ERCC1和XPD单核苷酸多态性与非小细胞肺癌铂类化疗敏感性的关系

目的：探讨DNA修复基因ERCC1 C118T和XPD Lys751Gln单核苷酸多态性与非小细胞肺癌（non-small-cell lung carcinoma,NSCLC）患者对含铂方案化疗敏感性的关系。方法：选择经病理确诊为NSCLC的患者73例,在实施化疗前采取静脉血,提取DNA,行DNA测序、用PCR-RFLP方法检测ERCC1 C118T和XPD Lys751Gln基因型。所有患者均经含铂方案化疗,观察疗效,统计临床获益率,分析NSCLC患者ERCC1和XPD单核苷酸多态性与含铂方案化疗敏感性的关系。结果：ERCC1 C118TC/C、C/T和T/T基因型临床获益率分别为94.9%、71.4%和83.8%。基因型C/C临床获益率明显高于C/T、T/T（P〈0.05）。XPD Lys751Gln基因型Lys/Lys、Lys/Gln临床获益率分别为80.3%和75.0%。基因型Lys/Lys与Lys/Gln临床获益率间的差异无统计学意义（P=0.702）。未检测到XPD Gln/Gln基因型。ERCC1 C118T、XPD Lys751Gln多态之间在对含铂方案的化疗敏感性方面无协同作用（P=0.134和P=0.236）。结论：DNA修复基因ERCC1 C118T单核苷酸多态性与NSCLC含铂方案化疗的敏感性有关,可作为预测NSCLC患者铂类药物化疗敏感性的参考指标之一。     

DNA损伤修复基因XRCC1和XPD遗传多态与晚期非小细胞肺癌对铂类药物的敏感性

目的 探讨DNA损伤修复基因XRCC1和XPD的遗传多态与晚期非小细胞肺癌（NSCLC）对以铂类为主化疗药物敏感性的关系。方法 以聚合酶链反应（PCR）结合限制性片段长度多态性（RFLP）,检测200例以顺铂（DDP）或卡铂（CBP）为主要化疗方案的NSCLC患者XRCC1 Arg194Trp和XPD Lys751Gln多态基因型,并比较不同基因型与化疗敏感性的关系。结果 化疗总有效（CR＋PR）率为36．0％,其中CR1例,PR71例,SD94例,PD34例。携带XRCC1第194位密码子Arg／Trp或Trp／Trp基因型的个体化疗敏感性是XRCC1第194位密码子Arg／Arg基因型携带者的2．48倍（95％CI为1．36～4．51,P=0．003）;未发现XPD Lys751Gln多态与化疗敏感性的相关性。联合分析这两个遗传多态发现,XRCC1 Arg194Trp和XPD Lys751Gln多态在NSCLC对铂类药物敏感性中存在一定的联合作用（趋势检验,P=0．004）。结论XRCC1 Arg194Trp和XPDLys751Gin遗传多态可能与NSCLC铂类药物敏感性有关。     

DNA修复基因多态性与肺癌顺铂化疗敏感性的研究

目的:研究切除修复交叉互补基因1(excision repair cross-complementing gene 1,ERCC1)Asn118Asn、切除修复交叉互补基因2(excision repair cross-complementing gene 2,ERCC2)Lys751Gln和X线修复交叉互补基因1(X-ray repair cross complementing group 1,XRCC1)Arg399Gln单核苷酸多态性与非小细胞肺癌(non-small cell lung cancer,NSCLC)对铂类药物化疗敏感性的相关性。方法:采用基因测序的方法,检测89例以铂类药物为主要化疗方案的NSCLC患者外周血DNA中ERCC1基因Asn118Asn、ERCC2基因Lys751Gln和XRCC1基因Arg399Gln的基因型;采用统计学方法分析不同基因型与化疗疗效的相关性。结果:89例NSCLC患者采用铂类药物化疗总有效率为29.2%;ERCC1基因Asn118Asn和ERCC2基因Lys751Gln基因型在化疗有效组和无效组之间的分布,差异无统计学意义(P>0.05);而携带XRCC1基因Arg399Arg与携带至少1个Gln等位基因(Arg399Gln和Gln399Gln)基因型患者的有效率分别为76.9%和23.1%(χ2=11.1,P=0.001)。携带XRCC1基因Arg399Arg基因型患者对化疗的敏感性明显高于携带至少1个Gln等位基因型的患者(比值比为5.228,95%可信区间为1.776～15.387,P=0.003)。ERCC1、ERCC2和XRCC1基因型的联合可以提高化疗的有效率。结论:ERCC1、ERCC2和XRCC1基因的单核苷酸多态性的联合可能与NSCLC对铂类药物化疗敏感性具有相关性。     

