Angiotensin-Converting Enzyme and Aldosterone Serum Levels as Prognostic and Predictive Biomarkers for Cediranib in NCIC Clinical Trials Group Study BR.24

Abstract

BackgroundTreatment-induced hypertension might correlate with antiangiogenesis treatment efficacy. We evaluated the prognostic and predictive significance of angiotensin-converting enzyme (ACE) and aldosterone serum levels, regulators of blood pressure, in patients with advanced non–small-cell lung cancer (NSCLC) enrolled in the NCIC Clinical Trials Group BR.24 trial. Results of BR.24 demonstrated marginal efficacy of cediranib (an inhibitor of vascular endothelial growth factor receptors) combination with carboplatin-paclitaxel. Patients and MethodsACE and aldosterone were measured retrospectively using enzyme-linked immunosorbent assays at baseline and at time of treatment in serum samples of 226 and 176 of 296 enrolled patients, respectively. Cox regression was performed to correlate biomarkers and patient characteristics with overall survival (OS) and progression-free survival. ResultsPatients who received placebo with high baseline ACE levels (> 115 ng/mL) had significantly better OS compared with patients with low ACE (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.31-0.78; P = .002). Low ACE levels (≤ 115 ng/mL) were predictive of OS benefit from cediranib (P = .05). Aldosterone changes with treatment predicted differential OS between treatment arms, with an increased trend to associate with longer OS (HR, 0.49; 95% CI, 0.23-1.06; P = .07) for patients who received cediranib, but shorter OS (HR, 1.90; 95% CI, 0.93-3.87; P = .08) for patients who received placebo (interaction P = .01). ConclusionLow baseline ACE levels were prognostic of poor OS and predictive of OS benefit from cediranib. An aldosterone level increase with treatment might also be predictive of OS benefit from cediranib. These biomarkers should be validated in additional antiangiogenic trials in NSCLC and other cancers.