Hypertension is a common toxicity induced by bevacizumab and other antiangiogenic drugs. There are no biomarkers to predict the risk of bevacizumab-induced hypertension. This study aimed to identify plasma proteins related to the function of the vasculature to predict the risk of severe bevacizumab-induced hypertension. Using pretreated plasma samples from 398 bevacizumab-treated patients in two clinical trials (CALGB 80303 and 90401), the levels of 17 proteins were measured via ELISA. The association between proteins and grade 3 bevacizumab-induced hypertension was performed by calculating the odds ratio (OR) from logistic regression adjusting for age, sex, and clinical trial. Using the optimal cut-point of each protein, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for hypertension were estimated. Five proteins showed no difference in levels between clinical trials and were used for analyses. Lower levels of angiopoietin-2 (p = 0.0013, OR 3.41, 95% CI 1.67–7.55), VEGF-A (p = 0.0008, OR 4.25, 95% CI 1.93–10.72), and VCAM-1 (p = 0.0067, OR 2.68, 95% CI 1.34–5.63) were associated with an increased risk of grade 3 hypertension. The multivariable model suggests independent effects of angiopoietin-2 (p = 0.0111, OR 2.71, 95% CI 1.29–6.10), VEGF-A (p = 0.0051, OR 3.66, 95% CI 1.54–9.73), and VCAM-1 (p = 0.0308, OR 2.27, 95% CI 1.10–4.92). The presence of low levels of 2–3 proteins had an OR of 10.06 (95% CI 3.92–34.18, p = 1.80 × 10^–5) for the risk of hypertension, with sensitivity of 89.7%, specificity of 53.5%, PPV of 17.3%, and NPV of 97.9%. This is the first study providing evidence of plasma proteins with potential value to predict patients at risk of developing bevacizumab-induced hypertension.

Clinical trial registration: ClinicalTrials.gov Identifier: NCT00088894 (CALGB 80303); and NCT00110214 (CALGB 90401).

高血压是贝伐单抗和其他抗血管生成药物引起的常见毒性。没有生物标志物可以预测贝伐单抗诱发的高血压的风险。本研究旨在确定与脉管系统功能相关的血浆蛋白，以预测严重贝伐单抗诱发的高血压的风险。在两项临床试验（CALGB 80303 和 90401）中，使用来自 398 名接受贝伐单抗治疗的患者的预处理血浆样本，通过 ELISA 测量了 17 种蛋白质的水平。通过根据年龄、性别和临床试验调整后的逻辑回归计算优势比 (OR) 来确定蛋白质与 3 级贝伐单抗诱发的高血压之间的关联。使用每种蛋白质的最佳切点，估计高血压的敏感性、特异性、阳性预测值 (PPV) 和阴性预测值 (NPV)。五种蛋白质在临床试验之间的水平没有差异，并用于分析。较低水平的血管生成素-2 (p  = 0.0013, OR 3.41, 95% CI 1.67–7.55), VEGF-A ( p  = 0.0008, OR 4.25, 95% CI 1.93–10.72), 和 VCAM-1 ( p  = 0.0067, OR 2.68, 95% CI 1.34 –5.63) 与 3 级高血压风险增加相关。多变量模型表明血管生成素-2 ( p  = 0.0111, OR 2.71, 95% CI 1.29–6.10)、VEGF-A ( p  = 0.0051, OR 3.66, 95% CI 1.54–9.73) 和 VCAM-1 ( p  = 0.0308，或 2.27，95% CI 1.10–4.92）。存在低水平的 2-3 种蛋白质的 OR 为 10.06（95% CI 3.92-34.18，p  = 1.80 × ^10-5) 对于高血压风险，敏感性为 89.7%，特异性为 53.5%，PPV 为 17.3%，NPV 为 97.9%。这是第一项提供血浆蛋白证据的研究，该证据具有预测贝伐单抗诱发的高血压风险的潜在价值。

临床试验注册： ClinicalTrials.gov 标识符：NCT00088894 (CALGB 80303)；和 NCT00110214 (CALGB 90401)。