2016年6月23日，《美国医学会杂志肿瘤学分册》在线发表荷兰多中心随机临床研究报告，发现血管紧张素Ⅱ受体抑制剂坎地沙坦无法防止或者减轻早期乳腺癌患者曲妥珠单抗相关心脏毒性。
这是第一项评估医学干预防止曲妥珠单抗相关心脏毒性反应的随机安慰剂对照研究，2007年10月～2011年10月在荷兰19家医院进行，共入组210例HER2阳性早期乳腺癌女性，所有患者接受蒽环类化疗序贯曲妥珠单抗的全身辅助治疗，并在曲妥珠单抗治疗开始同时按照1∶1随机服用78周坎地沙坦（32mg/d）或安慰剂，持续到曲妥珠单抗治疗完成后26周。主要心脏结局终点为LVEF，定义为LVEF下降＞15%或绝对值＜45%。次要终点包括：脑利钠肽激素前体N-末端（NT-proBNP）和高敏肌钙蛋白T（hs-TnT）是否可以作为替代标志物、种系ERBB2（HER2或HER2/neu）遗传变异性是否与曲妥珠单抗相关心脏毒性相关。
结果206例患者可被评估（平均年龄49岁，范围：25～69岁），其中坎地沙坦组103例（平均年龄50岁，范围：25～69岁），安慰剂组103例（平均年龄50岁，范围：30～67岁），36例至少出现2项主要心脏终点中的1项。坎地沙坦组与安慰剂组相比，心脏事件多3.8%（95%置信区间：-7%～15%，P=0.58），分别为20例（19%）和16例（16%），心脏事件2年累积发生率分别为0.28（95%置信区间：0.13～0.40）和0.16（95%置信区间：0.08～0.22，P=0.56）。坎地沙坦对NT-proBNP和hs-TnT水平变化无影响，而且这些生物标志物与LVEF变化无显著相关性。根据多变量分析，Ala1170Pro纯合ERBB2基因型与Pro/Pro＋Ala/Pro基因型相比，似乎与心脏事件发生率较低有显著相关性（比值比：0.09，95%置信区间：0.02～0.45，P=0.003）。
因此，该研究结果不支持在曲妥珠单抗治疗早期乳腺癌期间或之后同时使用坎地沙坦防止左室射血分数（LVEF）降低的假说。ERBB2种系Ala1170Pro单核苷酸多态性可能被用来确定曲妥珠单抗相关心脏毒性风险增加的患者。
JAMA Oncol. 2016 Jun 23. [Epub ahead of print]
Angiotensin II-Receptor Inhibition With Candesartan to Prevent Trastuzumab-Related Cardiotoxic Effects in Patients With Early Breast Cancer: A Randomized Clinical Trial.
Annelies H. Boekhout; Jourik A. Gietema; Bojana Milojkovic Kerklaan; Erik D. van Werkhoven; Renske Altena; Aafke Honkoop; Maartje Los; Willem M. Smit; Peter Nieboer; Carolien H. Smorenburg; Caroline M. P. W. Mandigers; Agnes J. van der Wouw; Lonneke Kessels; Annette W. G. van der Velden; Petronella B. Ottevanger; Tineke Smilde; Jaap de Boer; Dirk J. van Veldhuisen; Ido P. Kema; Elisabeth G. E. de Vries; Jan H. M. Schellens.
Netherlands Cancer Institute, Amsterdam, the Netherlands; University of Groningen, Groningen, the Netherlands; Isala Clinics, Zwolle, the Netherlands; Antonius Hospital, Nieuwegein, the Netherlands; Medisch Spectrum Twente, Enschede, the Netherlands; Wilhelmina Hospital, Assen, the Netherlands; Medical Center Alkmaar, Alkmaar, the Netherlands; Canisius Wilhemina Hospital, Nijmegen, the Netherlands; VieCuri Medical Center Noord-Limburg, Venlo, the Netherlands; Deventer Hospital, Deventer, the Netherlands; Martini Hospital, Groningen, the Netherlands; Radboud University Medical Center, Nijmegen, the Netherlands; Jeroen Bosch Hospital, Den Bosch, the Netherlands; Hospital de Tjongerschans, Heerenveen, the Netherlands; University Medical Center Groningen, the Netherlands; Science Faculty Utrecht University, Utrecht, the Netherlands.
Importance: This is the first randomized placebo-controlled evaluation of a medical intervention for the prevention of trastuzumab-related cardiotoxic effects.
Objective: To determine as the primary end point whether angiotensin II antagonist treatment with candesartan can prevent or ameliorate trastuzumab-related cardiotoxic effects, defined as a decline in left ventricular ejection fraction (LVEF) of more than 15% or a decrease below the absolute value 45%.
Design: This randomized, placebo-controlled clinical study was conducted between October 2007 and October 2011 in 19 hospitals in the Netherlands, enrolling 210 women with early breast cancer testing positive for human epidermal growth factor receptor 2 (HER2) who were being considered for adjuvant systemic treatment with anthracycline-containing chemotherapy followed by trastuzumab.
Interventions: A total of 78 weeks of candesartan (32 mg/d) or placebo treatment; study treatment started at the same day as the first trastuzumab administration and continued until 26 weeks after completion of trastuzumab treatment.
Main Outcomes and Measures: The primary outcome was LVEF. Secondary end points included whether the N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT) can be used as surrogate markers and whether genetic variability in germline ERBB2 (formerly HER2 or HER2/neu) correlates with trastuzumab-related cardiotoxic effects.
Results: A total of 206 participants were evaluable (mean age, 49 years; age range, 25-69 years) 103 in the candesartan group (mean age, 50 years; age range, 25-69 years) and 103 in the placebo group (mean age, 50 years; age range, 30-67 years). Of these, 36 manifested at least 1 of the 2 primary cardiac end points. There were 3.8% more cardiac events in the candesartan group than in the placebo group (95% CI, -7% to 15%; P = .58): 20 events (19%) and 16 events (16%), respectively. The 2-year cumulative incidence of cardiac events was 0.28 (95% CI, 0.13-0.40) in the candesartan group and 0.16 (95% CI, 0.08-0.22) in the placebo group (P = .56). Candesartan did not affect changes in NT-proBNP and hs-TnT values, and these biomarkers were not associated with significant changes in LVEF. The Ala1170Pro homozygous ERBB2 genotype was associated with a lower likelihood of the occurrence of a cardiac event compared with Pro/Pro + Ala/Pro genotypes in multivariate analysis (odds ratio, 0.09; 95% CI, 0.02-0.45; P = .003).
Conclusions and Relevance: The findings do not support the hypothesis that concomitant use of candesartan protects against a decrease in left ventricular ejection fraction during or shortly after trastuzumab treatment in early breast cancer. The ERBB2 germline Ala1170Pro single nucleotide polymorphism may be used to identify patients who are at increased risk of trastuzumab-related cardiotoxic effects.
Trial Registration: clinicaltrials.gov Identifier: NCT00459771
DOI: 10.1001/jamaoncol.2016.1726
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