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Randomised, 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): the OCOG ZAMBONEY study

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Abstract

Biomarkers of bone turnover, including urine N-telopeptide (uNTx), have been used as surrogate measures of response to bone-targeted therapies. Vascular endothelial growth factor (VEGF) levels correlate with extent of bone metastases. We assessed whether vandetanib, an inhibitor of VEGF, epidermal growth factor receptor and RET signalling, improved uNTx response when added to fulvestrant (F) in breast cancer patients with bone metastases. Postmenopausal patients with bone predominant, hormone-receptor-positive metastatic breast cancer were randomised to F (500 mg IM days 1, 15, 29, then monthly) with either vandetanib (100 mg PO OD) (FV) or placebo (FP). The primary objective was uNTx response. Secondary objectives included PFS, OS, RECIST response, pain scores and toxicity. Sixty-one patients were allocated to FV and 68 to FP. Out of 127 analyzable patients, an uNTx response occurred in 66 % for FV and 54 % for FP (p = 0.21). No difference was detected between groups for PFS; HR = 0.95 (95 % CI 0.65–1.38) or OS HR = 0.69 (95 % CI 0.37–1.31). For the 62 patients with measurable disease, clinical benefit rates were 41 and 43 %, respectively (p = 0.47). Serious adverse events were similar, 3.3 % for FV versus 5.9 % for FP. Elevated baseline uNTx (>65 nM BCE/mmol Cr) was prognostic for PFS, HR = 1.55 (95 % CI 1.04–2.30) and for OS, HR = 2.32 (95 % CI 1.25–4.33). The addition of vandetanib to fulvestrant did not improve biomarker response, PFS or OS in patients with bone metastases. Baseline bone turnover was prognostic for PFS and OS.

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References

  1. Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, Lichinitser M, Fujiwara Y, Yardley DA, Viniegra M, Fan M, Jiang Q, Dansey R, Jun S, Braun A (2010) Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 28:5132–5139. doi:10.1200/JCO.2010.29.7101

    Article  CAS  PubMed  Google Scholar 

  2. Santini D, Vincenzi B, Hannon RA, Brown JE, Dicuonzo G, Angeletti S, La Cesa A, Coleman RE, Tonini G, Budillon A, Caraglia M, Holen I (2006) Changes in bone resorption and vascular endothelial growth factor after a single zoledronic acid infusion in cancer patients with bone metastases from solid tumours. Oncol Rep 15:1351–1357

    CAS  PubMed  Google Scholar 

  3. Amir E, Trinkaus M, Simmons CE, Dranitsaris G, Clemons MJ (2009) Vascular endothelial growth factor activity after switching of bisphosphonate treatment for metastatic breast cancer. J Clin Pathol 62:474–476. doi:10.1136/jcp.2008.062505

    Article  CAS  PubMed  Google Scholar 

  4. Poon RT, Fan ST, Wong J (2001) Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol 19:1207–1225

    CAS  PubMed  Google Scholar 

  5. Wedge SR, Ogilvie DJ, Dukes M, Kendrew J, Chester R, Jackson JS, Boffey SJ, Valentine PJ, Curwen JO, Musgrove HL, Graham GA, Hughes GD, Thomas AP, Stokes ES, Curry B, Richmond GH, Wadsworth PF, Bigley PL, Hennequin LF (2002) ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res 62:4645–4655

    CAS  PubMed  Google Scholar 

  6. Carlomagno F, Vitagliano D, Guida T, Ciardiello F, Tortora G, Vecchio G, Ryan AJ, Fontanini G, Fusco A, Santoro A (2002) ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res 62:7284–7290

    CAS  PubMed  Google Scholar 

  7. Plaza-Menacho I, Morandi A, Robertson D, Pancholi S, Drury S, Dowsett M, Martin LA, Isacke CM (2010) Targeting the receptor tyrosine kinase RET sensitizes breast cancer cells to tamoxifen treatment and reveals a role for RET in endocrine resistance. Oncogene 29:4648–4657. doi:10.1038/onc.2010.209

    Article  CAS  PubMed  Google Scholar 

  8. Wang C, Mayer JA, Mazumdar A, Brown PH (2012) The rearranged during transfection/papillary thyroid carcinoma tyrosine kinase is an estrogen-dependent gene required for the growth of estrogen receptor positive breast cancer cells. Breast Cancer Res Treat 133:487–500. doi:10.1007/s10549-011-1775-9

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Natale RB, Thongprasert S, Greco FA, Thomas M, Tsai CM, Sunpaweravong P, Ferry D, Mulatero C, Whorf R, Thompson J, Barlesi F, Langmuir P, Gogov S, Rowbottom JA, Goss GD (2011) Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol 29:1059–1066. doi:10.1200/JCO.2010.28.5981

