Plasma levels of angiopoietin-2, VEGF-A, and VCAM-1 as markers of bevacizumab-induced hypertension: CALGB 80303 and 90401 (Alliance)

Abstract

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).

Keywords: Angiopoietin-2; Bevacizumab; Hypertension; VCAM-1; VEGF-A.

Conflict of interest statement

Conflict of interest/ Competing interests: JCFQ and FI are coinventors of a patent application, serial number 16/932,002. FI is an advisor for Emerald Lake Safety. These relationships have been disclosed to and are under management by UNC-Chapel Hill.

Declarations

Availability of data and material: Data will be made available on reasonable request.

Code availability: Code will be made available on reasonable request.

Ethics approval: all trials were conducted in accordance with recognized ethical guidelines. The study was performed in accordance with the Declaration of Helsinki and was approved by the local IRB.

Consent to participate: All participants provided written informed consent for sample collection and analysis.

Consent for publication: Not applicable

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

© 2021. The Author(s), under exclusive licence to Springer Nature B.V.

Figures

Fig. 1

CONSORT diagrams for CALGB 80303 and 90401.

Fig. 2

Inverse quantile normalized levels of angiopoietin-2, VEGF-A, and VCAM-1 in patients with and without grade 3 hypertension.

Fig. 3. Spearman correlation for angiopoietin-2, VEGF-A, and VCAM-1.

Shaded areas indicate the 95% confidence interval.

Fig. 4

Prevalence of patients with and without grade 3 hypertension in relation to the number of proteins (angiopoietin-2, VEGF-A, and VCAM-1) with levels below the optimal cut-point (A) and in relation to whether patients have 0–1 or 2–3 proteins with levels below the optimal cut-point (B).