Bone effects of mammalian target of rapamycin (mTOR) inhibition with everolimus

Critical Reviews in Oncology/Hematology

Volumn 87, Issue 2, 2013, Pages 101-111

  Hadji, Peyman ^a   Coleman, Robert ^b,c   Gnant, Michael ^d  

^a PHILIPPS UNIVERSITY MARBURG   (Germany)

^b WESTON PARK HOSPITAL   (United Kingdom)

^c Yorkshire Cancer Research Sheffield Cancer Research Centre   (United Kingdom)

^d MEDICAL UNIVERSITY OF VIENNA   (Austria)

Author keywords

Aromatase inhibitors; Bone; Breast cancer; Everolimus; MTOR; Postmenopausal women

Indexed keywords

ANASTROZOLE; AROMATASE INHIBITOR; BISPHOSPHONIC ACID DERIVATIVE; ESTROGEN; ESTROGEN RECEPTOR; EVEROLIMUS; EXEMESTANE; FULVESTRANT; LETROZOLE; MAMMALIAN TARGET OF RAPAMYCIN; PHOSPHATIDYLINOSITOL 3 KINASE; PLACEBO; PROTEIN KINASE B; TAMOXIFEN;

ADJUVANT THERAPY; BONE; BONE DENSITY; BONE METASTASIS; BONE TURNOVER; BREAST CANCER; DRUG DOSE COMPARISON; DRUG MECHANISM; DRUG POTENTIATION; ENZYME INHIBITION; ESTROGEN RECEPTOR POSITIVE BREAST CANCER; FRACTURE; HORMONAL THERAPY; HUMAN; NONHUMAN; OSTEOLYSIS; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); POSTMENOPAUSE; PROGRESSION FREE SURVIVAL; REVIEW; RISK FACTOR; SIGNAL TRANSDUCTION;

AROMATASE INHIBITORS; BONE; BREAST CANCER; EVEROLIMUS; MTOR; POSTMENOPAUSAL WOMEN;

ANIMALS; ANTINEOPLASTIC AGENTS; BONE AND BONES; BONE NEOPLASMS; BREAST NEOPLASMS; FEMALE; HUMANS; SIROLIMUS; TOR SERINE-THREONINE KINASES;

EID: 84881227235     PISSN: 10408428     EISSN: 18790461     Source Type: Journal    
DOI: 10.1016/j.critrevonc.2013.05.015     Document Type: Review

References (73)

