Angiotensin-converting enzyme and aldosterone serum levels as prognostic and predictive biomarkers for cediranib in NCIC Clinical Trials Group Study BR.24

Jair Bar*, Keyue Ding, Huijun Zhao, Lei Han, Scott A. Laurie, Lesley Seymour, Christina L. Addison, Frances A. Shepherd, Glenwood D. Goss, Jim Dimitroulakos, Penelope A. Bradbury

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Background Treatment-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 Methods ACE 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. Results Patients 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). Conclusion Low 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.

Original languageEnglish
Pages (from-to)e189-e201
JournalClinical Lung Cancer
Volume16
Issue number6
DOIs
StatePublished - Nov 2015
Externally publishedYes

Funding

FundersFunder number
Ottawa Regional Cancer Centre
Ottawa Regional Cancer Foundation
Canadian Cancer Society Research Institute021039

    Keywords

    • ACE
    • Angiogenesis
    • Endothelial dysfunction
    • NSCLC
    • VEGFR

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