Correlation of CDA, ERCC1, and XPD polymorphisms with response and survival in gemcitabine/cisplatin -: Treated advanced non-small cell lung cancer patients
Correlation of CDA, ERCC1, and XPD polymorphisms with response and survival in gemcitabine/cisplatin -: Treated advanced non-small cell lung cancer patients
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DOI：
10.1158/1078-0432.ccr-07-1364
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发表时间：
2008-03-15
影响因子：
11.5
通讯作者：
Danesi, Romano
中科院分区：
文献类型：
--
作者：
Tibaldi, Carmelo;Giovannetti, Elisa;Danesi, Romano
目的：根据非小细胞肺癌(NSCLC)的关键基因特征选择患者，有助于指导化疗和优化治疗方案。色素性干皮病D组(XPD)、切除修复交叉互补1(ERCC1)和胞苷脱氨酶(CDA)基因的多态与酶活性的改变相关，并可能改变对广泛使用的顺铂-吉西他滨方案的敏感性。实验设计：对65名接受顺铂-吉西他滨化疗的晚期非小细胞肺癌患者的血液样本进行CDA、XPD和ERCC1多态分析。此外，还用高效液相色谱法对CDA的酶活性进行了评价。用Pearson‘s chi(2)检验、Kaplan-Meier法、LOG-RANK检验和COX比例风险模型分析XPD Asp(312)Asn与Lys(751)Gln、ERCC1 C118T和CDA Lys(27)Gin多态与疗效、临床益处、毒性、进展时间(TTP)和总生存期(OS)的关系。结果：CDA Lys(27)Lys多态与临床疗效(P=0.04)和GT分级显著相关；=3中性粒细胞减少和血小板减少，TTP和OS延长(分别为P=0.006和P=0.002)，而ERCC1和XPD基因多态性与疗效和临床结局均无显著关联。结论：CDA-Lys(27)-Lys多态可作为顺铂和吉西他滨联合治疗的晚期非小细胞肺癌患者的活性、毒性、TTP和OS的预测标记物。这些结果可能是与Lys(27)Lys CDA相关的较低的酶活性所解释的，并为治疗优化提供了一个潜在的新工具。
Purpose: Selecting patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in non-small cell lung cancer (NSCLC). Polymorphisms at the xeroderma pigmentosum group D (XPD), excision repair cross-complementing 1 (ERCC1), and cytidine deaminase (CDA) genes have been associated with alterations in enzymatic activity and may change sensitivity to the widely used cisplatin-gemcitabine regimen.Experimental Design: Analyses of CDA, XPD, and ERCC1 polymorphisms were done on blood samples of 65 chemotherapy-naiive, advanced NSCLC patients treated with cisplatin-gemcitabine. Furthermore, CDA enzymatic activity was evaluated by high-performance liquid chromatography analysis. Association between XPD Asp(312) Asn and LyS(751)Gln, ERCC1 C118T, and CDA Lys(27) Gin polymorphisms and response, clinical benefit, toxicity, time to progression (TTP), and overall survival (OS) was estimated using Pearson's chi(2) tests, the Kaplan-Meier method, the log-rank test, and the Cox proportional hazards model.Results: The CDA Lys(27) Lys polymorphism significantly correlated with better clinical benefit (P = 0.04) and grade >= 3 neutropenia and thrombocytopenia, as well as with longer TTP and OS (P = 0.006 and P = 0.002, respectively), whereas no significant associations were found among ERCC1 and XPD polymorphisms and both response and clinical outcome. Finally, the enzymatic activity assay showed a significant lower mean in subjects harboring the CDA Lys(27) Lys polymorphism.Conclusions: Our data suggested the role of CDA Lys(27) Lys polymorphism as a possible predictive marker of activity, toxicity, TTP, and OS in advanced NSCLC patients treated with cisplatin and gemcitabine. These results may be explained by the lower enzymatic activity associated with the Lys(27) Lys CDA and offer a potential new tool for treatment optimization.