Retrospective study of the impact of pharmacogenetic variants on paclitaxel toxicity and survival in patients with ovarian cancer
Retrospective study of the impact of pharmacogenetic variants on paclitaxel toxicity and survival in patients with ovarian cancer
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DOI：
10.1007/s00228-011-1007-6
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发表时间：
2011-07-01
影响因子：
2.9
通讯作者：
Peterson, Curt
中科院分区：
文献类型：
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作者：
Bergmann, Troels K.;Green, Henrik;Peterson, Curt
紫杉醇具有广谱的抗肿瘤活性，可用于卵巢癌、乳腺癌和肺癌的治疗。紫杉醇在肝脏中通过CYP2C8和CYP3A4代谢，p -糖蛋白转运。剂量限制性毒性是神经病变和中性粒细胞减少，但毒性和存活率的个体间差异很大。本研究的主要目的是探讨CYP2C8和ABCB1基因变异对毒性和生存的影响。在丹麦或瑞典进行的AGO-OVAR-9或NSGO-OC9804试验中接受卡铂和紫杉醇治疗的182例卵巢癌患者符合本研究的条件。对福尔马林固定组织进行基因分型。患者的毒性概况和生存数据来自回顾性数据。选择CYP2C8*3、ABCB1 C1236T、G2677T/A、C3435T进行先验分析；许多其他的变体被纳入探索性分析。总共有119名患者的临床资料和组织。在10个基因中检测到22个单核苷酸多态性（snp）。在710个治疗周期中进行了毒性登记。初步分析中，CYP2C8*3、ABCB1 C1236T、G2677T/A、C3435T与中性粒细胞减少症、感觉神经病变及总生存率无统计学意义相关。在119例紫杉醇/卡铂治疗的卵巢癌患者中，CYP2C8*3和ABCB1 snp C1236T、G2677T/A、C3435T与总生存率、感觉神经病变、中性粒细胞减少无统计学意义。
Paclitaxel has a broad spectrum of anti-tumor activity and is useful in the treatment of ovarian, breast, and lung cancer. Paclitaxel is metabolized in the liver by CYP2C8 and CYP3A4 and transported by P-glycoprotein. The dose-limiting toxicities are neuropathy and neutropenia, but the interindividual variability in toxicity and also survival is large. The main purpose of this study was to investigate the impact of genetic variants in CYP2C8 and ABCB1 on toxicity and survival.The 182 patients previously treated for ovarian cancer with carboplatin and paclitaxel in either the AGO-OVAR-9 or the NSGO-OC9804 trial in Denmark or Sweden were eligible for this study. Genotyping was carried out on formalin-fixed tissue. The patients' toxicity profiles and survival data were derived from retrospective data. CYP2C8*3, ABCB1 C1236T, G2677T/A, and C3435T were chosen a priori for primary analysis; a host of other variants were entered into an exploratory analysis.Clinical data and tissue were available from a total of 119 patients. Twenty-two single nucleotide polymorphisms (SNPs) in 10 genes were determined. Toxicity registration was available from 710 treatment cycles. In the primary analysis, no statistically significant correlation was found between CYP2C8*3, ABCB1 C1236T, G2677T/A, and C3435T and neutropenia, sensoric neuropathy, and overall survival.CYP2C8*3 and the ABCB1 SNPs C1236T, G2677T/A, and C3435T were not statistically significantly correlated to overall survival, sensoric neuropathy, and neutropenia in 119 patients treated for ovarian cancer with paclitaxel/carboplatin.