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

Abstract

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.