Dynamics of circulating vascular endothelial growth factor-A predict benefit from antiangiogenic cediranib in metastatic or recurrent cervical cancer patients

Zhou, C. et al. (2019) Dynamics of circulating vascular endothelial growth factor-A predict benefit from antiangiogenic cediranib in metastatic or recurrent cervical cancer patients. British Journal of Clinical Pharmacology, 85(8), pp. 1781-1789. (doi: 10.1111/bcp.13965) (PMID:30980733) (PMCID:PMC6624436)

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Aims: 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. Methods: 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. Results: 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). Conclusion: Patterns of early elevation in plasma VEGF-A should be studied further as a potential biomarker to predict treatment benefit from cediranib.

Item Type:Articles
Additional Information:This work was supported by funding for the CIRCCa trial from Cancer Research UK (C1256/A11416) and an investigator sponsored study collaboration with AstraZeneca. Additional support was received from CRUK funding to the Cancer Research Manchester Centre (C5759/A25254), to the CRUK Manchester Institute (C5759/ A27412), and CRUK Manchester Experimental Cancer Medicines Centre (A25146). C.W. is supported by the NIHR Manchester Biomedical Research Centre.
Glasgow Author(s) Enlighten ID:McCartney, Miss Elaine and Paul, Mr James and Carty, Mrs Karen and Rai, Miss Debbie
Authors: Zhou, C., Taylor, S., Tugwood, J., Simpson, K., Jayson, G. C., Symonds, P., Paul, J., Davidson, S., Carty, K., McCartney, E., Rai, D., Dive, C., and West, C.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:British Journal of Clinical Pharmacology
ISSN (Online):1365-2125
Published Online:13 April 2019

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