Introduction: Myocardial strain imaging and blood biomarkers have been proposed as adjuncts to left ventricular ejection fraction (LVEF) monitoring for the early detection of cardiotoxicity during cancer therapy. We report the results of a preplanned cardiac safety analysis of global longitudinal strain (GLS), and troponin-I (TnI) and brain natriuretic peptide (BNP) levels in the phase II study of paclitaxel, trastuzumab, and pertuzumab (THP) for metastatic HER2-positive breast cancer.
Patients and methods: Patients with 0-1 lines of prior therapy were treated with weekly paclitaxel (80 mg/m(2)) plus trastuzumab (8 mg/kg loading dose followed by 6 mg/kg) and pertuzumab (840 mg loading dose followed by 420 mg) every 3 weeks. Exploratory endpoints were GLS measured with speckle-tracking echocardiography every 3 months and TnI and BNP levels measured every 6 weeks (immediately pre- and postchemotherapy infusion) at 6 time points.
Results: Sixty-seven of 69 enrolled patients were treated with THP: 19 (28%) had hypertension, 8 (12%) had diabetes, 11 (16%) had hyperlipidemia, and 26 (38%) had smoking history. After a median follow-up of 21 months (range: 3-38 months), no patients developed symptomatic heart failure. Two patients (3.0%) experienced asymptomatic LVEF decline (grade 2). The mean GLS (±SD) was 19% ± 2% (baseline), 19% ± 2% (month 6), and 19% ± 3% (month 12). Detectable TnI (>0.06 ng/mL) and elevated BNP (>100 pg/mL) levels were observed in 3 (4.3%) and 2 (3.0%) patients, respectively, but were not associated with LVEF decline.
Conclusion: The absence of any significant changes in GLS and cardiac biomarkers (TnI and BNP) further support the cardiac safety of THP in patients with metastatic HER2-positive breast cancer.
Implications for practice: Dual anti-HER2 therapy with trastuzumab and pertuzumab in combination with taxane-based chemotherapy improves overall survival in patients with metastatic HER2-positive breast cancer. There is a critical need to investigate the potential cardiotoxicity of dual anti-HER2 blockade, given the importance of HER2 signaling in cardiac homeostasis and stress response. Global longitudinal strain and cardiac biomarkers have been proposed as adjuncts to left ventricular ejection fraction for the early detection of cardiotoxicity. In this phase II study of combination trastuzumab and pertuzumab with paclitaxel, no clinically significant change was observed in global longitudinal strain or cardiac biomarkers. These results further support the cardiac safety of dual anti-HER2 blockade previously reported in the CLEOPATRA study. The findings in the current study also call into question the role of intensive cardiac monitoring among patients treated with anti-HER2 therapy in the absence of anthracyclines. Less frequent cardiac assessments could lead to a reduction in unnecessary treatment interruption and is an important consideration given the rise in medical expenditures, but this requires further investigation.
摘要
引言. 有人提出使用心肌应变成像和血液生物标记物作为左心室射血分数 （LVEF） 监测的辅助检查, 用于早期发现癌症治疗过程中的心脏毒性。本研究报告了紫杉醇、曲妥珠单抗和帕妥珠单抗 （THP） 治疗 HER2 阳性转移性乳腺癌的II期研究中, 对整体纵向应变 （GLS）、 肌钙蛋白-I （TnI） 以及大脑钠尿肽 （BNP） 水平进行的预先计划的心脏安全性分析结果。
患者与方法. 初治和曾接受过一线治疗的患者在本研究中接受紫杉醇 （80 mg/m2） 每周一次联合曲妥珠单抗 （8 mg/kg负荷剂量后6 mg/kg） 和帕妥珠单抗 （840 mg 负荷剂量后 420 mg） 每 3 周一次治疗。探索性终点为每 3 个月一次使用斑点追踪超声心动图测量的 GLS, 以及每 6 周测定一次 TnI 和 BNP 水平 （化疗输注前后即刻）, 共 6 个时间点。
结果. 67/69 例纳入的患者接受了 THP 治疗, 其中 19 例 （28%） 有高血压, 8 例 （12%） 有糖尿病, 11例 （16%） 有高脂血症, 26 例 （38%） 有吸烟史。中位随访 21 个月 （范围: 3∼38 个月） 后, 没有患者发生症状性心力衰竭。2 例 （3.0%） 患者发生了无症状的 LVEF 下降 （2 级）。平均 GLS （±SD） 为 19%±2% （基线）、 19%±2% （6 个月） 和 19%±3% （12 个月）。3 例 （4.3%） 患者 TnI 可测 （> 0.06 ng/mL）, 2 例 （3.0%） 患者 BNP 水平升高 （> 100 pg/mL）, 但均与 LVEF 下降无关。
结论. GLS和心脏标记物 （TnI和BNP） 未发生任何显著变化进一步支持了THP在HER2阳性转移性乳腺癌患者中的心脏安全性。The Oncologist 2016;21:418–424
对临床实践的提示: 曲妥珠单抗与帕妥珠单抗的二联抗 HER2 治疗, 与以紫杉烷类为基础的化疗联用时, 能够改善 HER2 阳性的转移性乳腺癌患者的总生存。鉴于 HER2 信号转导在心脏稳态和应激反应中具有重要作用, 因此非常有必要对 HER2 双重阻断是否有潜在的心脏毒性进行研究。整体纵向应变和心脏生物标记物可作为左心室射血分数的辅助检查, 用于早期发现心脏毒性。本项 II 期研究中, 曲妥珠单抗、帕妥珠单抗与紫杉醇联合治疗后整体纵向应变和心脏生物标记物水平均无具有临床意义的改变。这些结果进一步支持了之前 CLEOPATRA 研究中报告的 HER2 双重阻断的心脏安全性。本研究的发现同时也对密切心脏监测在接受抗 HER2 治疗而未接受蒽环类治疗的患者中的作用提出了疑问。降低心脏评估的频率可减少不必要的治疗中断, 并且在医疗成本不断增加的大环境下也是一个值得考虑的重要问题, 但这需要开展进一步研究。
Keywords: Biomarkers; Cardiotoxicity; Heart failure; Imaging; Pertuzumab; Trastuzumab.
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