遗传多态性对癌症患儿心脏生物标志物浓度的影响：来自“欧洲儿科肿瘤非专利药物联盟”（EPOC）试验的分析。

Genetic Polymorphisms Affecting Cardiac Biomarker Concentrations in Children with Cancer: an Analysis from the "European Paediatric Oncology Off-patents Medicines Consortium" (EPOC) Trial.

机构信息

Department of Pharmaceutical and Medical Chemistry, University of Muenster, Muenster, Germany.

Division of Pharmacology, Leiden Academic Centre for Drug Research, Cluster Systems Pharmacology, Leiden University, Leiden, The Netherlands.

出版信息

Eur J Drug Metab Pharmacokinet. 2020 Jun;45(3):413-422. doi: 10.1007/s13318-019-00592-6.

DOI:10.1007/s13318-019-00592-6

PMID:31981210

Abstract

BACKGROUND AND OBJECTIVES

Doxorubicin plays an essential role in the treatment of paediatric cancers. Defining genotypes with a higher risk for developing anthracycline-induced cardiotoxicity could help to reduce cardiotoxicity.

METHODS

Data originated from a phase II study assessing the pharmacokinetics of doxorubicin in 100 children. Studied patients (0-17 years) were treated for solid tumours or leukaemia. Two cycles of doxorubicin were studied. Concentrations of natriuretic peptides proANP, BNP and NT-proBNP and cardiac troponins T and I were measured at five time points before, during and after two cycles of doxorubicin treatment. Genotypes of 17 genetic polymorphisms in genes encoding for anthracycline metabolizing enzymes and drug transporters were determined for each patient. We analysed the influence of genotypes on cardiac biomarker concentrations at different time points by a Kruskal-Wallis test. To perform a pairwise comparison significant genetic polymorphisms with more than two genotypes were analysed by a post hoc test.

RESULTS

The Kruskal-Wallis tests and the post hoc-tests showed a significant association for seven genetic polymorphisms (ABCB1-rs1128503, ABCB1-rs1045642, ABCC1-rs4148350, CBR3-rs8133052, NQO2-in/del, SLC22A16-rs714368 and SLC22A16-rs6907567) with the concentration of at least one biomarker at one or more time points. We could not identify any polymorphism with a consistent effect on any biomarker over the whole treatment period.

CONCLUSIONS

In this study of patients treated with doxorubicin for different tumour entities, seven genetic polymorphisms possibly influencing the pharmacokinetics and pharmacodynamics of doxorubicin could lead occasionally to differences in the concentration of cardiac biomarkers. Since, the role of cardiac biomarkers for monitoring anthracycline-induced cardiotoxicity has not yet been clarified, further trials with a long follow-up time are required to assess the impact of these genetic polymorphisms on chemotherapy-related cardiotoxicity.

TRIAL REGISTRATION

EudraCT number: 2009-011454-17.

摘要

背景与目的

多柔比星在儿科癌症的治疗中发挥着重要作用。确定发生蒽环类药物诱导性心脏毒性风险较高的基因型，有助于降低心脏毒性。

方法

数据来源于一项评估 100 例儿童多柔比星药代动力学的 II 期研究。研究患者（0-17 岁）患有实体瘤或白血病。研究了两个周期的多柔比星治疗。在两个周期的多柔比星治疗前后的五个时间点测量了前利尿肽 proANP、BNP 和 NT-proBNP 以及心脏肌钙蛋白 T 和 I 的浓度。为每位患者确定了编码蒽环类药物代谢酶和药物转运蛋白的 17 个基因的 17 个遗传多态性的基因型。我们通过 Kruskal-Wallis 检验分析了基因型对不同时间点心脏生物标志物浓度的影响。为了进行两两比较，对具有两个以上基因型的显著遗传多态性进行了事后检验。

结果

Kruskal-Wallis 检验和事后检验显示，7 个遗传多态性（ABCB1-rs1128503、ABCB1-rs1045642、ABCC1-rs4148350、CBR3-rs8133052、NQO2-in/del、SLC22A16-rs714368 和 SLC22A16-rs6907567）与至少一个生物标志物在一个或多个时间点的浓度有显著关联。我们无法确定任何多态性在整个治疗期间对任何生物标志物都有一致的影响。

结论

在这项针对不同肿瘤实体接受多柔比星治疗的患者的研究中，7 个遗传多态性可能会影响多柔比星的药代动力学和药效动力学，偶尔会导致心脏生物标志物浓度的差异。由于心脏生物标志物在监测蒽环类药物诱导性心脏毒性方面的作用尚未明确，因此需要进行具有长期随访时间的进一步试验，以评估这些遗传多态性对化疗相关心脏毒性的影响。