Trial Information

Characterization of the Cardiotoxic Effects of Chemotherapies With Anthracyclines and Trastuzumab for Breast Cancer by Contrast-enhanced Cardiovascular Magnetic Resonance Imaging (CMR).

Study Focus and Design:

Breast cancer is one of the leading cancers among white and African American women; its
incidence has increased from one in 20 in 1960 to one in eight today ARMSTRONG 2000. In
Canada alone, approximately 22,000 women are diagnosed each year with breast cancer and over
5,000 die from it VERMA 2007. Surgery, radiation therapy and/or chemotherapy are the most
commonly used treatment options. Anthracyclines, especially doxorubicin, are a class of
chemotherapeutic agents with efficacy against a variety of solid tumors, including breast
cancer. Unfortunately, cardiotoxic effects occur with cumulative doses and limit the
clinical use of doxorubicin. The incidence of heart failure is less than 5% at doses below
500 mg/m2, but increases to 18% with doses of 500 - 550 mg/m2 and exceeds 30% at doses of
more than 600 mg/m2 1-5. Although several mechanism have been proposed for the cardiotoxic
effects, little is known about prevention and effective treatment of this drug-induced
cardiomyopathy.

The human epidermal growth factor receptor 2 (HER-2), also known as ErbB2, is a member of
the group of transmembrane tyrosine kinases and is involved in the regulation of cell
proliferation GSCHWIND2004. In mice with genetic defects in ErbB2, the ventricle fails to
undergo trabeculation CRONE 2002; mice with reduced expression of HER-2 develop a dilated
cardiomyopathy.

Approximately one quarter of patients with breast cancer have increased expression of HER-2,
which is associated with a poorer prognosis including positive lymph nodes, decreased
hormone receptor expression and high proliferative rates.

Trastuzumab (Herceptin) is a monoclonal antibody against the extracellular domain of HER-2
CARTER1992 and was approved for treatment of patients with HER-2 positive metastatic breast
cancer in the 1990´s VOGEL 2002. Later, trastuzumab was approved for the use following
anthracycline-based chemotherapies to decrease disease progression and to improve survival.
The combination of anthracyclines and trastuzumab in the adjuvant setting reduced the risk
of breast cancer relapse by 50% and the risk of death from breast cancer by 33% PICCARD 2005
und ROMOND 2005.

Despite the proven therapeutic benefits, trastuzumab shows cardiotoxic side effects in up to
25% of treated patients, especially if used in combination with doxorubicin. Approximately
5-10% of all patients treated with trastuzumab in the adjuvant setting develop (mostly
asymptomatic) cardiac dysfunction and 1-3% develops severe and highly symptomatic heart
failure with NYHA functional class III - IV CHIEN 2006. While both early (peaking 4 months
post chemotherapy) and late (up to several years post exposure) cardiac toxicities leading
to congestive heart failure have been described following administration of
anthracycline-based chemotherapy, the pathophysiology of this toxicity, particularly in the
late phase remains incompletely understood and several mechanism have been proposed; the
interruption of the HER-2 signaling pathway in the heart seems to affect the ability of
cardiomyocytes to grow, repair and survive. Studies in HER-2 knock-out mice have shown that
a dilated cardiomyopathy develops following cardiac stress with anthracycline administration
OZCELIK 2002. A direct toxic effect of the HER-2 blockade on the myocardial tissue level has
been discussed, too OZCELIK 2002, trastuzumab seems to block anti-apoptotic signaling
pathways, leading to cardiac dysfunction OZCELIK 2002.

An autopsy series of cancer patients having received anthracyclines demonstrated that 65% of
patients with clinical CHF had microscopic evidence of drug toxicity, but that 35% did not
6. It may be difficult to distinguish anthracycline cardiac toxicity (ACT) from other causes
using other currently available non-invasive modalities 3.

The trastuzumab-induced left ventricular dysfunction seems to reversible in the majority of
cases, but little is known on the real-world effects of anthracyclines and trastuzumab on
cardiac function during chemotherapy and shortly after.

CMR is the non-invasive gold standard in cardiac imaging for the assessment of cardiac
function and also for the characterization of the myocardium and is used for the assessment
of other acquired myocardial changes as myocarditis 7 and non-ischemic cardiomyopathies.
Pilot studies have shown that CMR can detect even sub-clinical cardiotoxic effects in
patients after anthracycline chemotherapy 8.

Our suggested study will prospectively include patients with a first diagnosis of breast
cancer undergoing potentially cardiotoxic chemotherapy to identify the predictive value of
several CMR-derived identifiers for cardiotoxicity and to evaluate an individually adjusted
follow-up by cardiologists during and after the chemotherapy.