title: Rationale and design of the Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research Trial (MANTICORE 101--Breast): a randomized, placebo-controlled trial to determine if conventional heart failure pharmacotherapy can prevent trastuzumab-mediated left ventricular remodeling among patients with HER2+ early breast cancer using cardiac MRI.
abstract: BACKGROUND
  MANTICORE 101 - Breast (Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research) is a randomized trial to determine if conventional heart failure pharmacotherapy (angiotensin converting enzyme inhibitor or beta-blocker) can prevent trastuzumab-mediated left ventricular remodeling, measured with cardiac MRI, among patients with HER2+ early breast cancer.
  
  
  METHODS
  One hundred and fifty-nine patients with histologically confirmed HER2+ breast cancer will be enrolled in a parallel 3-arm, randomized, placebo controlled, double-blind design. After baseline assessments, participants will be randomized in a 1:1:1 ratio to an angiotensin-converting enzyme inhibitor (perindopril), beta-blocker (bisoprolol), or placebo. Participants will receive drug or placebo for 1 year beginning 7 days before trastuzumab therapy. Dosages for all groups will be systematically up-titrated, as tolerated, at 1 week intervals for a total of 3 weeks. The primary objective of this randomized clinical trial is to determine if conventional heart failure pharmacotherapy can prevent trastuzumab-mediated left ventricular remodeling among patients with HER2+ early breast cancer, as measured by 12 month change in left ventricular end-diastolic volume using cardiac MRI. Secondary objectives include 1) determine the evolution of left ventricular remodeling on cardiac MRI in patients with HER2+ early breast cancer, 2) understand the mechanism of trastuzumab mediated cardiac toxicity by assessing for the presence of myocardial injury and apoptosis on serum biomarkers and cardiac MRI, and 3) correlate cardiac biomarkers of myocyte injury and extra-cellular matrix remodeling with left ventricular remodeling on cardiac MRI in patients with HER2+ early breast cancer.
  
  
  CONCLUSIONS
  Cardiac toxicity as a result of cancer therapies is now recognized as a significant health problem of increasing prevalence. To our knowledge, MANTICORE will be the first randomized trial testing proven heart failure pharmacotherapy in the prevention of trastuzumab-mediated cardiotoxicity. We expect the findings of this trial to provide important evidence in the development of guidelines for preventive therapy.
  
  
  BACKGROUND
  ClinicalTrials.gov: NCT01016886.
authors.affiliation: University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Edith
authors.initials: E
authors.lastname: Pituskin
authors.forename: Mark
authors.initials: M
authors.lastname: Haykowsky
authors.forename: John R
authors.initials: JR
authors.lastname: Mackey
authors.forename: Richard B
authors.initials: RB
authors.lastname: Thompson
authors.forename: Justin
authors.initials: J
authors.lastname: Ezekowitz
authors.forename: Sheri
authors.initials: S
authors.lastname: Koshman
authors.forename: Gavin
authors.initials: G
authors.lastname: Oudit
authors.forename: Kelvin
authors.initials: K
authors.lastname: Chow
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Pagano
authors.forename: Ian
authors.initials: I
authors.lastname: Paterson
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects* / Q000627:therapeutic use; D017209:Apoptosis; D017298:Bisoprolol / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D005260:Female; D006333:Heart Failure / Q000188:drug therapy / Q000517:prevention & control*; D006801:Humans; D008279:Magnetic Resonance Imaging; D020913:Perindopril / Q000627:therapeutic use*; D010919:Placebos; D016032:Randomized Controlled Trials as Topic / Q000379:methods; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012107:Research Design; D000068878:Trastuzumab; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D017298:Bisoprolol; D020913:Perindopril; D010919:Placebos; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab