Dimitrios Zardavas, Breast International Group; Martine J. Piccart-Gebhart and Evandro de Azambuja, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; Thomas M. Suter, Bern University Hospital, Bern; Jutta Steinseifer, Johannes Noe, Sabine Lauer, and Nedal Al-Sakaff, F. Hoffmann-La Roche, Basel, Switzerland; and Dirk J. Van Veldhuisen, University Medical Center Groningen, University of Groningen, The Netherlands.
J Clin Oncol. 2017 Mar 10;35(8):878-884. doi: 10.1200/JCO.2015.65.7916. Epub 2016 Oct 23.
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 ventricular 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 significant 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 significant 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.
接受曲妥珠单抗联合化疗的女性存在曲妥珠单抗相关性心脏功能障碍（TRCD）风险。本研究旨在探讨心脏标志物（肌钙蛋白 I 和 T、脑钠肽前体 N 端（NT-proBNP））预测基线发生 TRCD 易感性的预后价值。我们还研究了心脏终点的发生或左心室射血分数（LVEF）显著下降是否与标志物的升高相关。
HERA 研究中，533 例同意参与本研究的患者在不同时间点进行心脏标志物评估和 LVEF 测量。排除未行标志物评估的患者，共纳入 452 例可评估患者。主要心脏终点定义为纽约心脏协会（NYHA）心功能 III 或 IV 级的有症状充血性心力衰竭，由心脏病专家确认，并伴有 LVEF 显著下降或确定或可能为心脏原因的死亡。次要心脏终点定义为确认的无症状或轻度症状性 LVEF 显著下降。
基线时肌钙蛋白 I（>40ng/L）和 T（>14ng/L）升高分别见于 412 例患者中的 56 例（13.6%）和 407 例患者中的 101 例（24.8%），与 LVEF 显著下降风险增加相关（单因素分析：危险比分别为 4.52，P<0.001 和 3.57，P<0.001）。少数患者在研究期间首次记录到肌钙蛋白升高（肌钙蛋白 I 升高 6 例，肌钙蛋白 T 升高 25 例）。2 例患者发生主要心脏终点，31 例患者发生次要心脏终点（恢复率 74%，23/31）。对于 NT-proBNP，LVEF 显著下降患者的基线升高幅度更大。
曲妥珠单抗治疗前肌钙蛋白 I 或 T 升高与 TRCD 风险增加相关。由于缺乏明确的升高阈值，无法得出 NT-proBNP 有类似结论；然而，与无 TRCD 的患者相比，发生 TRCD 的患者 NT-proBNP 升高幅度更大。
