Side Effects Involving the Heart in Women With Breast Cancer Receiving Doxorubicin and Trastuzumab
Condition: Breast Cancer; Cardiac Toxicity; Cardiovascular Complications
MeSH terms: Breast Neoplasms; Cardiotoxicity
Study type: Observational

Summary: 
      RATIONALE: Studying samples of blood and tissue in the laboratory from women receiving
      doxorubicin and trastuzumab for breast cancer may help doctors learn more about changes that
      occur in DNA and identify biomarkers for increased risk of cardiac effects.

      PURPOSE: This clinical trial is studying side effects involving the heart in women with
      breast cancer receiving doxorubicin and trastuzumab.
    

Detailed description: 
      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 .
    

Intervention name(s): trastuzumab; doxorubicin hydrochloride; polymorphism analysis; laboratory biomarker analysis; questionnaire administration; assessment of therapy complications; magnetic resonance imaging
Intervention type(s): Biological; Drug; Genetic; Other; Other; Procedure; Procedure
Intervention MeSH terms: Doxorubicin; Liposomal doxorubicin; Trastuzumab
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Persons with newly diagnosed breast cancer with planned anthracycline-based chemotherapy.
      
Biospecimen description: 
      Serum, Plasma, Mononuclear Cells
    
Keywords: cardiac toxicity; cardiovascular complications; stage I breast cancer; stage II breast cancer; stage IIIA breast cancer; stage IIIB breast cancer; stage IIIC breast cancer