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Endocrine Resistance in Breast Cancer- Where Are We NowWith Intelligent Combination Therapies?

  • Stephen R.D. Johnston

Abstract

Despite the improvements in breast cancer brought about by endocrine therapy, their success clinically is limited by a significant number of patients which continue to acquire resistance and die of the disease. An increased understanding of the various biological mechanisms responsible for the development of endocrine resistance has identified new therapeutic targets, providing the rationale for combining signal transduction inhibitors with endocrine therapies to delay the emergence of acquired resistance and enhance the efficacy of current endocrine treatments. Although therapeutic targeting of mTOR, Ras activation and erbB family members alongside the ER have shown promise in pre-clinical models, clinical results have been disappointing, partly due to poor patient selection. The application of rigorous trial design and tumour selection criteria to future clinical trials may allow more accurate evaluation of intelligent combination therapies in breast cancer patients.

Keywords

Combination therapy mTOR inhibitors Endocrine therapy Signal transduction inhibitors 

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References

  1. Ali S, Coombes RC. Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer2002;2:101–12.PubMedCrossRefGoogle Scholar
  2. Atkins D, Reiffen KA, Tegtmeier CL, Winther H, Bonato MS, StorkelS. Immunohistochemical detection of EGFR in paraffin-embedded tumor tissues: variation in staining intensity due to choice of fixative and storage time of tissue sections. J Histochem Cytochem 2004;52:893–901.PubMedCrossRefGoogle Scholar
  3. Bachman KE, Argani P, Samuels Y, et al. The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther2004;3:772–5.PubMedGoogle Scholar
  4. Baselga J, Roche H, Fumoleau P, et al. Treatment of postmenopausal women with locally advanced or metastatic breast cancer withletrozole alone or in combination with temsirolimus: a randomized,3-arm, phase 2 study. Breast Cancer Res Treat005;94(Suppl1):Abstract 1068.Google Scholar
  5. Baselga JS, van Dam P, Manikhas A, Bellet M, Mayordomo J, CamponeM, Kubista E, Greil R, Bianchi G, Steinseifer J, Molloy B, Tokaji E, Dixon JM, Jonat W, Rugo HS. Phase II double-blind randomized trial of daily oral RAD001 (everolimus) plus letrozole (LET) or placebo (P) plus LET as neoadjuvant therapy for {ER}+$breast cancer. Beast Cancer Res Treat 2007;106(Suppl1):Abstract 2066.Google Scholar
  6. Bautista S, Valles H, Walker RL, et al. In breast cancer,amplification of the steroid receptor coactivator gene AIB1 is correlated with estrogen and progesterone receptor positivity. Clin Cancer Res 1998;4:2925–9.PubMedGoogle Scholar
  7. Boulay A, Rudloff J, Ye J, et al. Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer. Clin Cancer Res 2005;11:5319–28.PubMedCrossRefGoogle Scholar
  8. Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H. Phosphatidylinositol -kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogenresistance. J Biol Chem 2001;276:9817–24.PubMedCrossRefGoogle Scholar
  9. Chen D, Washbrook E, Sarwar N, et al. Phosphorylation of human estrogen receptor alpha at serine 118 by two distinct signaltransduction pathways revealed by phosphorylation-specificantisera. Oncogene 2002;21:4921–31.PubMedCrossRefGoogle Scholar
  10. Chow LS, Sun Y, Jassem J, Baselga J, Hayes DF, Wolff, AC et al. Phase 3 study of temsirolimus with letrozole or letrozole alone inpostmenopausal women with locally advanced or metastatic breast cancer. Breast Cancer Res Treat 2006;100(Suppl 1):Abstract 6091.Google Scholar
  11. Chu I, Blackwell K, Chen S, Slingerland J. The dual ErbB1/ErbB2 inhibitor, lapatinib (GW572016), cooperates with tamoxifen to inhibit both cell proliferation- and estrogen-dependent gene expression in antiestrogen-resistant breast cancer. Cancer Res 2005;65:18–25.PubMedGoogle Scholar
