Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
Clinical & Experimental Pharmacology Group, Cancer Research UK Manchester Institute and Manchester Centre for Cancer Biomarker Sciences, University of Manchester, UK.
Br J Clin Pharmacol. 2019 Aug;85(8):1781-1789. doi: 10.1111/bcp.13965. Epub 2019 Apr 13.
There is a need for predictive and surrogate response biomarkers to support treatment with antiangiogenic vascular endothelial growth factor (VEGF) inhibitors. We aimed to identify a minimally-invasive biomarker predicting benefit from cediranib pretreatment or early during treatment in patients with recurrent or metastatic cervical cancer.
Blood samples were collected before treatment, during treatment and upon disease progression where appropriate from patients enrolled in CIRCCa, a randomised phase II trial of carboplatin and paclitaxel with or without cediranib. Plasma concentrations of VEGF-A, VEGF-receptor 2, Ang1 and Tie2 were measured using multiplex enzyme-linked immunosorbent assay. Pretreatment and temporal changes of the biomarkers were investigated using proportional hazard regression and unsupervised clustering analysis.
Samples (n = 556) from 52 patients were analysed. VEGF-receptor 2 (P = .0006) and Tie2 (P = .04) were downregulated following cediranib, while VEGF-A (P = .0025) was upregulated. High Eastern Cooperative Oncology Group performance status (P = .02, hazard ratio [HR] = 2.15, 95% confidence interval [CI] 1.13-4.09) and low pretreatment Tie2 concentrations (P = .003, HR = 0.57, 95%CI 0.39-0.83) were independent prognostic factors associated with reduced progression-free survival. Two patterns of changes in VEGF-A following cediranib were identified. Patients with elevated VEGF-A in the first 3 treatment cycles, regardless of magnitude, had reduced progression-free survival in the placebo arm but improved survival with the addition of cediranib (P = .019, HR = 0.13, 95% CI 0.02-0.71).
Patterns of early elevation in plasma VEGF-A should be studied further as a potential biomarker to predict treatment benefit from cediranib.
需要预测性和替代反应生物标志物来支持抗血管内皮生长因子（VEGF）抑制剂的治疗。我们旨在确定一种微创生物标志物，以预测复发性或转移性宫颈癌患者接受西地尼布预处理或治疗早期的获益。
从参加 CIRCCa 的患者中采集治疗前、治疗期间和适当情况下疾病进展时的血液样本，CIRCCa 是一项卡铂和紫杉醇联合或不联合西地尼布的随机 II 期试验。使用多重酶联免疫吸附试验测量 VEGF-A、VEGF 受体 2、Ang1 和 Tie2 的血浆浓度。使用比例风险回归和无监督聚类分析研究生物标志物的预处理和时间变化。
对 52 名患者的 556 个样本进行了分析。西地尼布治疗后，VEGF 受体 2（P =.0006）和 Tie2（P =.04）下调，而 VEGF-A（P =.0025）上调。高东部合作肿瘤学组表现状态（P =.02，风险比 [HR] = 2.15，95%置信区间 [CI] 1.13-4.09）和低预处理 Tie2 浓度（P =.003，HR = 0.57，95%CI 0.39-0.83）是与无进展生存期缩短相关的独立预后因素。西地尼布后 VEGF-A 变化的两种模式。在前 3 个治疗周期中 VEGF-A 升高的患者，无论幅度如何，在安慰剂组中的无进展生存期较短，但添加西地尼布后生存改善（P =.019，HR = 0.13，95%CI 0.02-0.71）。
血浆 VEGF-A 早期升高的模式应进一步研究作为预测西地尼布治疗获益的潜在生物标志物。
