scholar
  11. 11.
    • Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, et al. 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. 2010;28(30):4594–600. doi: 10.1200/JCO.2010.28.8415. This trial established the optimal doses for fulvestrant as 500 mg im monthly after a loading dose schedule.PubMedCrossRefGoogle Scholar
  12. 12.
    • 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. doi: 10.1200/JCO.2007.13.5822. This trial showed and fulvestrant and exemestane are equally effective following progression on NSAI.PubMedCrossRefGoogle Scholar
  13. 13.
    Johnston SR, Kilburn LS, Ellis P, Dodwell D, Cameron D, Hayward L, et al. 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, multicentre, phase 3 randomised trial. Lancet Oncol. 2013;14(10):989–98. doi: 10.1016/S1470-2045(13)70322-X.PubMedCrossRefGoogle Scholar
  14. 14.
    Shim WS, Conaway M, Masamura S, Yue W, Wang JP, Kmar R, et al. Estradiol hypersensitivity and mitogen-activated protein kinase expression in long-term estrogen deprived human breast cancer cells in vivo. Endocrinology. 2000;141(1):396–405.PubMedCrossRefGoogle Scholar
  15. 15.
    Stephen RL, Shaw LE, Larsen C, Corcoran D, Darbre PD. Insulin-like growth factor receptor levels are regulated by cell density and by long term estrogen deprivation in MCF7 human breast cancer cells. J Biol Chem. 2001;276(43):40080–6. doi: 10.1074/jbc.M105892200.PubMedCrossRefGoogle Scholar
  16. 16.
    Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H. Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J Biol Chem. 2001;276(13):9817–24. doi: 10.1074/jbc.M010840200.PubMedCrossRefGoogle Scholar
  17. 17.
    Johnston SR. Enhancing the efficacy of hormonal agents with selected targeted agents. Clin Breast Cancer. 2009;9 Suppl 1:S28–36. doi: 10.3816/CBC.2009.s.003.PubMedCrossRefGoogle Scholar
  18. 18.
    deGraffenried LA, Friedrichs WE, Russell DH, Donzis EJ, Middleton AK, Silva JM, et al. Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt activity. Clin Cancer Res. 2004;10(23):8059–67. doi: 10.1158/1078-0432.CCR-04-0035.PubMedCrossRefGoogle Scholar
  19. 19.
    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. doi: 10.1158/1078-0432.CCR-04-2402.PubMedCrossRefGoogle Scholar
  20. 20.
    Massarweh S, Osborne CK, Creighton CJ, Qin L, Tsimelzon A, Huang S, et al. Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function. Cancer Res. 2008;68(3):826–33. doi: 10.1158/0008-5472.CAN-07-2707.PubMedCrossRefGoogle Scholar
  21. 21.
    Osborne CK, Neven P, Dirix LY, Mackey JR, Robert J, Underhill C, et al. Gefitinib or placebo in combination with tamoxifen in patients with hormone receptor-positive metastatic breast cancer: a randomized phase II study. Clin Cancer Res. 2011;17(5):1147–59. doi: 10.1158/1078-0432.CCR-10-1869.PubMedCrossRefGoogle Scholar
  22. 22.
    Cristofanilli M, Valero V, Mangalik A, Royce M, Rabinowitz I, Arena FP, et al. Phase II, randomized trial to compare anastrozole combined with gefitinib or placebo in postmenopausal women with hormone receptor-positive metastatic breast cancer. Clin Cancer Res. 2010;16(6):1904–14. doi: 10.1158/1078-0432.CCR-09-2282.PubMedCrossRefGoogle Scholar
  23. 23.
    Cristofanilli M, Schiff R, Valero V, Iacona R, Yu J, Speake G, et al. Exploratory subset analysis according to prior endocrine treatment of two randomized phase II trials comparing gefitinib (G) with placebo (P) in combination with tamoxifen (T) or anastrozole (A) in hormone receptor-positive (HR+) metastatic breast cancer (MBC) J Clin Oncol. 2009;27(15S(May 20 Supplement)).Google Scholar
  24. 24.
