JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T Role of Troponins I and T and N-Terminal Prohormone of Brain Natriuretic Peptide in Monitoring Cardiac Safety of Patients With Early-Stage Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer Receiving Trastuzumab: A Herceptin Adjuvant Study Cardiac Marker Substudy Dimitrios Zardavas, Thomas M. Suter, Dirk J. Van Veldhuisen, Jutta Steinseifer, Johannes Noe, Sabine Lauer, Nedal Al-Sakaff, Martine J. Piccart-Gebhart, and Evandro de Azambuja A B S T R A C T Purpose Women receiving trastuzumab with chemotherapy are at risk for trastuzumab-related cardiac dysfunction (TRCD). We explored the prognostic value of cardiac markers (troponins I and T, N-terminal prohormone of brain natriuretic peptide [NT-proBNP]) to predict baseline susceptibility to develop TRCD. We examined whether development of cardiac end points or significant left ven- tricular ejection fraction (LVEF) drop was associated with markers’ increases. Patients and Methods Cardiac marker assessments were coupled with LVEF measurements at different time points for 533 patients from the Herceptin Adjuvant (HERA) study who agreed to participate in this study. Patients with missing marker assessments were excluded, resulting in 452 evaluable patients. A primary cardiac end point was defined as symptomatic congestive heart failure of New York Heart Association class III or IV, confirmed by a cardiologist, and a significant LVEF drop, or death of definite or probable cardiac causes. A secondary cardiac end point was defined as a confirmed significant asymptomatic or mildly symptomatic LVEF drop. Results Elevated baseline troponin I ( . 40 ng/L) and T (. 14 ng/L), occurring in 56 of 412 (13.6%) and 101 of 407 (24.8%) patients, respectively, were associated with an increased signi ficant LVEF drop risk (univariate analysis: hazard ratio, 4.52; P , .001 and hazard ratio, 3.57; P , .001, respectively). Few patients had their first elevated troponin value recorded during the study (six patients for troponin I and 25 patients for troponin T). Two patients developed a primary and 31 patients a secondary cardiac end point (recovery rate of 74%, 23 of 31). For NT-proBNP, higher increases from baseline were seen in patients with signi ficant LVEF drop. Conclusion Elevated troponin I or T before trastuzumab is associated with increased risk for TRCD. A similar conclusion for NT-proBNP could not be drawn because of the lack of a well-established elevation threshold; however, higher increases from baseline were seen in patients with TRCD compared with patients without. J Clin Oncol 35:878-884. © 2016 by American Society of Clinical Oncology INTRODUCTION Trastuzumab revolutionized the treatment of patients with human epidermal growth factor receptor 2 (HER2) –overexpressing breast cancer (BC). Despite its favorable safety profile, 1 it can induce left ventricular dysfunction when admin- istered with anthracyclines. 2 Trastuzumab-related cardiac dysfunction (TRCD) is different from anthracycline-induced cardiotoxicity. 3,4 Anthra- cyclines induce myocardial ultrastructural changes not seen in TRCD. 5 TRCD is mostly reversible. 6,7 Left ventricular ejection fraction (LVEF) assess- ment represents the standard cardiac monitoring in routine practice, but it neither detects early TRCD signs nor predicts deterioration of cardiac function. We explored the potential of troponin I (cTnI) and T (cTnT) and N-terminal prohormone of brain Author affiliations and support information (if applicable) appear at the end of this article. Published at jco.org on October 26, 2016. Corresponding author: Evandro de Azambuja, MD, PhD, Br.E.A.S.T. Data Centre, Jules Bordet Institute, Blvd de Waterloo, 121 (7th Floor), 1000 Brussels, Belgium; e-mail: evandro.azambuja@ bordet.be © 2016 by American Society of Clinical Oncology 0732-183X/17/3508w-878w/$20.00 ASSOCIATED CONTENT Listen to the podcast by Dr Rangachari at ascopubs.org/jco/podcasts Appendix DOI: 10.1200/JCO.2015.65.7916 DOI: 10.1200/JCO.2015.65.7916 878 © 2016 by American Society of Clinical Oncology VOLUME 35 • NUMBER 8 • MARCH 10, 2017 Downloaded from ascopubs.org by 52.73.204.196 on May 16, 2022 from 052.073.204.196 Copyright © 2022 American Society of Clinical Oncology. All rights reserved.