    Article  CAS  PubMed  Google Scholar 

  10. Wells SA, Robinson BJ, Gagel RF, Dralle H, Fagin JA, Santoro M, Baudin E, Elisei R, Jarzab B, Vasselli JR, Read J, Langmuir P, Ryan AJ, Schlumberger MJ (2012) Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol 30:134–141. doi:10.1200/JCO.2011.35.5040

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Miller KD, Trigo JM, Wheeler C, Barge A, Rowbottom J, Sledge G, Baselga J (2005) A multicenter phase II trial of ZD6474, a vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinase inhibitor, in patients with previously treated metastatic breast cancer. Clin Cancer Res 11:3369–3376

    Article  CAS  PubMed  Google Scholar 

  12. Mayer EL, Isakoff SJ, Klement G, Downing SR, Chen WY, Hannagan K, Gelman R, Winer EP, Burstein HJ (2012) Combination antiangiogenic therapy in advanced breast cancer: a phase 1 trial of vandetanib, a VEGFR inhibitor, and metronomic chemotherapy, with correlative platelet proteomics. Breast Cancer Res Treat 36:169–178

    Article  Google Scholar 

  13. Boér K, Láng I, Llombart-Cussac A, Andreasson I, Vivanco GL, Sanders N, Pover GM, Murray E (2012) Vandetanib with docetaxel as second-line treatment for advanced breast cancer: a double-blind, placebo-controlled, randomized Phase II study. Invest New Drugs 30:681–687

    Article  PubMed  Google Scholar 

  14. Chia S, Gradishar W, Mauriac L, Bines J, Amant F, Federico M, Fein L, Romieu G, Buzdar A, Robertson JF, Brufsky A, Possinger K, Rennie P, Sapunar F, Lowe E, Piccart M (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 EFECT. J Clin Oncol 26:1664–1670. doi:10.1200/JCO.2007.13.5822

    Article  CAS  PubMed  Google Scholar 

  15. Simmons C, Broom RJ, Cole DE, Dranitsaris G, Clemons M (2007) Urinary N-telopeptide is a rapid predictor of response to and palliative benefit from bisphosphonate therapy in patients with metastatic breast cancer. Support Cancer Ther 4:182–187

    Article  CAS  PubMed  Google Scholar 

  16. Vinholes J, Coleman R, Lacombe D, Rose C, Tubiana-Hulin M, Bastit P, Wildiers J, Michel J, Leonard R, Nortier J, Mignolet F, Ford J (1999) Assessment of bone response to systemic therapy in an EORTC trial: preliminary experience with the use of collagen cross-link excretion. European Organization for Research and Treatment of Cancer. Br J Cancer 80:221–228

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Clemons MJ, Dranitsaris G, Ooi WS, Yogendran G, Sukovic T, Wong BY, Verma S, Pritchard KI, Trudeau M, Cole DE (2006) Phase II trial evaluating the palliative benefit of second-line zoledronic acid in breast cancer patients with either a skeletalrelated event or progressive bone metastases despite first-line bisphosphonate therapy. J Clin Oncol 24:4895–4900

    Article  CAS  PubMed  Google Scholar 

  18. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216

    Article  CAS  PubMed  Google Scholar 

  19. Tan G, Jensen MP, Thornby JI, Shanti BF (2004) Validation of the brief pain inventory for chronic nonmalignant pain. J Pain 5:133–137

    Article  PubMed  Google Scholar 

  20. Broom R, Du H, Clemons M, Eton D, Dranitsaris G, Simmons C, Ooi W, Cella D (2009) Switching breast cancer patients with progressive bone metastases to third generation bisphosphonates: measuring impact using the functional assessment of cancer therapy-bone pain. J Pain Symptom Manag 38:244–257. doi:10.1016/j.jpainsymman.2008.08.005

    Article  CAS  Google Scholar 

  21. Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A, Tjulandin S, Jahn M, Lehle M, Feyereislova A, Revil C, Jones A (2009) 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 27:5529–5537. doi:10.1200/JCO.2008.20.6847

    Article  CAS  PubMed  Google Scholar 

  22. Baselga J, Campone M, Piccart M, Burris HA, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN (2012) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. New Engl J Med 366:520–529. doi:10.1056/NEJMoa1109653

    Article  CAS  PubMed  Google Scholar 

  23. Gnant M, Baselga J, Rugo HS, Noguchi S, Burris HA, Piccart M, Hortobagyi GN, Eakle J, Mukai H, Iwata H, Geberth M, Hart LL, Hadji P, El-Hashimy M, Rao S, Taran T, Sahmoud T, Lebwohl D, Campone M, Pritchard KI (2013) Effect of everolimus on bone marker levels and progressive disease in bone in BOLERO-2. J Natl Cancer Inst 105:654–663. doi:10.1093/jnci/djt026

    Article  CAS  PubMed  Google Scholar 

  24. Osborne CK, Neven P, Dirix LY, Mackey JR, Robert J, Underhill C, Schiff R, Gutierrez C, Migliaccio I, Anagnostou VK, Rimm DL, Magill P, Sellers M (2011) Gefitinib or placebo in combination with tamoxifen in patients with hormone receptorpositive metastatic breast cancer: a randomized phase II study. Clin Cancer Res 17:1147–1159. doi:10.1158/1078-0432

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Wagner AD, Thomssen C, Haerting J, Unverzagt S (2012) Vascular-endothelial-growth-factor (VEGF) targeting therapies for endocrine refractory or resistant metastatic breast cancer. Cochrane Database Syst Rev 7:008941

    Google Scholar 

  26. Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, Verhoeven D, Pedrini JL, Smirnova I, Lichinitser MR, Pendergrass K, Garnett S, Lindemann JP, Sapunar F, Martin M (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 

  27. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247

    Article  CAS  PubMed  Google Scholar 

  28. Lipton A, Costa L, Coleman RE (2011) Bone turnover markers: tools for prognosis and monitoring response to bisphosphonates? Breast Dis 33:59–69. doi:10.3233/BD-2010-0327

    PubMed  Google Scholar 

  29. Fizazi K, Lipton A, Mariette X, Body JJ, Rahim Y, Gralow JR, Gao G, Wu L, Sohn W, Jun S (2009) Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol 27:1564–1571

    Article  CAS  PubMed  Google Scholar 

  30. Amir E, Freedman O, Carlsson L, Dranitsaris G, Tomlinson G, Laupacis A, Tannock IF, Clemons M (2013) Randomized feasibility study of de-escalated (Every 12 wk) versus standard (Every 3 to 4 wk) intravenous pamidronate in women with low-risk bone metastases from breast cancer. Am J Clin Oncol 36:436–442

    Article  CAS  PubMed  Google Scholar 

  31. Clemons M, Dranitsaris G, Ooi W, Cole DE (2008) A phase II trial evaluating the palliative benefit of second-line oral ibandronate in breast cancer patients with either a skeletal related event (SRE) or progressive bone metastases (BM) despite standard bisphosphonate (BP) therapy. Breast Cancer Res Treat 108:79–85

    Article  CAS  PubMed  Google Scholar 

  32. Lipton A, Cook R, Brown J, Body JJ, Smith M, Coleman R (2013) Skeletal-related events and clinical outcomes in patients with bone metastases and normal levels of osteolysis: exploratory analyses. Clin Oncol 25:217–226

    Article  CAS  Google Scholar 

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Acknowledgments

Funding for this study was received from AstraZeneca. The funding source had no role in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. We are grateful to the patients and research staff involved in this study and the members of the Data Safety Monitoring Committee: Dr. Joel Singer (University of British Columbia), Dr. Charles Geyer (CTNeT—Statewide Clinical Trials Network of Texas), Dr. Frederick R. Rickles (The George Washington University) and Dr. P. J. Devereaux (McMaster University). Preliminary results were presented at the 2013 ASCO meeting, abstract number 574. The following (and site) were co-investigators on this study; Dr. Som Mukherjee (Juravinski Cancer Centre, Hamilton), Dr. Xinni Song (The Ottawa Hospital Regional Cancer Centre), Dr. Nadia Califaretti (Grand River Regional Cancer Centre), Dr. Jose Chang (R.S. McLaughlin Durham Regional Cancer Centre), Dr. Scott Young (Health Sciences North, Sudbury), Dr. Christine Brezden-Masley St. Michael’s Hospital, Toronto), Dr. Sunil Verma (Sunnybrook Odette Cancer Centre, Toronto), Dr. David Warr (Princess Margaret Hospital, Toronto), Dr. Stephen Chia (BCCA—Vancouver), Dr. Sanraj Basi Cross Cancer Institute), Dr. Daniel Rayson (QE II HSC—Nova Scotia Cancer Centre), Dr. Florence Plaza Arnold (Saskatoon Cancer Centre), Dr. Andre Robidoux (CHUM, Montreal).

Conflict of interest

Mark Clemons: Honoraria for talks and attendances at advisory boards: AstraZeneca. Brandy Cochrane: no conflicts to declare. Gregory R Pond: no conflicts to declare. Nadia Califaretti: Honoraria for attendances at advisory boards: AstraZeneca. Stephen K. L. Chia: Honoraria for attendances at advisory boards: AstraZeneca. Rebecca Alexandra Dent: Honoraria for attendances at advisory boards: AstraZeneca. Xinni Song: no conflicts to declare. Andre Robidoux: Honoraria for attendances at advisory boards: AstraZeneca. Sameer Parpia: no conflicts to declare. David Warr: no conflicts to declare. Daniel Rayson: Honoraria for attendances at advisory boards: AstraZeneca. Kathleen I. Pritchard: Honoraria for talks and attendances at advisory boards: AstraZeneca. Mark N Levine: no conflicts to declare.

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Clemons, M.J., Cochrane, B., Pond, G.R. et al. Randomised, 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): the OCOG ZAMBONEY study. Breast Cancer Res Treat 146, 153–162 (2014). https://doi.org/10.1007/s10549-014-3015-6

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