    Johnston SRD, Basik M, Hegg R, Lausoontornsiri W, Grzeda L, Clemons M, et al. Phase II randomized study of the EGFR, HER2, HER3 signaling inhibitor AZD8931 in combination with anastrozole (A) in women with endocrine therapy (ET) naive advanced breast cancer (MINT). J Clin Oncol. 2013;31(suppl; abstr 531).Google Scholar
  25. 25.
    Johnston S, Pippen Jr J, Pivot X, Lichinitser M, Sadeghi S, Dieras V, et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2009;27(33):5538–46. doi: 10.1200/JCO.2009.23.3734.PubMedCrossRefGoogle Scholar
  26. 26.
    Sabnis G, Schayowitz A, Goloubeva O, Macedo L, Brodie A. Trastuzumab reverses letrozole resistance and amplifies the sensitivity of breast cancer cells to estrogen. Cancer Res. 2009;69(4):1416–28. doi: 10.1158/0008-5472.CAN-08-0857.PubMedCrossRefGoogle Scholar
  27. 27.
    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, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol. 2009;27(33):5529–37. doi: 10.1200/JCO.2008.20.6847.PubMedCrossRefGoogle Scholar
  28. 28.
    Huober J, Fasching PA, Barsoum M, Petruzelka L, Wallwiener D, Thomssen C, et al. Higher efficacy of letrozole in combination with trastuzumab compared to letrozole monotherapy as first-line treatment in patients with HER2-positive, hormone-receptor-positive metastatic breast cancer—results of the eLEcTRA trial. Breast. 2012;21(1):27–33. doi: 10.1016/j.breast.2011.07.006.PubMedCrossRefGoogle Scholar
  29. 29.
    Fagan DH, Uselman RR, Sachdev D, Yee D. Acquired resistance to tamoxifen is associated with loss of the type I insulin-like growth factor receptor: implications for breast cancer treatment. Cancer Res. 2012;72(13):3372–80. doi: 10.1158/0008-5472.CAN-12-0684.PubMedCrossRefGoogle Scholar
  30. 30.
    Fox EM, Miller TW, Balko JM, Kuba MG, Sanchez V, Smith RA, et al. A kinome-wide screen identifies the insulin/IGF-I receptor pathway as a mechanism of escape from hormone dependence in breast cancer. Cancer Res. 2011;71(21):6773–84. doi: 10.1158/0008-5472.CAN-11-1295.PubMedCrossRefGoogle Scholar
  31. 31.
    Zhang Y, Moerkens M, Ramaiahgari S, de Bont H, Price L, Meerman J, et al. Elevated insulin-like growth factor 1 receptor signaling induces antiestrogen resistance through the MAPK/ERK and PI3K/Akt signaling routes. Breast Cancer Res. 2011;13(3):R52. doi: 10.1186/bcr2883.PubMedCrossRefGoogle Scholar
  32. 32.
    Turner N, Pearson A, Sharpe R, Lambros M, Geyer F, Lopez-Garcia MA, et al. FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res. 2010;70(5):2085–94. doi: 10.1158/0008-5472.CAN-09-3746.PubMedCrossRefGoogle Scholar
  33. 33.
    Andre F, Bachelot T, Campone M, Dalenc F, Perez-Garcia JM, Hurvitz SA, et al. Targeting FGFR with Dovitinib (TKI258): preclinical and clinical data in breast cancer. Clin Cancer Res. 2013;19(13):3693–702. doi: 10.1158/1078-0432.CCR-13-0190.PubMedCrossRefGoogle Scholar
  34. 34.
    Sanchez CG, Ma CX, Crowder RJ, Guintoli T, Phommaly C, Gao F, et al. Preclinical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer. Breast Cancer Res. 2011;13(2):R21. doi: 10.1186/bcr2833.PubMedCrossRefGoogle Scholar
  35. 35.
    •• Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol. 2012;30(22):2718–24. doi: 10.1200/JCO.2011.39.0708. An important phase II study, which first showed the efficacy of everolimus and tamoxifen in ER+ MBC that had acquired secondary resistance.PubMedCrossRefGoogle Scholar
  36. 36.