1. Trinkaus M., Simmons C., Myers J., Dranatisaris G., Clemons M. Skeletal-related events (SREs) in breast cancer patients with bone metastases treated in the nontrial setting. Support Care Cancer 2010, 18:197-203.
2. Gnant M., Baselga J., Rugo H.S., et al. Effect of everolimus on bone marker levels and progressive disease in bone in BOLERO-2. Journal of the National Cancer Institute 2013, 105:654-663.
3. Baselga J., Campone M., Piccart M., et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. New England Journal of Medicine 2012, 366:520-529.
4. Mundy G.R. Metastasis to bone: causes, consequences and therapeutic opportunities. Nature Reviews Cancer 2002, 2:584-593.
5. Coleman R.E. Skeletal complications of malignancy. Cancer 1997, 80:1588-1594.
6. Coleman R.E., Banks L.M., Girgis S.I., et al. Skeletal effects of exemestane on bone-mineral density, bone biomarkers, and fracture incidence in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES): a randomised controlled study. Lancet Oncology 2007, 8:119-127.
7. Eastell R., Adams J.E., Coleman R.E., et al. Effect of anastrozole on bone mineral density: 5-year results from the anastrozole, tamoxifen, alone or in combination trial 18233230. Journal of Clinical Oncology 2008, 26:1051-1057.
8. Gnant M., Mlineritsch B., Luschin-Ebengreuth G., et al. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density substudy. Lancet Oncology 2008, 9:840-849.
9. Goss P.E., Hadji P., Subar M., Abreu P., Thomsen T., Banke-Bochita J. Effects of steroidal and nonsteroidal aromatase inhibitors on markers of bone turnover in healthy postmenopausal women. Breast Cancer Research 2007, 9:R52.
10. Hadji P., Asmar L., van Nes J.G., et al. The effect of exemestane and tamoxifen on bone health within the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial: a meta-analysis of the US, German, Netherlands, and Belgium sub-studies. Journal of Cancer Research and Clinical Oncology 2011, 137:1015-1025.
11. Hadji P., Ziller M., Kieback D.G., et al. Effects of exemestane and tamoxifen on bone health within the Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial: results of a German, 12-month, prospective, randomised substudy. Annals of Oncology 2009, 20:1203-1209.
12. Hadji P., Ziller M., Kieback D.G., et al. The effect of exemestane or tamoxifen on markers of bone turnover: results of a German sub-study of the Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial. Breast 2009, 18:159-164.
13. Shapiro C.L., Halabi S., Hars V., et al. Zoledronic acid preserves bone mineral density in premenopausal women who develop ovarian failure due to adjuvant chemotherapy: final results from CALGB trial 79809. European Journal of Cancer 2011, 47:683-689.
14. National Osteoporosis Foundation Clinician's guide to prevention and treatment of osteoporosis 2010, National Osteoporosis Foundation, Washington, DC, Revised January http://www.nof.org/sites/default/files/pdfs/NOF_ClinicianGuide2009_v7.pdf [accessed 19.03.12].
15. Hofbauer L.C., Khosla S., Dunstan C.R., Lacey D.L., Spelsberg T.C., Riggs B.L. Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells. Endocrinology 1999, 140:4367-4370.
16. Lindberg M.K., Erlandsson M., Alatalo S.L., et al. Estrogen receptor alpha, but not estrogen receptor beta, is involved in the regulation of the OPG/RANKL (osteoprotegerin/receptor activator of NF-kappa B ligand) ratio and serum interleukin-6 in male mice. Journal of Endocrinology 2001, 171:425-433.
17. Rachner T.D., Schoppet M., Niebergall U., Hofbauer L.C. 17beta-Estradiol inhibits osteoprotegerin production by the estrogen receptor-alpha-positive human breast cancer cell line MCF-7. Biochemical and Biophysical Research Communications 2008, 368:736-741.
18. Saika M., Inoue D., Kido S., Matsumoto T. 17beta-estradiol stimulates expression of osteoprotegerin by a mouse stromal cell line, ST-2, via estrogen receptor-alpha. Endocrinology 2001, 142:2205-2212.
19. Rannevik G., Jeppsson S., Johnell O., Bjerre B., Laurell-Borulf Y., Svanberg L. A longitudinal study of the perimenopausal transition: altered profiles of steroid and pituitary hormones, SHBG and bone mineral density. Maturitas 2008, 61:67-77.
20. Lipton A., Chapman J.A., Demers L., et al. Elevated bone turnover predicts for bone metastasis in postmenopausal breast cancer: results of NCIC CTG MA.14. Journal of Clinical Oncology 2011, 29:3605-3610.
21. Coleman R., Rathbone E., Marshall H., et al. Vitamin D, but not bone turnover markers, predict relapse in women with early breast cancer: an AZURE translational study [abstract]. Cancer Research 2012, 72(24 Suppl.):108s. [Abstract S64].
22. 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, 365:1687-1717.
23. Hadji P. Aromatase inhibitor-associated bone loss in breast cancer patients is distinct from postmenopausal osteoporosis. Critical Reviews in Oncology/Hematology 2009, 69:73-82.
24. Buzdar A.U. 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. Journal of Clinical Oncology 2004, 22:3199-3200. author reply 200-1.
25. Forbes J.F., Cuzick J., Buzdar A., Howell A., Tobias J.S., Baum M. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncology 2008, 9:45-53.
