Clemons Mark J, Cochrane Brandy, Pond Gregory R, Califaretti Nadia, Chia Stephen K L, Dent Rebecca Alexandra, Song Xinni, Robidoux Andre, Parpia Sameer, Warr David, Rayson Daniel, Pritchard Kathleen I, Levine Mark N
Division of Medical Oncology, The Ottawa Hospital Cancer Centre, Ottawa Hospital Research Institute and University of Ottawa, Box 912, 501 Smyth Road, Ottawa, ON, K1H 8L6, Canada,
Breast Cancer Res Treat. 2014 Jul;146(1):153-62. doi: 10.1007/s10549-014-3015-6. Epub 2014 Jun 13.
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.
包括尿N-端肽（uNTx）在内的骨转换生物标志物已被用作评估骨靶向治疗反应的替代指标。血管内皮生长因子（VEGF）水平与骨转移程度相关。我们评估了凡德他尼（一种VEGF、表皮生长因子受体和RET信号通路的抑制剂）在联合氟维司群（F）用于骨转移乳腺癌患者时，是否能改善uNTx反应。绝经后以骨转移为主、激素受体阳性的转移性乳腺癌患者被随机分为接受氟维司群（第1、15、29天肌肉注射500mg，随后每月一次）联合凡德他尼（口服100mg，每日一次）（FV组）或安慰剂（FP组）。主要目标是uNTx反应。次要目标包括无进展生存期（PFS）、总生存期（OS）、实体瘤疗效评价标准（RECIST）反应、疼痛评分和毒性。61例患者被分配至FV组，68例被分配至FP组。在127例可分析的患者中，FV组uNTx反应发生率为66%，FP组为54%（p = 0.21）。两组在PFS方面未检测到差异；风险比（HR）= 0.95（95%置信区间0.65 - 1.38），OS的HR = 0.69（95%置信区间0.37 - 1.31）。对于62例有可测量病灶的患者，临床获益率分别为41%和43%（p = 0.47）。严重不良事件相似，FV组为3.3%，FP组为5.9%。基线uNTx升高（>65 nM BCE/mmol Cr）对PFS具有预后意义，HR = 1.55（95%置信区间1.04 - 2.30），对OS也具有预后意义，HR = 2.32（95%置信区间1.25 - 4.33）。在氟维司群中添加凡德他尼并不能改善骨转移患者的生物标志物反应、PFS或OS。基线骨转换对PFS和OS具有预后意义。
