Validating the pharmacogenomics of chemotherapy-induced cardiotoxicity: What is missing?

The cardiotoxicity of certain chemotherapeutic agents is now well established, and has led to the development the field cardio-oncology, increased cardiac screening of cancer patients, and limitation of patients’ maximum cumulative chemotherapeutic dose. The effect of chemotherapeutic regimes on the heart largely involves cardiomyocytes death, leading to cardiomyopathy and heart failure, or the induction of arrhythmias. Of these cardiotoxic drugs, those resulting in clinical cardiotoxicity can range from 8–26% for doxorubicin, 7–28% for trastuzumab, or 5–30% for paclitaxel. For tyrosine kinase inhibitors, QT prolongation and arrhythmia, ischemia and hypertension has been reported in 2–35% of patients. Furthermore, newly introduced chemotherapeutic agents are commonly used as part of changed combinational regimens with significantly increased cardiotoxicity incidence. It is widely believed that the mechanism of action of these drugs is often independent of their cardiotoxicity, and the basis for why these drugs specifically effect the heart has yet to be established. The genetic rationale for why certain patients experience cardiotoxicity whilst other patients can tolerate high chemotherapy doses has proven highly illusive. This has led to significant genomic efforts using targeted and genome-wide association studies (GWAS) to divine the pharmacogenomic cause of this predilection. With the advent of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), the putative risk and protective role of single nucleotide polymorphisms (SNPs) can now be validated in a human model. Here we review the state of the art knowledge of the genetic predilection to chemotherapy-induced cardiotoxicity and discuss the future for establishing and validating the role of the genome in this disease.

某些化疗药物的心脏毒性现已得到充分证实，这促使了心脏肿瘤学领域的发展，增加了对癌症患者的心脏筛查，并限制了患者的最大累计化疗剂量。化疗方案对心脏的影响主要涉及心肌细胞死亡，导致心肌病和心力衰竭，或诱发心律失常。在这些具有心脏毒性的药物中，导致临床心脏毒性的比例，阿霉素为8% - 26%，曲妥珠单抗为7% - 28%，紫杉醇为5% - 30%。对于酪氨酸激酶抑制剂，据报道2% - 35%的患者出现QT间期延长和心律失常、缺血以及高血压。此外，新引入的化疗药物通常作为改变的联合方案的一部分使用，其心脏毒性发生率显著增加。人们普遍认为，这些药物的作用机制往往与其心脏毒性无关，这些药物为何特异性影响心脏的基础尚未确定。为何某些患者会出现心脏毒性而其他患者能耐受高剂量化疗的遗传学原理已被证明非常难以捉摸。这促使人们利用靶向研究和全基因组关联研究（GWAS）进行大量的基因组研究，以探究这种倾向性的药物基因组学原因。随着人类诱导多能干细胞衍生的心肌细胞（hiPSC - CMs）的出现，单核苷酸多态性（SNPs）的假定风险和保护作用现在可以在人类模型中得到验证。在此，我们综述了化疗诱导的心脏毒性的遗传倾向性的最新知识，并讨论了确定和验证基因组在这种疾病中的作用的未来方向。