title: Angiotensin II-Receptor Inhibition With Candesartan to Prevent Trastuzumab-Related Cardiotoxic Effects in Patients With Early Breast Cancer: A Randomized Clinical Trial.
abstract: OBJECTIVE
  This is the first randomized placebo-controlled evaluation of a medical intervention for the prevention of trastuzumab-related cardiotoxic effects.
  
  
  OBJECTIVE
  To determine as the primary end point whether angiotensin II antagonist treatment with candesartan can prevent or ameliorate trastuzumab-related cardiotoxic effects, defined as a decline in left ventricular ejection fraction (LVEF) of more than 15% or a decrease below the absolute value 45%.
  
  
  METHODS
  This randomized, placebo-controlled clinical study was conducted between October 2007 and October 2011 in 19 hospitals in the Netherlands, enrolling 210 women with early breast cancer testing positive for human epidermal growth factor receptor 2 (HER2) who were being considered for adjuvant systemic treatment with anthracycline-containing chemotherapy followed by trastuzumab.
  
  
  METHODS
  A total of 78 weeks of candesartan (32 mg/d) or placebo treatment; study treatment started at the same day as the first trastuzumab administration and continued until 26 weeks after completion of trastuzumab treatment.
  
  
  METHODS
  The primary outcome was LVEF. Secondary end points included whether the N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT) can be used as surrogate markers and whether genetic variability in germline ERBB2 (formerly HER2 or HER2/neu) correlates with trastuzumab-related cardiotoxic effects.
  
  
  RESULTS
  A total of 206 participants were evaluable (mean age, 49 years; age range, 25-69 years) 103 in the candesartan group (mean age, 50 years; age range, 25-69 years) and 103 in the placebo group (mean age, 50 years; age range, 30-67 years). Of these, 36 manifested at least 1 of the 2 primary cardiac end points. There were 3.8% more cardiac events in the candesartan group than in the placebo group (95% CI, -7% to 15%; P = .58): 20 events (19%) and 16 events (16%), respectively. The 2-year cumulative incidence of cardiac events was 0.28 (95% CI, 0.13-0.40) in the candesartan group and 0.16 (95% CI, 0.08-0.22) in the placebo group (P = .56). Candesartan did not affect changes in NT-proBNP and hs-TnT values, and these biomarkers were not associated with significant changes in LVEF. The Ala1170Pro homozygous ERBB2 genotype was associated with a lower likelihood of the occurrence of a cardiac event compared with Pro/Pro + Ala/Pro genotypes in multivariate analysis (odds ratio, 0.09; 95% CI, 0.02-0.45; P = .003).
  
  
  CONCLUSIONS
  The findings do not support the hypothesis that concomitant use of candesartan protects against a decrease in left ventricular ejection fraction during or shortly after trastuzumab treatment in early breast cancer. The ERBB2 germline Ala1170Pro single nucleotide polymorphism may be used to identify patients who are at increased risk of trastuzumab-related cardiotoxic effects.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00459771.
authors.affiliation: Division of Clinical Pharmacology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Annelies H
authors.initials: AH
authors.lastname: Boekhout
authors.affiliation: Department of Medical Oncology University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Jourik A
authors.initials: JA
authors.lastname: Gietema
authors.affiliation: Division of Clinical Pharmacology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Bojana
authors.initials: B
authors.lastname: Milojkovic Kerklaan
authors.affiliation: Biometrics Department, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Erik D
authors.initials: ED
authors.lastname: van Werkhoven
authors.affiliation: Department of Medical Oncology University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Renske
authors.initials: R
authors.lastname: Altena
authors.affiliation: Department of Internal Medicine, Isala Clinics, Zwolle, the Netherlands.
authors.forename: Aafke
authors.initials: A
authors.lastname: Honkoop
authors.affiliation: Department of Internal Medicine, Antonius Hospital, Nieuwegein, the Netherlands.
authors.forename: Maartje
authors.initials: M
authors.lastname: Los
authors.affiliation: Department of Internal Medicine, Medisch Spectrum Twente, Enschede, the Netherlands.
authors.forename: Willem M
authors.initials: WM
authors.lastname: Smit
authors.affiliation: Department of Internal Medicine, Wilhelmina Hospital, Assen, the Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Nieboer
authors.affiliation: Department of Internal Medicine, Medical Center Alkmaar, Alkmaar, the Netherlands.
authors.forename: Carolien H
authors.initials: CH
authors.lastname: Smorenburg
authors.affiliation: Department of Internal Medicine, Canisius Wilhemina Hospital, Nijmegen, the Netherlands.
authors.forename: Caroline M P W
authors.initials: CM
authors.lastname: Mandigers
authors.affiliation: Department of Internal Medicine, VieCuri Medical Center Noord-Limburg, Venlo, the Netherlands.
authors.forename: Agnes J
authors.initials: AJ
authors.lastname: van der Wouw
authors.affiliation: Department of Internal Medicine, Deventer Hospital, Deventer, the Netherlands.
authors.forename: Lonneke
authors.initials: L
authors.lastname: Kessels
authors.affiliation: Department of Internal Medicine, Martini Hospital, Groningen, the Netherlands.
authors.forename: Annette W G
authors.initials: AW
authors.lastname: van der Velden
authors.affiliation: Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Petronella B
authors.initials: PB
authors.lastname: Ottevanger
authors.affiliation: Department of Internal Medicine, Jeroen Bosch Hospital, Den Bosch, the Netherlands.
authors.forename: Tineke
authors.initials: T
authors.lastname: Smilde
authors.affiliation: Department of Internal Medicine, Hospital de Tjongerschans, Heerenveen, the Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: de Boer
authors.affiliation: Department of Cardiology, University Medical Center Groningen, the Netherlands.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: van Veldhuisen
authors.affiliation: Department of Laboratory Medicine University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Ido P
authors.initials: IP
authors.lastname: Kema
authors.affiliation: Department of Medical Oncology University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
authors.affiliation: Division of Clinical Pharmacology, Netherlands Cancer Institute, Amsterdam, the Netherlands18Department of Pharmaceutical Sciences, Science Faculty Utrecht University, Utrecht, the Netherlands.
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: D000328:Adult; D000368:Aged; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D066126:Cardiotoxicity / Q000097:blood / Q000000981:diagnostic imaging / Q000209:etiology / Q000517:prevention & control*; D017024:Chemotherapy, Adjuvant; D004311:Double-Blind Method; D004452:Echocardiography; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D015999:Multivariate Analysis; D020097:Natriuretic Peptide, Brain / Q000097:blood; D009367:Neoplasm Staging; D009426:Netherlands; D016017:Odds Ratio; D010446:Peptide Fragments / Q000097:blood; D020641:Polymorphism, Single Nucleotide; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D013318:Stroke Volume; D013777:Tetrazoles / Q000627:therapeutic use*; D000068878:Trastuzumab / Q000009:adverse effects*; D020107:Troponin T / Q000097:blood; D016277:Ventricular Function, Left
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D020097:Natriuretic Peptide, Brain; D010446:Peptide Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; D013777:Tetrazoles; D000068878:Trastuzumab; D020107:Troponin T; C109794:pro-brain natriuretic peptide (1-76); C508053:ERBB2 protein, human; C081643:candesartan