title: Baseline Immunoglobulin E Levels as a Marker of Doxorubicin- and Trastuzumab-Associated Cardiac Dysfunction.
abstract: BACKGROUND
  There is a critical need to develop robust, mechanistic strategies to identify patients at increased risk of cancer therapeutics-related cardiac dysfunction (CTRCD).
  
  
  OBJECTIVE
  We aimed to discover new biomarkers associated with doxorubicin- and trastuzumab-induced CTRCD using high-throughput proteomic profiling.
  
  
  RESULTS
  Plasma, echocardiograms, and clinical outcomes were collected at standardized intervals in breast cancer patients undergoing doxorubicin and trastuzumab cancer therapy. Thirty-one longitudinal plasma samples from 3 cases with CTRCD and 4 age- and cancer-matched controls without CTRCD were processed and analyzed using label-free liquid chromatography-mass spectrometry. From these analyses, 862 proteins were identified from case/control pairs 1 and 2 and 1360 proteins from case/control pair 3. Proteins with a >1.5-fold change in cases compared with controls with a P<0.05 either at the time of CTRCD diagnosis or across all time points were considered candidate diagnostic or predictive biomarkers, respectively. The protein that demonstrated the largest differences between cases and controls was immunoglobulin E, with higher levels detected at baseline and across all time points in controls without CTRCD as compared with matched CTRCD cases (P<0.05). Similarly, in a validation study of 35 participants treated with doxorubicin and trastuzumab, high baseline immunoglobulin E levels were associated with a significantly lower risk of CTRCD (P=0.018).
  
  
  CONCLUSIONS
  In patients receiving doxorubicin and trastuzumab, high baseline immunoglobulin E levels are associated with a lower risk of CTRCD. These novel findings suggest a new paradigm in cardio-oncology, implicating the immune system as a potential mediator of doxorubicin- and trastuzumab-induced cardiac dysfunction.
authors: From the Center for Systems and Computational Biology, and Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA (L.A.B., A.V.K., Q.L., D.W.S.); Department of Pathology and Laboratory Medicine (E.L.P.), Division of Hematology and Oncology (S.D.), Abramson Cancer Center (S.D., B.K.), and Division of Cardiovascular Medicine (B.K.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
authors: Lynn A
authors: LA
authors: Beer
authors: From the Center for Systems and Computational Biology, and Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA (L.A.B., A.V.K., Q.L., D.W.S.); Department of Pathology and Laboratory Medicine (E.L.P.), Division of Hematology and Oncology (S.D.), Abramson Cancer Center (S.D., B.K.), and Division of Cardiovascular Medicine (B.K.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
authors: Andrew V
authors: AV
authors: Kossenkov
authors: From the Center for Systems and Computational Biology, and Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA (L.A.B., A.V.K., Q.L., D.W.S.); Department of Pathology and Laboratory Medicine (E.L.P.), Division of Hematology and Oncology (S.D.), Abramson Cancer Center (S.D., B.K.), and Division of Cardiovascular Medicine (B.K.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
authors: Qin
authors: Q
authors: Liu
authors: From the Center for Systems and Computational Biology, and Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA (L.A.B., A.V.K., Q.L., D.W.S.); Department of Pathology and Laboratory Medicine (E.L.P.), Division of Hematology and Oncology (S.D.), Abramson Cancer Center (S.D., B.K.), and Division of Cardiovascular Medicine (B.K.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
authors: Eline
authors: E
authors: Luning Prak
authors: From the Center for Systems and Computational Biology, and Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA (L.A.B., A.V.K., Q.L., D.W.S.); Department of Pathology and Laboratory Medicine (E.L.P.), Division of Hematology and Oncology (S.D.), Abramson Cancer Center (S.D., B.K.), and Division of Cardiovascular Medicine (B.K.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
authors: Susan
authors: S
authors: Domchek
authors: From the Center for Systems and Computational Biology, and Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA (L.A.B., A.V.K., Q.L., D.W.S.); Department of Pathology and Laboratory Medicine (E.L.P.), Division of Hematology and Oncology (S.D.), Abramson Cancer Center (S.D., B.K.), and Division of Cardiovascular Medicine (B.K.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
authors: David W
authors: DW
authors: Speicher
authors: From the Center for Systems and Computational Biology, and Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA (L.A.B., A.V.K., Q.L., D.W.S.); Department of Pathology and Laboratory Medicine (E.L.P.), Division of Hematology and Oncology (S.D.), Abramson Cancer Center (S.D., B.K.), and Division of Cardiovascular Medicine (B.K.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia. bonnie.ky@uphs.upenn.edu.
authors: Bonnie
authors: B
authors: Ky
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015415:Biomarkers; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy; D009202:Cardiomyopathies / Q000097:blood / Q000139:chemically induced*; D016022:Case-Control Studies; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D005500:Follow-Up Studies; D006333:Heart Failure / Q000097:blood / Q000139:chemically induced; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood*; D007074:Immunoglobulin G / Q000097:blood; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage; D040901:Proteomics / Q000379:methods; D013318:Stroke Volume; D000068878:Trastuzumab / Q000008:administration & dosage / Q000009:adverse effects*; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D007074:Immunoglobulin G; D007073:Immunoglobulin E; D004317:Doxorubicin; D003520:Cyclophosphamide; D000068878:Trastuzumab; D017239:Paclitaxel
keywords: CTRCD; cardiomyopathy; immune mediators; label-free quantitation; plasma biomarkers; proteomics