Bonnie Ky1, Mary Putt2, Heloisa Sawaya3, Benjamin French2, James L Januzzi3, Igal A Sebag4, Juan Carlos Plana5, Victor Cohen6, Jose Banchs7, Joseph R Carver8, Susan E Wiegers9, Randolph P Martin10, Michael H Picard3, Robert E Gerszten3, Elkan F Halpern11, Jonathan Passeri3, Irene Kuter12, Marielle Scherrer-Crosbie13. 1. Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: bonnie.ky@uphs.upenn.edu. 2. Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. 3. Cardiac Ultrasound Laboratory and Division of Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. 4. Echocardiography Laboratory and Cardiology Division, Sir Mortimer B. Davis-Jewish General Hospital and McGill University, Montreal, Quebec, Canada. 5. Division of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio. 6. Department of Medicine, Segal Cancer Center, Sir Mortimer B. Davis-Jewish General Hospital and McGill University, Montreal, Quebec, Canada. 7. Department of Cardiovascular Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. 8. Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. 9. Division of Cardiovascular Medicine, Temple University, Philadelphia, Pennsylvania. 10. Piedmont Heart Institute, Atlanta, Georgia. 11. Institute for Technology Assessment, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. 12. Gillette Center for Breast Cancer, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. 13. Cardiac Ultrasound Laboratory and Division of Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address: marielle@crosbie.com.
Abstract
OBJECTIVES: The aim of this study was to determine if individual or multiple biomarkers are associated with cardiotoxicity in patients with breast cancer undergoing cancer therapy. BACKGROUND: Current methods to identify patients at risk for cardiotoxicity from cancer therapy are inadequate. METHODS: We measured 8 biomarkers in a multicenter cohort of 78 patients with breast cancer undergoing doxorubicin and trastuzumab therapy: ultrasensitive troponin I (TnI), high-sensitivity C-reactive protein (CRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), growth differentiation factor (GDF)-15, myeloperoxidase (MPO), placental growth factor (PlGF), soluble fms-like tyrosine kinase receptor (sFlt)-1, and galectin (gal)-3. Cardiotoxicity, defined by the Cardiac Review and Evaluation Committee criteria, was assessed every 3 months for up to 15 months. Hazard ratios (HRs) of cardiotoxicity risk were assessed for each biomarker at baseline, at visit 2 (3 months), and as a function of the difference between visit 2 and baseline. Joint models were assessed for the most promising biomarkers. RESULTS: TnI, CRP, GDF-15, MPO, PlGF, and sFlt-1 levels increased from baseline to visit 2 (p < 0.05). A greater risk of cardiotoxicity was associated with interval changes in TnI (HR: 1.38 per SD; 95% confidence interval: 1.05 to 1.81; p = 0.02) and MPO (HR: 1.34 per SD; 95% confidence interval: 1.00 to 1.80; p = 0.048) and in models combining both markers (p = 0.007 and p = 0.03, respectively). The risk of cardiotoxicity was 46.5% in patients with the largest changes in both markers (ΔTnI >121.8 μg/l; ΔMPO >422.6 pmol/l). CONCLUSIONS: Early increases in TnI and MPO levels offer additive information about the risk of cardiotoxicity in patients undergoing doxorubicin and trastuzumab therapy. Independent validation of these findings is necessary before application to clinical practice.
OBJECTIVES: The aim of this study was to determine if individual or multiple biomarkers are associated with cardiotoxicity in patients with breast cancer undergoing cancer therapy. BACKGROUND: Current methods to identify patients at risk for cardiotoxicity from cancer therapy are inadequate. METHODS: We measured 8 biomarkers in a multicenter cohort of 78 patients with breast cancer undergoing doxorubicin and trastuzumab therapy: ultrasensitive troponin I (TnI), high-sensitivity C-reactive protein (CRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), growth differentiation factor (GDF)-15, myeloperoxidase (MPO), placental growth factor (PlGF), soluble fms-like tyrosine kinase receptor (sFlt)-1, and galectin (gal)-3. Cardiotoxicity, defined by the Cardiac Review and Evaluation Committee criteria, was assessed every 3 months for up to 15 months. Hazard ratios (HRs) of cardiotoxicity risk were assessed for each biomarker at baseline, at visit 2 (3 months), and as a function of the difference between visit 2 and baseline. Joint models were assessed for the most promising biomarkers. RESULTS: TnI, CRP, GDF-15, MPO, PlGF, and sFlt-1 levels increased from baseline to visit 2 (p < 0.05). A greater risk of cardiotoxicity was associated with interval changes in TnI (HR: 1.38 per SD; 95% confidence interval: 1.05 to 1.81; p = 0.02) and MPO (HR: 1.34 per SD; 95% confidence interval: 1.00 to 1.80; p = 0.048) and in models combining both markers (p = 0.007 and p = 0.03, respectively). The risk of cardiotoxicity was 46.5% in patients with the largest changes in both markers (ΔTnI >121.8 μg/l; ΔMPO >422.6 pmol/l). CONCLUSIONS: Early increases in TnI and MPO levels offer additive information about the risk of cardiotoxicity in patients undergoing doxorubicin and trastuzumab therapy. Independent validation of these findings is necessary before application to clinical practice.
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