Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Weill Cornell Medical College, New York, New York.
JAMA Cardiol. 2020 Mar 1;5(3):309-317. doi: 10.1001/jamacardio.2019.5586.
Trastuzumab improves outcomes in patients with ERBB2-positive (formerly HER2) breast cancer but is associated with treatment-induced cardiotoxicity, most commonly manifest by an asymptomatic decline in left ventricular ejection fraction (LVEF). Little is known to date regarding the long-term effects of treatment-induced cardiotoxicity on cardiopulmonary function in patients who survive trastuzumab-treated breast cancer.
To determine whether treatment-induced cardiotoxicity recovers or is associated with long-term cardiopulmonary dysfunction in survivors of ERBB2-positive breast cancer.
DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional case-control study enrolled patients with nonmetastatic ERBB2-positive breast cancer after completion of trastuzumab-based therapy (median, 7.0 [interquartile range (IQR), 6.2-8.7] years after therapy) who met 1 of 2 criteria: (1) cardiotoxicity (TOX group) developed during trastuzumab treatment (ie, asymptomatic decrease of LVEF≥10% from baseline to <55% [n = 22]) or (2) no evidence of cardiotoxicity during trastuzumab treatment (NOTOX group [n = 20]). Patients were treated at the Memorial Sloan Kettering Cancer Center. Fifteen healthy control participants (HC group) were also enrolled for comparison purposes. All groups were frequency matched by age strata (<55, 55-64, and ≥65 years). Data were collected from September 9, 2016, to August 10, 2018, and analyzed from November 20, 2018, to August 12, 2019.
Speckle-tracking echocardiography and maximal cardiopulmonary exercise testing were performed to measure indices of left ventricular function (including LVEF and global longitudinal strain [GLS]) and peak oxygen consumption (peak VO2).
A total of 57 participants (median age, 60.8 [IQR, 52.7-65.7] years) were included in the analysis. Overall, 38 of 42 patients with breast cancer (90%) were treated with anthracyclines before trastuzumab. Resting mean (SD) LVEF was significantly lower in the TOX group (56.9% [5.2%]) compared with the NOTOX (62.4% [4.0%]) and HC (65.3% [2.9%]) groups; similar results were found for GLS (TOX group, -17.8% [2.2%]; NOTOX group, -19.8% [2.2%]; HC group, -21.3% [1.8%]) (P < .001). Mean peak VO2 in the TOX group (22.9 [4.4] mL/kg/min) was 15% lower compared with the NOTOX group (27.0 [5.3] mL/kg/min; P = .03) and 25% lower compared with the HC group (30.5 [3.4] mL/ kg/min; P < .001). In patients with breast cancer, GLS was significantly associated with peak VO2 (β coefficient, -0.75; 95% CI, -1.32 to -0.18).
Treatment-induced cardiotoxicity appears to be associated with long-term marked impairment of cardiopulmonary function and may contribute to increased risk of late-occurring cardiovascular disease in survivors of ERBB2-positive breast cancer.
重要性：曲妥珠单抗可改善 ERBB2 阳性（以前称为 HER2）乳腺癌患者的预后，但与治疗引起的心脏毒性相关，最常见的表现为左心室射血分数（LVEF）的无症状下降。目前对于曲妥珠单抗治疗的乳腺癌幸存者中，治疗引起的心脏毒性对心肺功能的长期影响知之甚少。
目的：确定 ERBB2 阳性乳腺癌幸存者的治疗诱导性心脏毒性是否恢复或与长期心肺功能障碍相关。
设计、地点和参与者：这项横断面病例对照研究纳入了接受曲妥珠单抗治疗后完成治疗（中位数为治疗后 7.0 [四分位距（IQR），6.2-8.7]年）的非转移性 ERBB2 阳性乳腺癌患者，符合以下 2 项标准之一：（1）在曲妥珠单抗治疗期间发生心脏毒性（TOX 组：LVEF 从基线下降≥10%，但<55%[n=22]）或（2）在曲妥珠单抗治疗期间无心脏毒性证据（NOTOX 组[n=20]）。患者在纪念斯隆凯特琳癌症中心接受治疗。还纳入了 15 名健康对照参与者（HC 组）进行比较。所有组均按年龄分层（<55 岁、55-64 岁和≥65 岁）进行频率匹配。数据于 2016 年 9 月 9 日至 2018 年 8 月 10 日收集，并于 2018 年 11 月 20 日至 2019 年 8 月 12 日进行分析。
主要结局和测量：进行斑点追踪超声心动图和最大心肺运动测试，以测量左心室功能指标（包括 LVEF 和整体纵向应变（GLS））和峰值耗氧量（peak VO2）。
结果：共有 57 名参与者（中位年龄，60.8 [IQR，52.7-65.7]岁）纳入分析。总体而言，42 名乳腺癌患者中有 38 名（90%）在接受曲妥珠单抗治疗前接受了蒽环类药物治疗。TOX 组的静息平均（SD）LVEF 显著低于 NOTOX 组（62.4% [4.0%]）和 HC 组（65.3% [2.9%]）；GLS 也存在类似的结果（TOX 组，-17.8% [2.2%]；NOTOX 组，-19.8% [2.2%]；HC 组，-21.3% [1.8%]）（P<0.001）。TOX 组的平均峰值 VO2（22.9 [4.4] mL/kg/min）比 NOTOX 组（27.0 [5.3] mL/kg/min；P=0.03）低 15%，比 HC 组（30.5 [3.4] mL/kg/min；P<0.001）低 25%。在乳腺癌患者中，GLS 与峰值 VO2 显著相关（β系数，-0.75；95%CI，-1.32 至-0.18）。
结论和相关性：治疗诱导的心脏毒性似乎与长期心肺功能显著受损相关，并可能导致 ERBB2 阳性乳腺癌幸存者发生迟发性心血管疾病的风险增加。
