title: Angiotensin-Converting Enzyme and Aldosterone Serum Levels as Prognostic and Predictive Biomarkers for Cediranib in NCIC Clinical Trials Group Study BR.24.
abstract: Predictive biomarkers of benefit from angiogenesis inhibition are lacking. Serum angiotensin-converting enzyme (ACE) and aldosterone levels of non-small-cell lung cancer patients treated with chemotherapy with or without cediranib were evaluated. Low baseline ACE serum levels were prognostic of poor chemotherapy outcome and predictive of benefit from cediranib. Aldosterone increase with use of cediranib was correlated with better outcome. These results merit further studies.
  
  
  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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Centre for Cancer Therapeutics the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Division of Medical Oncology, The Ottawa Hospital Cancer Center, Ottawa, Ontario, Canada. Electronic address: bar.jair@gmail.com.
authors.forename: Jair
authors.initials: J
authors.lastname: Bar
authors.affiliation: NCIC Clinical Trials Group and Queen's University, Kingston, Ontario, Canada.
authors.forename: Keyue
authors.initials: K
authors.lastname: Ding
authors.affiliation: Centre for Cancer Therapeutics the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Huijun
authors.initials: H
authors.lastname: Zhao
authors.affiliation: NCIC Clinical Trials Group and Queen's University, Kingston, Ontario, Canada.
authors.forename: Lei
authors.initials: L
authors.lastname: Han
authors.affiliation: Division of Medical Oncology, The Ottawa Hospital Cancer Center, Ottawa, Ontario, Canada.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Laurie
authors.affiliation: NCIC Clinical Trials Group and Queen's University, Kingston, Ontario, Canada.
authors.forename: Lesley
authors.initials: L
authors.lastname: Seymour
authors.affiliation: Centre for Cancer Therapeutics the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Faculty of Medicine and the Department of Biochemistry at the University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Addison
authors.affiliation: University Health Network, Ontario Cancer Institute, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Frances A
authors.initials: FA
authors.lastname: Shepherd
authors.affiliation: Division of Medical Oncology, The Ottawa Hospital Cancer Center, Ottawa, Ontario, Canada.
authors.forename: Glenwood D
authors.initials: GD
authors.lastname: Goss
authors.affiliation: Centre for Cancer Therapeutics the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Faculty of Medicine and the Department of Biochemistry at the University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Jim
authors.initials: J
authors.lastname: Dimitroulakos
authors.affiliation: NCIC Clinical Trials Group and Queen's University, Kingston, Ontario, Canada.
authors.forename: Penelope A
authors.initials: PA
authors.lastname: Bradbury
mesh_terms: D000450:Aldosterone / Q000097:blood*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological / Q000097:blood*; D002170:Canada; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis* / Q000188:drug therapy / Q000401:mortality; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000401:mortality; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000097:blood*; D011237:Predictive Value of Tests; D011379:Prognosis; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D016019:Survival Analysis; D016896:Treatment Outcome; D007211:Indoles
chemical_list: D000450:Aldosterone; D054316:Biomarkers, Pharmacological; D007703:Peptidyl-Dipeptidase A; D011799:Quinazolines; C488034:ACE protein, human; C500926:cediranib; D007211:Indoles
keywords: ACE; Angiogenesis; Endothelial dysfunction; NSCLC; VEGFR