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

The addition of trastuzumab to the standard adjuvant chemotherapy in
HER2-positive breast cancer patients markedly improves treatment outcome.
Cardiac dysfunction is an important side effect observed with the use of
trastuzumab for the treatment of patients with HER2-positive breast cancer. In
recent clinical trials evaluating the addition of trastuzumab to the adjuvant
treatment of these patients, trastuzumab treatment had to be discontinued in
approximately 20% due to the occurrence of a significant decrease in LVEF.
In a fraction of the patients trastuzumab was stopped before completion of the
treatment. These patients with HER2 positive breast cancer are excluded from
the best adjuvant systemic treatment at this moment. It is imperative in
practice to follow the stringent criteria for eligibility and cardiac
monitoring used by the HERA and NSABP B-31 trials. However, cardio-protective
drugs and optimizing screening methods are important measurements to
investigate. It is important to decrease the morbidity and mortality of
trastuzumab treatment to enable optimal therapy with trastuzumab in the
adjuvant setting, but also in patients with metastatic disease.

Primary objectives:
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 to an absolute value <45%

Secondary objectives:
1) 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 relevant genes such as 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

Prospective, randomized pharmacological intervention study

Arm I : placebo
Arm II : AT1 blocker candesartan (32 mg/day; run in 16 mg during week 1)

Three bloodsamples and two MUGA scans more than in standard medical care.

There are no data about the preventive use of candesartan to protect against
cardiotoxicity during treatment with trastuzumab.