  12. Clark GJ, Der CJ. Aberrant function of the Ras signal transduction pathway in human breast cancer. Breast Cancer Res Treat 1995;35:133–44.PubMedCrossRefGoogle Scholar
  13. Creighton CJ, Hilger AM, Murthy S, Rae JM, Chinnaiyan AM, El-AshryD. Activation of mitogen-activated protein kinase in estrogen receptor alpha-positive breast cancer cells in vitro induces an in vivo molecular phenotype of estrogen receptor alpha-negative human breast tumors. Cancer Res 2006;66:3903–11.PubMedCrossRefGoogle Scholar
  14. Dalenc F, Lacroix-Tikri M, Mourey L. Tipifarnib with tamoxifen as a rescue for tamoxifen acquired clinical resistance for metastatic ER and/or PgR positive breast cancer after relapse under tamoxifen. Preliminary results. Breast Cancer Res Treat 2005;94:S241.Google Scholar
  15. Dauvois S, White R, Parker MG. The antiestrogen ICI 182780 disrupts estrogen receptor nucleocytoplasmic shuttling. J Cell Sci 1993;106(Pt 4):1377–88.PubMedGoogle Scholar
  16. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 1998;351:1451–67.CrossRefGoogle Scholar
  17. Encarnacion CA, Ciocca DR, McGuire WL, Clark GM, Fuqua SA, Osborne CK. Measurement of steroid hormone receptors in breast cancer patients on tamoxifen. Breast Cancer Res Treat 1993;26:237–46.PubMedCrossRefGoogle Scholar
  18. Fan P, Wang J, Santen RJ, Yue W. Long-term treatment with tamoxifen facilitates translocation of estrogen receptor alpha out of the nucleus and enhances its interaction with EGFR in MCF-7 breast cancer cells. Cancer Res 2007;67:1352–60.PubMedCrossRefGoogle Scholar
  19. Ferguson AT, Lapidus RG, Baylin SB, Davidson NE. Demethylation of the estrogen receptor gene in estrogen receptor-negative breast cancer cells can reactivate estrogen receptor gene expression. Cancer Res 1995;55:2279–83.PubMedGoogle Scholar
  20. Gardner H, Bandaru R, Barret C, et al. Biomarker analysis of a phase II double-blind randomised trial of daily oral RAD001 (Everolimus) plus letrozole or placebo plus letrozole as neoadjuvant therapy for patienst with estrogen receptor positive breast cancer. Breast Cancer Res. Treat. 2007;106(Suppl 1):Abstract 4006.Google Scholar
  21. Gradishar WJ, Chia S, Piccart M. on behalf of the EFECT writing committee. Fulvestrant versus exemestane following prior non-steroidal aromatase inhibitor therapy: first results from EFECT, a randomized, phase III trial in postmenopausal women with advanced breast cancer. Breast Cancer Res Treat 2006;100(suppl 1):Abstract 12.Google Scholar
  22. Gutierrez MC, Detre S, Johnston SR, et al. Molecular changes in tamoxifen-resistant breast cancer: relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase. J Clin Oncol 2005;23:2469–76.PubMedCrossRefGoogle Scholar
  23. Ingle JR, Suman VJ, Rowland KM, et al. Fulvestrant in women with advanced breast cancer after progression on prior aromatase inhibitor therapy: North Central Cancer Treatment Group Trial N0032. J Clin Oncol 2006;24(7):1052–1056.PubMedCrossRefGoogle Scholar
  24. Johnston SR, Lu B, Dowsett M, et al. Comparison of estrogen receptor DNA binding in untreated and acquired antiestrogen-resistant human breast tumors. Cancer Res 1997;57:3723–7.PubMedGoogle Scholar
  25. Johnston SR, Saccani-Jotti G, Smith IE, et al. Changes in estrogen receptor, progesterone receptor, and pS2 expression in tamoxifen-resistant human breast cancer. Cancer Res 1995;55:3331–8.PubMedGoogle Scholar
  26. Johnston SR, Semiglazov VF, Manikhas GM, et al. A phase II,randomized, blinded study of the farnesyltransferase inhibitor tipifarnib combined with letrozole in the treatment of advanced breast cancer after antiestrogen therapy. Breast Cancer Res Treat 2008 Jul;110(2):327–35. Epub 2007 Sep 13.Google Scholar
  27. Kahlert S, Nuedling S, van Eickels M, Vetter H, Meyer R, Grohe C. Estrogen receptor alpha rapidly activates the IGF-1 receptorpathway. J Biol Chem 2000;275:18447–53.PubMedCrossRefGoogle Scholar
  28. Kato S, Endoh H, Masuhiro Y, et al. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science 1995;270:1491–4.PubMedCrossRefGoogle Scholar
