title: Longitudinal Changes in Multiple Biomarkers Are Associated with Cardiotoxicity in Breast Cancer Patients Treated with Doxorubicin, Taxanes, and Trastuzumab.
abstract: BACKGROUND
  Biomarkers may play an important role in identifying patients at risk for cancer therapy cardiotoxicity. Our objectives were to define the patterns of change in biomarkers with cancer therapy and their associations with cardiotoxicity.
  
  
  METHODS
  In a multicenter cohort of 78 breast cancer patients undergoing doxorubicin and trastuzumab therapy, 8 biomarkers were evaluated at baseline and every 3 months over a maximum follow-up of 15 months. These biomarkers, hypothesized to be mechanistically relevant to cardiotoxicity, included high-sensitivity cardiac troponin I (hs-cTnI), high-sensitivity C-reactive protein (hsCRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), myeloperoxidase (MPO), placental growth factor (PlGF), soluble fms-like tyrosine kinase receptor-1 (sFlt-1), and galectin 3 (gal-3). We determined if biomarker increases were associated with cardiotoxicity at the same visit and the subsequent visit over the entire course of therapy. Cardiotoxicity was defined by the Cardiac Review and Evaluation Criteria; alternative definitions were also considered.
  
  
  RESULTS
  Across the entire cohort, all biomarkers except NT-proBNP and gal-3 demonstrated increases by 3 months; these increases persisted for GDF-15, PlGF, and hs-cTnI at 15 months. Increases in MPO, PlGF, and GDF-15 were associated with cardiotoxicity at the same visit [MPO hazard ratio 1.38 (95% CI 1.10-1.71), P = 0.02; PlGF 3.78 (1.30-11.0), P = 0.047; GDF-15 1.71 (1.15-2.55), P = 0.01] and the subsequent visit. MPO was robust to alternative outcome definitions.
  
  
  CONCLUSIONS
  Increases in MPO are associated with cardiotoxicity over the entire course of doxorubicin and trastuzumab therapy. Assessment with PlGF and GDF-15 may also be of value. These findings motivate validation studies in additional cohorts.
authors.affiliation: University of Pennsylvania, Philadelphia, PA;
authors.forename: Mary
authors.initials: M
authors.lastname: Putt
authors.affiliation: University of Pennsylvania, Philadelphia, PA;
authors.forename: Virginia Shalkey
authors.initials: VS
authors.lastname: Hahn
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, MA;
authors.forename: James L
authors.initials: JL
authors.lastname: Januzzi
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, MA;
authors.forename: Heloisa
authors.initials: H
authors.lastname: Sawaya
authors.affiliation: Sir Mortimer B. Davis-Jewish General Hospital and McGill University, Montreal, CA;
authors.forename: Igal A
authors.initials: IA
authors.lastname: Sebag
authors.affiliation: Baylor College of Medicine, Houston, TX;
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Plana
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, MA;
authors.forename: Michael H
authors.initials: MH
authors.lastname: Picard
authors.affiliation: University of Pennsylvania, Philadelphia, PA;
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Carver
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, MA;
authors.forename: Elkan F
authors.initials: EF
authors.lastname: Halpern
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, MA;
authors.forename: Irene
authors.initials: I
authors.lastname: Kuter
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, MA;
authors.forename: Jonathan
authors.initials: J
authors.lastname: Passeri
authors.affiliation: Sir Mortimer B. Davis-Jewish General Hospital and McGill University, Montreal, CA;
authors.forename: Victor
authors.initials: V
authors.lastname: Cohen
authors.affiliation: MD Anderson Cancer Center, Houston, TX;
authors.forename: Jose
authors.initials: J
authors.lastname: Banchs
authors.affiliation: Piedmont Heart Institute, Atlanta, GA.
authors.forename: Randolph P
authors.initials: RP
authors.lastname: Martin
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, MA;
authors.forename: Robert E
authors.initials: RE
authors.lastname: Gerszten
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, MA;
authors.forename: Marielle
authors.initials: M
authors.lastname: Scherrer-Crosbie
authors.affiliation: University of Pennsylvania, Philadelphia, PA; bonnie.ky@uphs.upenn.edu.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Ky
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects*; D015415:Biomarkers / Q000032:analysis; D001940:Breast / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy*; D002097:C-Reactive Protein / Q000032:analysis; D066126:Cardiotoxicity / Q000175:diagnosis* / Q000209:etiology; D054715:Cardiotoxins / Q000009:adverse effects*; D004317:Doxorubicin / Q000009:adverse effects*; D005260:Female; D037502:Galectin 3 / Q000032:analysis; D055436:Growth Differentiation Factor 15 / Q000032:analysis; D006321:Heart / Q000187:drug effects*; D006801:Humans; D008137:Longitudinal Studies; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000032:analysis; D010446:Peptide Fragments / Q000032:analysis; D011379:Prognosis; D000068878:Trastuzumab / Q000009:adverse effects*; D019210:Troponin I / Q000032:analysis; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000032:analysis
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D054715:Cardiotoxins; D037502:Galectin 3; D055436:Growth Differentiation Factor 15; D010446:Peptide Fragments; D019210:Troponin I; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D004317:Doxorubicin; D002097:C-Reactive Protein; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D000068878:Trastuzumab