26. Nabholtz J.M., Buzdar A., Pollak M., 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. Journal of Clinical Oncology 2000, 18:3758-3767.
27. Eastell R., Hannon R.A., Cuzick J., Dowsett M., Clack G., Adams J.E. Effect of an aromatase inhibitor on BMD and bone turnover markers: 2-year results of the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial (18233230). Journal of Bone and Mineral Research 2006, 21:1215-1223.
28. Perez E.A., Josse R.G., Pritchard K.I., et al. Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen: a companion study to NCIC CTG MA.17. Journal of Clinical Oncology 2006, 24:3629-3635.
29. Rabaglio M., Sun Z., Price K.N., et al. Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial. Annals of Oncology 2009, 20:1489-1498.
30. Bliuc D., Nguyen N.D., Milch V.E., Nguyen T.V., Eisman J.A., Center J.R. Mortality risk associated with low-trauma osteoporotic fracture and subsequent fracture in men and women. JAMA 2009, 301:513-521.
31. Coombes R.C., Hall E., Gibson L.J., et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. New England Journal of Medicine 2004, 350:1081-1092.
32. Howell A., Cuzick J., Baum M., et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 2005, 365:60-62.
33. Thurlimann B., Keshaviah A., Coates A.S., et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. New England Journal of Medicine 2005, 353:2747-2757.
34. Lonning P.E., Geisler J., Krag L.E., et al. Effects of exemestane administered for 2 years versus placebo on bone mineral density, bone biomarkers, and plasma lipids in patients with surgically resected early breast cancer. Journal of Clinical Oncology 2005, 23:5126-5137.
35. van de Velde C.J., Rea D., Seynaeve C., et al. Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet 2011, 377:321-331.
36. Journe F., Body J.J., Leclercq G., Laurent G. Hormone therapy for breast cancer, with an emphasis on the pure antiestrogen fulvestrant: mode of action, antitumor efficacy and effects on bone health. Expert Opinion on Drug Safety 2008, 7:241-258.
37. Agrawal A., Hannon R.A., Cheung K.L., Eastell R., Robertson J.F. Bone turnover markers in postmenopausal breast cancer treated with fulvestrant - a pilot study. Breast 2009, 18:204-207.
38. Kuter I., Gee J.M., Hegg R., et al. Dose-dependent change in biomarkers during neoadjuvant endocrine therapy with fulvestrant: results from NEWEST, a randomized Phase II study. Breast Cancer Research and Treatment 2012, 133:237-246.
39. Gnant M. Overcoming endocrine resistance in breast cancer: importance of mTOR inhibition. Expert Review of Anticancer Therapy 2012, 12:1579-1589.
40. Bjornsti M.A., Houghton P.J. The TOR pathway: a target for cancer therapy. Nature Reviews Cancer 2004, 4:335-348.
41. Campbell R.A., Bhat-Nakshatri P., Patel N.M., Constantinidou D., Ali S., Nakshatri H. Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. Journal of Biological Chemistry 2001, 276:9817-9824.
42. Miller T.W., Hennessy B.T., Gonzalez-Angulo A.M., et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. Journal of Clinical Investigation 2010, 120:2406-2413.
43. Santen R.J., Song R.X., Zhang Z., et al. Adaptive hypersensitivity to estrogen: mechanisms and clinical relevance to aromatase inhibitor therapy in breast cancer treatment. The Journal of Steroid Biochemistry and Molecular Biology 2005, 95:155-165.
44. Tokunaga E., Kimura Y., Mashino K., et al. Activation of PI3K/Akt signaling and hormone resistance in breast cancer. Breast Cancer 2006, 13:137-144.
45. Yue W., Fan P., Wang J., Li Y., Santen R.J. Mechanisms of acquired resistance to endocrine therapy in hormone-dependent breast cancer cells. The Journal of Steroid Biochemistry and Molecular Biology 2007, 106:102-110.
46. European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). Summary of opinion (post authorisation) June 21, 2012. Afinitor (everolimus). EMA/CHMP/402772/2012. [accessed 21.06.12]. http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion/human/001038/WC500129092.pdf.
47. U.S. Food and Drug Administration. Supplement approval July 20, 2012 [letter of approval for new indication]. [accessed 20.07.12]. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2012/022334Orig1s016ltrRepl.pdf.
48. Yamnik R.L., Digilova A., Davis D.C., Brodt Z.N., Murphy C.J., Holz M.K. S6 kinase 1 regulates estrogen receptor alpha in control of breast cancer cell proliferation. Journal of Biological Chemistry 2009, 284:6361-6369.
49. Crowder R.J., Phommaly C., Tao Y., et al. PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer. Cancer Research 2009, 69:3955-3962.
50. 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. Clinical Cancer Research 2005, 11:5319-5328.
51. Beeram M., Tan Q.T., Tekmal R.R., Russell D., Middleton A., DeGraffenried L.A. Akt-induced endocrine therapy resistance is reversed by inhibition of mTOR signaling. Annals of Oncology 2007, 18:1323-1328.
52. Moriceau G., Ory B., Mitrofan L., et al. Zoledronic acid potentiates mTOR inhibition and abolishes the resistance of osteosarcoma cells to RAD001 (Everolimus): pivotal role of the prenylation process. Cancer Research 2010, 70:10329-10339.
53. Glantschnig H., Fisher J.E., Wesolowski G., Rodan G.A., Reszka A.A. M-CSF, TNFalpha and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase. Cell Death & Differentiation 2003, 10:1165-1177.