  29. Konecny G, Pauletti G, Pegram M, et al. Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. J Natl Cancer Inst 2003;95:142–53.PubMedGoogle Scholar
  30. Kurokawa H, Lenferink AE, Simpson JF, et al. Inhibition of HER2/neu (erbB-2) and mitogen-activated protein kinases enhances tamoxifen action against HER2-overexpressing, tamoxifen-resistant breast cancer cells. Cancer Res 2000;60:5887–94.PubMedGoogle Scholar
  31. Kushner PJ, Agard DA, Greene GL, et al. Estrogen receptor pathways to AP-1. J Steroid Biochem Mol Biol 2000;74:311–7.PubMedCrossRefGoogle Scholar
  32. Kuukasjarvi T, Kononen J, Helin H, Holli K, Isola J. Loss of estrogen receptor in recurrent breast cancer is associated with poor response to endocrine therapy. J Clin Oncol 1996;14:2584–9.PubMedGoogle Scholar
  33. Lavinsky RM, Jepsen K, Heinzel T, et al. Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRTcomplexes. Proc Natl Acad Sci U S A 1998;95:2920–5.PubMedCrossRefGoogle Scholar
  34. Leary AM, LA; Lykkesfeldt, AE; Dowsett, M; Johnston, SRD. Enhancing endocrine responsiveness using the dual EGFR/HER2 tyrosine kinase inhibitor lapatinib in cell models of endocrine resistance. Breast Cancer Research and Treatment 2006;100(Suppl 1):Abstract 303.Google Scholar
  35. Lipton A, Ali SM, Leitzel K, et al. Serum HER-2/neu and response to the aromatase inhibitor letrozole versus tamoxifen. J Clin Oncol 2003;21:1967–72.PubMedCrossRefGoogle Scholar
  36. Mackey JR KB, Clemens M, et al. Trastuzumab prolongs progression-free survival in hormone-dependent and HER2-positive metastatic breast cancer. Breast Cancer Res Treat. 2006; 100(Suppl 1):Abstract 3.Google Scholar
  37. Marcom PK, Isaacs C, Harris L, et al. The combination of letrozole and trastuzumab as first or second-line biological therapy produces durable responses in a subset of HER2 positive and ER positive advanced breast cancers. Breast Cancer Res Treat 2007;102:43–9.PubMedCrossRefGoogle Scholar
  38. Martin LA, Farmer I, Johnston SR, Ali S, Marshall C, Dowsett M. Enhanced estrogen receptor (ER) alpha, ERBB2, and MAPK signal transduction pathways operate during the adaptation of MCF-7 cells to long term estrogen deprivation. J Biol Chem 2003;278:30458–68.PubMedCrossRefGoogle Scholar
  39. Martin LA, Head JE, Pancholi S, et al. The farnesyltransferase inhibitor R115777 (tipifarnib) in combination with tamoxifen acts synergistically to inhibit MCF-7 breast cancer cell proliferation and cell cycle progression in vitro and in vivo. Mol Cancer Ther 2007;6:2458–67.PubMedCrossRefGoogle Scholar
  40. Martin LA, Pancholi S, Chan CM, et al. The anti-oestrogen ICI 182,780, but not tamoxifen, inhibits the growth of MCF-7 breast cancer cells refractory to long-term oestrogen deprivation through down-regulation of oestrogen receptor and IGF signalling. Endocr Relat Cancer 2005;12:>p>1017–36.Google Scholar
  41. Masamura S, Santner SJ, Heitjan DF, Santen RJ. Estrogen deprivation causes estradiol hypersensitivity in human breast cancer cells. J Clin Endocrinol Metab 1995;80:2918–25.PubMedCrossRefGoogle Scholar
  42. Massarweh S, Osborne CK, Jiang S, 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;66:8266–73.PubMedCrossRefGoogle Scholar
  43. Mayer I, Ganja N, Shyr Y, Muldowney N, Arteaga C. A phase II trial of letrozole plus erlotinib in post-menopausal women with hormone-sensitive metastatic breast cancer: preliminary results of toxicities and correlative studies. Breast Cancer Res Treat 2006;100(Suppl 1):Abstract 4052.Google Scholar
  44. Mita M, Bono J, Mita A. A phase II and biologic correlative study investigating anastrozole (A) in combination with gefitinib (G) in postmenopausal patients with estrogen receptor positive (ER) metastatic breast carcinoma (MBC) who have previously failed hormonal therapy. Breast Cancer Res Treat 2005;94(Suppl 1):Abstract 1117.Google Scholar
  45. Munzone E, Curigliano G, Rocca A, et al. Reverting estrogen-receptor-negative phenotype in HER-2-overexpressing advanced breast cancer patients exposed to trastuzumab plus chemotherapy. Breast Cancer Res 2006;8(1):R4 Epub 2005 Dec. 7.Google Scholar
