title: Early increases in multiple biomarkers predict subsequent cardiotoxicity in patients with breast cancer treated with doxorubicin, taxanes, and trastuzumab.
abstract: OBJECTIVE
  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.
authors.affiliation: 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.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Ky
authors.affiliation: 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.
authors.forename: Mary
authors.initials: M
authors.lastname: Putt
authors.affiliation: Cardiac Ultrasound Laboratory and Division of Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Heloisa
authors.initials: H
authors.lastname: Sawaya
authors.affiliation: 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.
authors.forename: Benjamin
authors.initials: B
authors.lastname: French
authors.affiliation: Cardiac Ultrasound Laboratory and Division of Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: James L
authors.initials: JL
authors.lastname: Januzzi
authors.affiliation: Echocardiography Laboratory and Cardiology Division, Sir Mortimer B. Davis-Jewish General Hospital and McGill University, Montreal, Quebec, Canada.
authors.forename: Igal A
authors.initials: IA
authors.lastname: Sebag
authors.affiliation: Division of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Plana
authors.affiliation: Department of Medicine, Segal Cancer Center, Sir Mortimer B. Davis-Jewish General Hospital and McGill University, Montreal, Quebec, Canada.
authors.forename: Victor
authors.initials: V
authors.lastname: Cohen
authors.affiliation: Department of Cardiovascular Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jose
authors.initials: J
authors.lastname: Banchs
authors.affiliation: Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Carver
authors.affiliation: Division of Cardiovascular Medicine, Temple University, Philadelphia, Pennsylvania.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Wiegers
authors.affiliation: Piedmont Heart Institute, Atlanta, Georgia.
authors.forename: Randolph P
authors.initials: RP
authors.lastname: Martin
authors.affiliation: Cardiac Ultrasound Laboratory and Division of Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Picard
authors.affiliation: Cardiac Ultrasound Laboratory and Division of Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Gerszten
authors.affiliation: Institute for Technology Assessment, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Elkan F
authors.initials: EF
authors.lastname: Halpern
authors.affiliation: Cardiac Ultrasound Laboratory and Division of Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Passeri
authors.affiliation: Gillette Center for Breast Cancer, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Irene
authors.initials: I
authors.lastname: Kuter
authors.affiliation: Cardiac Ultrasound Laboratory and Division of Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address: marielle@crosbie.com.
authors.forename: Marielle
authors.initials: M
authors.lastname: Scherrer-Crosbie
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects*; D015415:Biomarkers / Q000097:blood; D001943:Breast Neoplasms / Q000097:blood* / Q000175:diagnosis / Q000188:drug therapy*; D002318:Cardiovascular Diseases / Q000097:blood* / Q000139:chemically induced / Q000175:diagnosis; D015331:Cohort Studies; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D008875:Middle Aged; D009195:Peroxidase / Q000097:blood*; D011237:Predictive Value of Tests; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects; D013997:Time Factors; D000068878:Trastuzumab; D016896:Treatment Outcome; D019210:Troponin I / Q000097:blood*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D043823:Taxoids; D019210:Troponin I; D004317:Doxorubicin; D009195:Peroxidase; D000068878:Trastuzumab
keywords: cardio-oncology; chemotherapy cardiotoxicity; trastuzumab cardiotoxicity