UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Genetic Medicine Bldg. 120 Mason Farm Rd, Campus Box 7361, Chapel Hill, NC, 27599-7361, USA.
Duke University School of Medicine, Duke University, Durham, NC, USA.
Angiogenesis. 2022 Feb;25(1):47-55. doi: 10.1007/s10456-021-09799-1. Epub 2021 May 24.
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) 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).
高血压是贝伐珠单抗和其他抗血管生成药物引起的常见毒性。目前尚无预测贝伐珠单抗诱导性高血压风险的生物标志物。本研究旨在确定与血管功能相关的血浆蛋白，以预测严重贝伐珠单抗诱导性高血压的风险。使用两项临床试验（CALGB 80303 和 90401）中 398 例接受贝伐珠单抗治疗的患者预处理后的血浆样本，通过 ELISA 测定 17 种蛋白质的水平。通过计算逻辑回归的优势比（OR），对蛋白与 3 级贝伐珠单抗诱导性高血压之间的关联进行调整，该回归考虑了年龄、性别和临床试验。使用每个蛋白的最佳截断值，估计了高血压的灵敏度、特异性、阳性预测值（PPV）和阴性预测值（NPV）。在两个临床试验中，有 5 种蛋白的水平没有差异，可用于分析。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）水平较低与 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，OR 2.27，95%CI 1.10-4.92）具有独立作用。存在 2-3 种低水平蛋白的患者发生高血压的风险比为 10.06（95%CI 3.92-34.18，p=1.80×10），灵敏度为 89.7%，特异性为 53.5%，阳性预测值为 17.3%，阴性预测值为 97.9%。这是第一项提供具有预测贝伐珠单抗诱导性高血压风险潜在价值的血浆蛋白的证据。临床试验注册：ClinicalTrials.gov 标识符：NCT00088894（CALGB 80303）；和 NCT00110214（CALGB 90401）。