  46. Osborne CK, Bardou V, Hopp TA, et al. Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer. J Natl Cancer Inst 2003;95:353–61.PubMedCrossRefGoogle Scholar
  47. Osborne CK, Coronado-Heinsohn EB, Hilsenbeck SG, et al. Comparison of the effects of a pure steroidal antiestrogen with those of tamoxifen in a model of human breast cancer. J Natl Cancer Inst 1995;87:746–50.PubMedCrossRefGoogle Scholar
  48. Osipo C, Gajdos C, Liu H, Chen B, Jordan VC. Paradoxical action of fulvestrant in estradiol-induced regression of tamoxifen-stimulated breast cancer. J. Natl. Cancer Instit. 2003;95;1597–1608.Google Scholar
  49. Osborne KN, P, Dirix L, Mackey J, Robert J, Underhill C, Gutierrez C, Magill P, Hargreaves L. Randomized Phase II study of gefitinib (IRESSA) or placebo in combination with tamoxifen in patients with hormone receptor positive metastatic breast cancer. Breast Cancer Res Treat 2007;106(Suppl 1):Abstract 2067.Google Scholar
  50. Osborne CK, Schiff R. Estrogen-receptor biology: continuing progress and therapeutic implications. J Clin Oncol 2005;23:1616–22.PubMedCrossRefGoogle Scholar
  51. Perey LP, Paridaens R, Hawle H, et al. Clinical benefit of fulvestrant in postmenopausal women with advanced breast cancer and primary or acquired resistance to aromatase inhibitors: final results of phase II Swiss Group for Clinical Cancer Research Trial (SAKK 21/00). Ann Oncol 2007;18(1):64–69.PubMedCrossRefGoogle Scholar
  52. Petz LN, Ziegler YS, Schultz JR, Nardulli AM. Fos and Jun inhibit estrogen-induced transcription of the human progesterone receptor gene through an activator protein-1 site. Mol Endocrinol 2004;18:521–32.PubMedCrossRefGoogle Scholar
  53. Polychronis A, Sinnet HD, Hadjiminas D, et al. Pre-operative gefitinib versus gefitinib and anastrozole in postmenopausal patients with oestrogen-receptor positive and epidermal growth factor receptor positive primary breast cancer: a double blind placebo-controlled phase II randomised trial. Lancet Oncol 2005;6:383–391.PubMedCrossRefGoogle Scholar
  54. Ring A, Dowsett M. Mechanisms of tamoxifen resistance. Endocr Relat Cancer 2004;11:643–58.PubMedCrossRefGoogle Scholar
  55. Saal LH, Holm K, Maurer M, et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res 2005;65:2554–9.PubMedCrossRefGoogle Scholar
  56. Santen R, Jeng MH, Wang JP, et al. Adaptive hypersensitivity to estradiol: potential mechanism for secondary hormonal responses in breast cancer patients. J Steroid Biochem Mol Biol 2001;79:115–25.PubMedCrossRefGoogle Scholar
  57. Shoman N, Klassen S, McFadden A, Bickis MG, Torlakovic E, Chibbar R. Reduced PTEN expression predicts relapse in patients with breast carcinoma treated by tamoxifen. Mod Pathol 2005;18:250–9.PubMedCrossRefGoogle Scholar
  58. Shou J, Massarweh S, Osborne CK, et al. Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst 2004;96:926–35.PubMedGoogle Scholar
  59. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177–82.PubMedCrossRefGoogle Scholar
  60. Smith IE, Walsh G, Skene A, et al. A phase II placebo-controlled trial of neo-adjuvant anastrozole alone or with gefitinib in early breast cancer. J Clin Oncol 2007;25:3816–3822.PubMedCrossRefGoogle Scholar
  61. Steger GG, Bartsch R, Wenzel C, et al. Fulvestrant in pre-treated patients with advanced breast cancer: a single centre experience. Eur J Cancer 2005;41(17):2655–2661.PubMedCrossRefGoogle Scholar
  62. Wakeling AE, Dukes M, Bowler J. A potent specific pure antiestrogen with clinical potential. Cancer Res 1991;51:3867–73.PubMedGoogle Scholar
  63. Wu G, Xing M, Mambo E, et al. Somatic mutation and gain of copy number of PIK3CA in human breast cancer. Breast Cancer Res 2005;7:R609–16.PubMedCrossRefGoogle Scholar
  64. Xia W, Bacus S, Hegde P, et al. A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer. Proc Natl Acad Sci U S A 2006;103:7795–800.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Stephen R.D. Johnston
    • 1
  1. 1.Consultant Medical Oncologist, Department of MedicineRoyal Marsden HospitalChelseaUK

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