Prospective, randomized, pharmacological intervention study; evaluating the effect of the angiotensin II-receptor (AT1) blocker candesartan versus placebo in prevention of trastuzumab-associated cardiotoxicity in patients with primary breast cancer treated with trastuzumab

INTERVENTION: Trade Name: Atacand Pharmaceutical Form: Tablet INN or Proposed INN: Candesartan Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 16‐ Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use CONDITION: WHO: 0‐2 Serum creatinine <140 umol/l Thyroid stimulating hormone between 0.5‐3.9 MU/l. Blood pressure systolic = 140 mmHg diastolic = 90 mmHg is acceptable at randomization. LVEF ? 50% assessed by multigated angiography (MUGA) or cardiac ultrasound PRIMARY OUTCOME: Main Objective: 1) To determine whether concurrent ATII‐antagonist treatment can prevent trastuzumab‐related cardiotoxicity, defined as a decline in LVEF of more than 15% or a decrease of less than 15% to an absolute value below50% Primary end point(s): The primary endpoint of the study is the occurrence of cardiotoxicity during the one year trastuzumab therapy and during the 26 weeks after discontinuation of trastuzumab treatment, defined as a decline in LVEF (MUGA) of more than 15% or a decrease of less than 15% to an absolute value below 50%. ; ; Secondary Objective: To determine if ‘Brain Natriuretic Peptide’ (NT‐proBNP) and troponin T can be used as surrogate marker in the monitoring of trastuzumab‐associated cardiotoxicity; ; 2. To determine genetic variability in the HER2 gene (by assessing single nucleotide polymorphisms [SNPs] in the kinase domain) and explore any correlations with trastuzumab induced cardiotoxicity ; ; 3. To determine the reversibility of a decrease in left ventricular ejection fraction (LVEF) associated with trastuzumab treatment; INCLUSION CRITERIA: Women aged =18 years 2. WHO: 0‐2 3. Strongly HER2‐positive breast cancer, defined as an immunohistochemistry score of 3+ using the HercepTestTM or gene amplification by fluorescence in situ hybridization, or chromogenic in situ hybridization (CISH) 4. Serum creatinine <140 umol/l or creatinine clearance > 50 ml/min (by Cockcroft‐Gault formula) 5. Thyroid stimulating hormone between 0.5‐3.9 MU/l 6. Blood pressure systolic = 140 mmHg diastolic = 90 mmHg is acceptable at randomization. However prior to the first administration of trastuzumab blood pressure should be regulated and should be systolic = 100 mmHg and = 180 mmHg and diastolic = 60 mmHg and = 100 mmHg (blood pressure should be regulated according to the guidelines of appendix 5). 7. LVEF ? 50% assessed by multigated angiography (MUGA) or cardiac ultrasound. 8. (Neo‐) adjuvant regimen: trastuzumab start = 3 weeks after day 1 of the last anthracycline chemotherapy cycle 9. Tras