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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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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DOI: https://doi.org/10.1007/s10549-014-3015-6