    Hortobagyi G, Piccart-Gebhart M, Rugo H, Burris H, Campone M, Noguchi S, et al. Correlation of molecular alterations with efficacy of everolimus in hormone receptor–positive, HER2-negative advanced breast cancer: Results from BOLERO-2. 2013 ASCO Annual Meeting; 2013.Google Scholar
  37. 37.
    • 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. doi: 10.1200/JCO.2011.38.3331. A key negative study for the mTOR inhibitor temsirolimus with letrozole in the first-line setting, with the majority of patients having endocrine naïve disease.PubMedCrossRefGoogle Scholar
  38. 38.
    Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer. 2006;6(9):729–34. doi: 10.1038/nrc1974.PubMedCrossRefGoogle Scholar
  39. 39.
    O’Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006;66(3):1500–8. doi: 10.1158/0008-5472.CAN-05-2925.PubMedCrossRefGoogle Scholar
  40. 40.
    Sun SY, Rosenberg LM, Wang X, Zhou Z, Yue P, Fu H, et al. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res. 2005;65(16):7052–8. doi: 10.1158/0008-5472.CAN-05-0917.PubMedCrossRefGoogle Scholar
  41. 41.
    Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307(5712):1098–101. doi: 10.1126/science.1106148.PubMedCrossRefGoogle Scholar
  42. 42.
    Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004;6(11):1122–8. doi: 10.1038/ncb1183.PubMedCrossRefGoogle Scholar
  43. 43.
    Varricchio L, Migliaccio A, Castoria G, Yamaguchi H, de Falco A, Di Domenico M, et al. Inhibition of estradiol receptor/Src association and cell growth by an estradiol receptor alpha tyrosine-phosphorylated peptide. Mol Cancer Res. 2007;5(11):1213–21. doi: 10.1158/1541-7786.MCR-07-0150.PubMedCrossRefGoogle Scholar
  44. 44.
    Hiscox S, Morgan L, Green T, Nicholson RI. Src as a therapeutic target in anti-hormone/anti-growth factor-resistant breast cancer. Endocr Relat Cancer. 2006;13 Suppl 1:S53–9. doi: 10.1677/erc.1.01297.PubMedCrossRefGoogle Scholar
  45. 45.
    Zhang XH, Wang Q, Gerald W, Hudis CA, Norton L, Smid M, et al. Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell. 2009;16(1):67–78. doi: 10.1016/j.ccr.2009.05.017.PubMedCrossRefGoogle Scholar
  46. 46.
    Llombart A, Ravaioli A, Strauss L, Sy O, Abrahao F, Geese WJ, et al. Randomized phase II study of Dasatinib vs placebo in addition to Exemestane in advanced ER/PR-positive breast cancer [BMS CA180-261 study]. Cancer Res. 2011;Suppl 3.Google Scholar
  47. 47.
    Wright GL, Blum J, Krekow LK, McIntyre KJ, Wilks ST, Rabe AC, et al. Randomized phase II trial of Fulvestrant with or without Dasatinib in postmenopausal patients with hormone receptor-positive metastatic breast cancer previously treated with an aromatase inhibitor. Cancer Res. 2011;Suppl 3.Google Scholar
  48. 48.
    Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–76. doi: 10.1038/nm0603-669.PubMedCrossRefGoogle Scholar
  49. 49.
    Nakamura J, Savinov A, Lu Q, Brodie A. Estrogen regulates vascular endothelial growth/permeability factor expression in 7,12-dimethylbenz(a)anthracene-induced rat mammary tumors. Endocrinology. 1996;137(12):5589–96.PubMedCrossRefGoogle Scholar
  50. 50.
    Manders P, Beex LV, Tjan-Heijnen VC, Span PN, Sweep CG. Vascular endothelial growth factor is associated with the efficacy of endocrine therapy in patients with advanced breast carcinoma. Cancer. 2003;98(10):2125–32. doi: 10.1002/cncr.11764.PubMedCrossRefGoogle Scholar
  51. 51.
    Traina TA, Rugo HS, Caravelli JF, Patil S, Yeh B, Melisko ME, et al. Feasibility trial of letrozole in combination with bevacizumab in patients with metastatic breast cancer. J Clin Oncol. 2010;28(4):628–33. doi: 10.1200/JCO.2009.21.8784.PubMedCrossRefGoogle Scholar
  52. 52.
