Angiotensin II-Receptor Inhibition With Candesartan to Prevent Trastuzumab-Related Cardiotoxic Effects in Patients With Early Breast Cancer A Randomized Clinical Trial
Angiotensin II-Receptor Inhibition With Candesartan to Prevent Trastuzumab-Related Cardiotoxic Effects in Patients With Early Breast Cancer A Randomized Clinical Trial
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DOI：
10.1001/jamaoncol.2016.1726
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发表时间：
2016-08-01
期刊：
影响因子：
28.4
通讯作者：
Schellens, Jan H. M.
中科院分区：
文献类型：
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作者：
Boekhout, Annelies H.;Gietema, Jourik A.;Schellens, Jan H. M.
重要性这是第一个随机安慰剂对照评价的医疗干预措施，预防曲妥珠单抗相关的心脏毒性作用。目的确定作为主要终点是否血管紧张素II拮抗剂治疗坎地沙坦可以预防或改善曲妥珠单抗相关的心脏毒性作用，定义为左心室射血分数（LVEF）下降超过15%或下降到绝对值45%以下。安慰剂对照临床研究于2007年10月至2011年10月在荷兰的19家医院进行，招募了210名人类表皮生长因子受体2（HER 2）检测阳性的早期乳腺癌女性，这些女性正在考虑接受蒽环类药物的辅助全身治疗，干预坎地沙坦（32 mg/d）或安慰剂治疗共78周;研究治疗在第一次曲妥珠单抗给药的同一天开始，并持续到曲妥珠单抗治疗完成后26周。次要终点包括脑利钠肽前体的N-末端是否（NT-proBNP）和高敏肌钙蛋白T（hs-TnT）可用作替代标记物，（以前称为HER 2或HER 2/neu）与曲妥珠单抗相关的心脏毒性作用相关。（平均年龄，49岁;年龄范围，25-69岁）坎地沙坦组103例（平均年龄，50岁;年龄范围，25-69岁）和安慰剂组103例（平均年龄，50岁;年龄范围，30-67岁）。其中，36例表现出2个主要心脏终点中的至少1个。坎地沙坦组的心脏事件比安慰剂组多3.8%（95%CI，-7%至15%; P= 0.58）：分别为20起事件（19%）和16起事件（16%）。坎地沙坦组心脏事件的2年累积发生率为0.28（95% CI，0.13 - 0.40），安慰剂组为0.16（95% CI，0.08-0.22）（P= 0.56）。坎地沙坦不影响NT-proBNP和hs-TnT值的变化，这些生物标志物与LVEF的显著变化无关。多变量分析显示，与Pro/Pro + Ala/Pro基因型相比，Ala 1170 Pro纯合子ERBB 2基因型与心脏事件发生的可能性较低相关（比值比，0.09; 95% CI，0.02-0.45; P=.003）结论和相关性研究结果并不支持坎地沙坦联合用药可防止左心室舒张功能下降的假设。早期乳腺癌患者曲妥珠单抗治疗期间或治疗后不久的射血分数。ERBB 2种系Ala 1170 Pro单核苷酸多态性可用于识别曲妥珠单抗相关心脏毒性作用风险增加的患者。
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 (32mg/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. Therewere 3.8% more cardiac events in the candesartan group than in the placebo group (95% CI, -7% to 15%; P=.58): 20events (19%) and 16 events (16%), respectively. The 2-year cumulative incidence of cardiac events was 0.28 (95% CI, 0.130.40) 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.