54. Kneissel M., Luong-Nguyen N.H., Baptist M., et al. Everolimus suppresses cancellous bone loss, bone resorption, and cathepsin K expression by osteoclasts. Bone 2004, 35:1144-1156.
55. Kovacic N., Grcevic D., Katavic V., Lukic I.K., Marusic A. Targeting Fas in osteoresorptive disorders. Expert Opinion on Therapeutic Targets 2010, 14:1121-1134.
56. Mogi M., Kondo A. Down-regulation of mTOR leads to up-regulation of osteoprotegerin in bone marrow cells. Biochemical and Biophysical Research Communications 2009, 384:82-86.
57. Ory B., Moriceau G., Redini F., Heymann D. mTOR inhibitors (rapamycin and its derivatives) and nitrogen containing bisphosphonates: bi-functional compounds for the treatment of bone tumours. Current Medicinal Chemistry 2007, 14:1381-1387.
58. Vandyke K., Dewar A.L., Diamond P., et al. The tyrosine kinase inhibitor dasatinib dysregulates bone remodeling through inhibition of osteoclasts in vivo. Journal of Bone and Mineral Research 2010, 25:1759-1770.
59. Benslimane-Ahmim Z., Heymann D., Dizier B., et al. Osteoprotegerin, a new actor in vasculogenesis, stimulates endothelial colony-forming cells properties. Journal of Thrombosis and Haemostasis 2011, 9:834-843.
60. Rachner T.D., Benad P., Rauner M., et al. Osteoprotegerin production by breast cancer cells is suppressed by dexamethasone and confers resistance against TRAIL-induced apoptosis. Journal of Cellular Biochemistry 2009, 108:106-116.
61. Bachelot T., Bourgier C., Cropet C., 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. Journal of Clinical Oncology 2012, 30:2718-2724.
62. Wolff A.C., Lazar A.A., Bondarenko I., 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. Journal of Clinical Oncology 2013, 31:195-202.
63. Piccart M., Baselga J., Noguchi S., et al. Final progression-free survival analysis of BOLERO-2: a phase III trial of everolimus for postmenopausal women with advanced breast cancer [poster]. Cancer Research 2012, 72(24 Suppl.):492s-493s. [Abstract P6-04-02].
64. U.S. National Institutes of Health. Randomized phase II trial of letrozole with or without dasatinib as first and second-line treatment for hormone receptor-positive, HER2-negative post-menopausal breast cancer that is unresectable, locally recurrent or metastatic. NLM Identifier: Updated June 18, 2012 [accessed 03.08.12]. ctgov:NCT00696072.
65. U.S. National Institutes of Health. Randomized trial of fulvestrant with or without dasatinib in men and postmenopausal women who have hormone receptor-positive advanced breast cancer previously treated with an aromatase inhibitor. NLM Identifier: Updated July 31, 2012 [accessed 02.08.12]. ctgov:NCT00754325.
66. U.S. National Institutes of Health. A randomized, double-blind, multi-center phase II trial of exemestane (Aromasin®) plus dasatinib versus exemestane plus placebo in advanced estrogen receptor-positive breast cancer after disease progression on a non-steroidal aromatase inhibitor (NSAI). NLM Identifier: Updated July 16, 2012 [accessed 02.08.12]. ctgov:NCT00767520.
67. Hurvitz S.A., Andre F., Burris H.A., et al. BOLERO-1: a randomized, phase 3, double-blind, placebo-controlled multicenter trial of everolimus in combination with trastuzumab and paclitaxel as first-line therapy in women with HER2-positive, locally advanced or metastatic breast cancer. Presented at: 2012 ASCO annual meeting 2012, Abstract TPS648.
68. Strauss L.C., O'Shaughnessy J.O., Jackson J. Three parallel randomized phase 2 trials of dasatinib plus hormonal therapy in advanced estrogen receptor-positive breast cancer. Presented at: 2010 ASCO annual meeting 2012, Abstract TPS133.
69. U.S. National Institutes of Health. A phase II trial of cabozantinib in women with metastatic hormone-receptor-positive breast cancer with involvement of bone. NML Identifier: Updated August 2, 2012 [accessed 04.12.12]. ctgov:NCT01441947.
70. U.S. National Institutes of Health. A phase III study of BKM120 with fulvestrant in patients with HR+, HER2-, AI treated, locally advanced or metastatic breast cancer who progressed on or after mTORi (BELLE-3). NLM Identifier: Updated October 5, 2012 [accessed 08.01.13]. ctgov:NCT01633060.
71. U.S. National Institutes of Health. Phase III study of BKM120/placebo with fulvestrant in postmenopausal patients with hormone receptor positive HER2-negative locally advanced or metastatic breast cancer refractory to aromatase inhibitor (BELLE-2). NLM Identifier: Updated December 17, 2012 [accessed 08.01.13]. ctgov:NCT01610284.
72. Andre F., Chabaud S., Martin A.-L., Lemonnier J., Bachelot T., Campone M. Everolimus plus adjuvant endocrine therapy in high risk breast cancer: the UNIRAD study. Presented at: St. Gallen international breast cancer conference 2013, Poster 220.
73. Chavez-MacGregor M., Barlow W.E., Gonzalez-Angulo A.M., et al. A phase III randomized, placebo-controlled clinical trial evaluating the use of adjuvant endocrine therapy ± one year of everolimus in patients with high-risk, hormone receptor- (HR) positive and HER2-negative breast cancer: SWOG/NSABPS1207. Cancer Research 2012, 72(24 Suppl.):570s. [Abstract OT2-2-04].