    Martin M, Loibl S, von Minckwitz G, Morales S, Crespo C, Anton A, et al. Phase III trial evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for advanced breast cancer-first efficacy results from the LEA study. Annual CTRC-AACR San Antonio Breast Cancer Symposium. Cancer Res. 2012;72(supp):24.Google Scholar
  53. 53.
    Clemons M, Cochrane B, Califaretti N, Chia S, Dent R, Song X et al. Randomized phase II placebo-controlled trial of fulvestrant plus vandetanib in postmenopausal women with bone only or bone predominant, hormone receptor-positive metastatic breast cancer (MBC): OCOG Zamboney study-NCT00811369. J Clin Oncol. 2013;31(suppl; abstr 574).Google Scholar
  54. 54.
    Hyams DM, Chan A, de Oliveira C, Snyder R, Vinholes J, Audeh MW, et al. Cediranib in combination with fulvestrant in hormone-sensitive metastatic breast cancer: a randomized phase II study. Invest New Drugs. 2013. doi: 10.1007/s10637-013-9991-2.PubMedGoogle Scholar
  55. 55.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. doi: 10.1016/j.cell.2011.02.013.PubMedCrossRefGoogle Scholar
  56. 56.
    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):R77. doi: 10.1186/bcr2419.PubMedCrossRefGoogle Scholar
  57. 57.
    •• Finn R, Crown J, Lang I, Boer K, Bondarenko IM, Kulyk SO et al. Results of a randomized phase 2 study of PD 0332991, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with Letrozole vs Letrozole alone for first-line treatment of ER/HER2-advanced breast cancer (BC). Cancer Res. 2012;(72:91s). A randomized phase II study of the combination CDK 4/6 inhibitor (palbociclib) with letrozole in the first-line setting of ER-positive breast cancer that showed significant improvement in median PFS and RR with manageable toxicities. These outcomes encourage the launch of a randomized phase III first-line study.Google Scholar
  58. 58.
    Zhou Q, Atadja P, Davidson NE. Histone deacetylase inhibitor LBH589 reactivates silenced estrogen receptor alpha (ER) gene expression without loss of DNA hypermethylation. Cancer Biol Ther. 2007;6(1):64–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Chen S, Ye J, Kijima I, Evans D. The HDAC inhibitor LBH589 (panobinostat) is an inhibitory modulator of aromatase gene expression. Proc Natl Acad Sci U S A. 2010;107(24):11032–7. doi: 10.1073/pnas.1000917107.PubMedCrossRefGoogle Scholar
  60. 60.
    Sabnis GJ, Goloubeva O, Chumsri S, Nguyen N, Sukumar S, Brodie AM. Functional activation of the estrogen receptor-alpha and aromatase by the HDAC inhibitor entinostat sensitizes ER-negative tumors to letrozole. Cancer Res. 2011;71(5):1893–903. doi: 10.1158/0008-5472.CAN-10-2458.PubMedCrossRefGoogle Scholar
  61. 61.
    • 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. doi: 10.1200/JCO.2012.43.7251. A randomized phase II trial of the combination entinostat and exemestane in second line setting after AI progression that significant prolongation of median OS, possibly reflecting longer-term effects of entinostat on breast cancer phenotype.PubMedCrossRefGoogle Scholar
  62. 62.
    Munster PN, Thurn KT, Thomas S, Raha P, Lacevic M, Miller A, et al. A phase II study of the histone deacetylase inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer. Br J Cancer. 2011;104(12):1828–35. doi: 10.1038/bjc.2011.156.PubMedCrossRefGoogle Scholar
  63. 63.
    Robertson JF, Lindemann JP, Llombart-Cussac A, Rolski J, Feltl D, Dewar J, et al. Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: follow-up analysis from the randomized “FIRST” study. Breast Cancer Res Treat. 2012;136(2):503–11. doi: 10.1007/s10549-012-2192-4.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of MedicineRoyal Marsden NHS Foundation TrustLondonUK

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