Trial Information

Predicting Cardiac Effects of Breast Cancer Therapy

OBJECTIVES:

Primary

- To determine if polymorphisms in genes (e.g., CYBA, RAC2, NCF4, MRP1, MRP2, GTSP and
CBR3) in women with breast cancer treated with doxorubicin hydrochloride increase the
relative risk of developing ≥ NCI grade 1 cardiotoxicity. (Primary study)

- To determine whether pre-treatment levels of biomarkers (e.g., neuregulin, IGF-1,
cardiotrophin-1, IL-6, VEGF, hepatocyte growth factor, and heparin binding EGF) in
these patients, correlate with relative risk of developing ≥ NCI grade 1 cardiotoxicity
to this regimen. (Primary study)

- To determine whether decreased heart rate variability and increased plasma levels of
norepinephrine at 3 weeks after completion of this regimen correlate with relative risk
of developing ≥ NCI grade 1 cardiotoxicity in these patients. (Primary study)

- To determine whether decrease in endothelial progenitor cell (EPC) number at 3 weeks
after completion of this regimen can be detected, and if so whether decreased EPC
number correlates with ≥ NCI grade 1 cardiotoxicity. (Primary study)

- To determine whether baseline physical fitness level of these patients, assessed by a
questionnaire and 6 minute walk distance, correlates with relative risk of developing ≥
NCI grade 1 cardiotoxicity to this regimen. (Primary study)

- To determine whether activity level of these patients during treatment, assessed by
questionnaire, correlates with relative risk of developing ≥ NCI grade 1 cardiotoxicity
to this regimen. (Primary study)

- To determine whether drop in functional capacity of these patients, measured by 6
minute walk distance at the end of treatment with this regimen, correlates with ≥ NCI
grade 1 cardiotoxicity. (Primary study)

- To determine whether MRI can detect changes in diastolic heart function in these
patients 48 hours after administration of this regimen. (Sub-study A)

- To determine if a greater decrease in diastolic dysfunction in these patients at 48
hours is predictive of greater decrease in systolic function at 3 weeks after treatment
with this regimen. (Sub-study A)

- To determine whether levels of certain biomarkers of cardiac myocyte damage, B-type
natriuretic peptide and the sarcomere protein troponin T at 48 hours after the initial
exposure to these drugs correlate with relative risk of developing ≥ NCI grade1
cardiotoxicity. (Sub-study A)

- To determine whether trastuzumab given concurrently with doxorubicin hydrochloride
decreases heart rate variability and increases plasma levels of norepinephrine in these
patients, and if so, whether these changes correlate with relative risk of developing
NCI grade ≥ 1 cardiotoxicity. (Sub-study B)

- To determine whether EPC number obtained from patients treated with trastuzumab have
decreased migration into microvascular structures in an ex vivo assay and whether these
changes correlate with ≥ NCI grade 1 cardiotoxicity. (Sub-study B)

- To determine whether levels of certain biomarkers in these patients , including
neuregulin, IGF-1, cardiotrophin-1, IL-6, VEGF, hepatocyte growth factor and heparin
binding EGF, change after exposure to trastuzumab. (Sub-study B)

OUTLINE: This is a multicenter study.

- Primary study: Patients make an initial visit (before beginning doxorubicin
hydrochloride treatment) and a visit 3 weeks after the 4th course of doxorubicin
hydrochloride (approximately 12 weeks after the initial visit). During these visits,
blood samples are also collected for measuring serum levels of neuregulin-1, IGF-1,
cardiotropin-1, IL-6, VEGF, hepatocyte growth factor, and plasma norepinephrine and
endothelial progenitor cells (EPC). Heart-rate variability (HRV) is measured and, if
necessary, a transthoracic echocardiogram is performed. Patients complete baseline
health and activity level questionnaire and suitable patients complete a 6-minute walk
test. Patients undergo blood collection for genotype analysis for single nucleotide
polymorphism sites during the initial visit.

Patients complete a questionnaire assessing physical activity at the beginning of the 2nd,
3rd, and 4th courses of chemotherapy.

- Sub-study A (MRI)*: In addition to the assessments performed in the primary study,
patients undergo some extra tests. During initial visit, patients have an additional
blood sample collected during initial visit for measurement of B-type natriuretic
peptide (BNP) and troponin T and undergo cardiac MRI. Approximately 48 hours after the
first dose of doxorubicin hydrochloride, patients undergo an additional visit, during
which blood samples are collected for BNP and troponin T and an cardiac MRI is
performed.

NOTE: *Patients who enroll in sub-study A must also be enrolled in the primary study.

- Sub-study B (trastuzumab)*: In addition to the assessments performed in the primary
study, patients undergo some extra tests. Patients undergo an additional visit after
the third treatment of trastuzumab (approximately 6 months after the first dose of
doxorubicin hydrochloride), during which patients have blood samples collected and
analyzed as in Primary study visit 2. HRV is measured and, if necessary, a
transthoracic echocardiogram is performed.

NOTE: *Patients who enroll in sub-study B must also be enrolled in the primary study.

After completion of study treatment, patients are followed periodically for up to 5 years .