Exploratory analysis of angiotensin converting enzyme (ACE) and aldosterone (Ald) serum levels as prognostic and predictive biomarkers on the NCIC CTG BR24 trial.

Abstract

8048 Background: Benefit from angiogenesis inhibitors (AI) has been linked to high blood pressure. One of the main determinants of blood pressure is the renin-angiotensin axis. We undertook an exploratory, retrospective analysis of ACE and Ald serum levels on specimens banked during the conduct of the BR24 study. The aim was to evaluate these markers for their prognostic significance and their predictive value regarding Cediranib (Ced) treatment. Methods: The NCIC CTG BR24 study randomized advanced non-small cell lung cancer patients (pts) to carboplatin and paclitaxel (CP) +/- Ced. ACE and Ald serum levels were retrospectively tested on baseline samples using commercial ELISA kits. A graphic method, differentiating treatment effect by the range of marker, was used to determine cutoff points (JCO 2010, 28: 5247). Exploratory analyses were performed to correlate biomarkers levels with pts characteristics and overall survival (OS). Association between categorical variables was assessed by Chi-square test or Fisher’s exact test; time to event correlation with biomarkers was tested using a Cox regression model. Potential confounding factors including medications were integrated into the statistical model. Results: Biomarker data was available in 226 of 296 randomized pts. The tested pts vs. all the randomized pts were more likely to have a lower performance status (PS, p=0.03), a normal LDH (p=0.05) and to be ever-smokers (p=0.015). The determined cutoffs were ACE: 115ng/ml and Ald: 250 pg/ml. High ACE was associated with a better PS (p=0.03). High ACE levels were prognostic for longer OS (adjusted HR 0.52 [95%C.I. 0.29-0.92], p=0.025). High ACE pts had no OS benefit (HR 1.27 [95% C.I. 0.78–2.08], p=0.34), while low ACE predicted OS benefit from the addition of Ced to CP (HR 0.64 [95%CI 0.42-0.97], p=0.03). Interaction p value=0.03; this remained significant after adjustment in multivariate analyses. Ald levels were neither prognostic nor predictive. Conclusions: This exploratory analysis suggests high ACE serum levels maybe prognostic for better OS, while low ACE may predict benefit from Ced when added to CP.