Ma Yuxiang, Xin Shuang, Lin Qingguang, Zhuang Wei, Zhao Yuanyuan, Zhu Xia, Zhao Hongyun, Huang Min, Xun Xu, Yang Yunpeng, Fang Wenfeng, Zhang Li, Wang Xueding
Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510060, China.
Ann Transl Med. 2019 Dec;7(24):806. doi: 10.21037/atm.2019.12.60.
The current study is aimed to examine the impact of pharmacokinetics and gene polymorphisms of enzymes involving in absorption, distribution, metabolism and excretion (ADME) on the efficacy of gefitinib in non-small cell lung cancer (NSCLC) patients.
Eligible patients with indication of gefitinib treatment were prospectively enrolled in this study. Two peripheral blood samples at baseline and before cycle 2 day 1 were collected for the detection of single nucleotide polymorphisms (SNPs) of drug ADME enzymes and trough drug concentration (C) at steady state. Thirteen SNPs were genotyped using the Sequenom Massarray system. C was determined by validated high-performance liquid chromatographic method with tandem mass spectrometric (LC-MS/MS).
Fifty-eight NSCLC patients were enrolled in this study. The median of C was 175ng/mL (range from 47.8 to 470 ng/mL). The trough concentration was not associated with either objective response or progression free survival (PFS). C was significantly lower in rs2242480 CC + CT genotype than in TT genotype (P=0.019) and in rs2231142 AA genotype than in AC + CC genotype (P=0.031). rs2032582 dominant model was significantly correlated with overall response rate (ORR) and patients with GG phenotype respond better than patients with GT + TT phenotypes (84.6% 51.2%, P=0.032). ABCB1 rs10256836 recessive model was significantly correlated with PFS and patients with GG phenotype achieved longer PFS than patients with GC + CC phenotypes (17.40 10.33 months, P=0.040).
The C of gefitinib was significantly different between and genotypes, but not with the efficacy of gefitinib treatment. rs2032582 and rs10256836 polymorphisms were correlated treatment outcome. Polymorphisms analysis of could be a predictive biomarker for gefitinib treatment.
本研究旨在探讨参与吸收、分布、代谢和排泄（ADME）的酶的药代动力学和基因多态性对吉非替尼在非小细胞肺癌（NSCLC）患者中疗效的影响。
符合吉非替尼治疗指征的患者被前瞻性纳入本研究。在基线和第2周期第1天之前采集两份外周血样本，用于检测药物ADME酶的单核苷酸多态性（SNP）和稳态时的谷浓度（C）。使用Sequenom Massarray系统对13个SNP进行基因分型。C通过经过验证的高效液相色谱串联质谱法（LC-MS/MS）测定。
本研究纳入了58例NSCLC患者。C的中位数为175ng/mL（范围为47.8至470 ng/mL）。谷浓度与客观缓解或无进展生存期（PFS）均无关联。rs2242480 CC + CT基因型的C显著低于TT基因型（P = 0.019），rs2231142 AA基因型的C显著低于AC + CC基因型（P = 0.031）。rs2032582显性模型与总缓解率（ORR）显著相关，GG表型的患者比GT + TT表型的患者反应更好（84.6%对51.2%，P = 0.032）。ABCB1 rs10256836隐性模型与PFS显著相关，GG表型的患者比GC + CC表型的患者获得更长的PFS（17.40对10.33个月，P = 0.040）。
吉非替尼的C在不同基因型之间存在显著差异，但与吉非替尼治疗的疗效无关。rs2032582和rs10256836多态性与治疗结果相关。ADME酶的多态性分析可能是吉非替尼治疗的预测生物标志物。
