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).
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Funding
This work was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821, and U24CA196171 (to the Alliance for Clinical Trials in Oncology), UG1CA233253, UG1CA233327, UG1CA233337, and UG1CA233373 (https://acknowledgments.alliancefound.org). Also supported in part by funds from Abraxis BioScience, Bristol Meyers Squibb, Celgene, and Genentech. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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Conceptualization: FI; methodology: JCFQ, AY, and FI; formal analysis and investigation: JCFQ, YL, ASE, AY, HLK, WKK, ABN, and FI; writing—original draft preparation: JCFQ; writing—review and editing: JCFQ, YL, ASE, AY, HLK, WKK, ABN, and FI; funding acquisition: FI; resources: ABN and FI; supervision: FI.
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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.
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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.
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Quintanilha, J.C.F., Liu, Y., Etheridge, A.S. et al. Plasma levels of angiopoietin-2, VEGF-A, and VCAM-1 as markers of bevacizumab-induced hypertension: CALGB 80303 and 90401 (Alliance). Angiogenesis 25, 47–55 (2022). https://doi.org/10.1007/s10456-021-09799-1
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DOI: https://doi.org/10.1007/s10456-021-09799-1