ERCC1和XPD基因SNPs与NSCLC含铂类药物化疗敏感相关性分析

目的:探讨切除修复交叉互补基因1(ERCC1)第118位密码子(C118T)和着色性干皮病基因D(XPD)第751位密码子(Lys751Gln)的单核苷酸多态性(SNPs),与晚期非小细胞肺癌(NSCLC)患者对含铂类药物化疗疗效的关系。方法:聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)技术检测78例NSCLC患者的ERCC1(C118T)和XPD(Lys751Gln)基因型。结果:ERCC1(C118T)SNPs与铂类化疗疗效有关,P<0.05。C/C型化疗有效者7例(8.9%),C/T型为11例(14.1%),T/T型2例(2.6%);C/C化疗无效41例(52.6%),C/T型17例(21.8%),T/T型0;两组差异有统计学意义,P=0.003。T等位基因(T/T+C/T)型与C等位基因(C/C)型的化疗疗效差异亦有统计学意义,P=0.005,比值比(OR)=0.223,95%的可信区间(CI)为0.076～0.657;XPD(Lys751gln)SNPs与含铂类药物化疗疗效无关。ERCC1(C118T)、XPD(Lys751Gln)SNPs分布与年龄、性别、吸烟史、临床分期、体力状况评分(ECOG)和病理类型无关,P>0.05。结论:ERCC1(C118T)含有T等位基因,可作为预测晚期NSCLC患者铂类药物化疗敏感性的预测指标。     

BAG-1和ERCC1基因多态性与晚期非小细胞肺癌患者铂类药物敏感性的关系

目的:探讨Bcl-2结合抗凋亡基因1(Bcl-2associated athanogene1,BAG-1)codon324(C→T,rs11551682)和切除修复交叉互补基因1(excision repair cross-complementing group1,ERCC1)codon118(C→T,rsl1615)基因多态性与晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者对铂类药物敏感性的关系。方法:以聚合酶链-限制性片段长度多态性(PCR-restriction fragment length polymorphism,PCR-RFLP)方法检测142例接受铂类药物化疗的晚期NSCLC患者的BAG-1codon324基因型和ERCC1codon118基因型,比较不同基因型与化疗敏感性的关系。结果:BAG-1codon324基因型频率分别为C/C占77.46%(110/142),C/T占22.54%(32/142),未发现T/T。142例患者中,完全缓解4例,部分缓解42例,疾病稳定55例,疾病进展41例;总有效率为32.39%。BAG-1codon324C/C基因型患者对顺铂类药物的敏感性是C/T基因型患者的2.852倍(95%可信区间:1.133～7.182,P=0.026),且BAG-1codon324C/C基因型与C/T基因型患者的中位无进展生存期差异有统计学意义(分别为5.7和5.3个月,P=0.002)。携带BAG-1codon324C/C和ERCC1codon118C/C基因型,对铂类药物的敏感性存在一定的联合作用(P=0.005)。结论:BAG-1codon324和ERCC1codon118基因型可能是晚期NSCLC患者铂类药物敏感性的预测因子。     

ERCC2、RAD51和BAG-1基因多态性与晚期非小细胞肺癌铂类化疗敏感性的研究

目的:研究着色性干皮病基因(ERCC2/XPD)、DNA修复基因RAD51 codon 135以及Bcl-2结合抗凋亡基因1(Bcl-2 associated athanogene 1,BAG-1)codon 324多态性与晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)以铂类药物为基础的化疗敏感性的关联。方法:选取100例晚期NSCLC患者,使用PCR-RFLP方法检测ERCC2/XPD Lys 751 Gln、RAD51 codon 135以及BAG-1 codon 324基因多态性,应用非条件Logistic回归计算OR值及95%CI,分析不同基因型与化疗敏感性的关系。结果:100例晚期NSCLC患者中,ERCC2/XPD 751基因Lys/Lys、Lys/Gln、Gln/Gln基因型的分布频率分别为69例(69%)、26例(26%)和5例(5%);RAD51 codon 135的基因型频率分布为G/G型占67%(67/100)、G/C型33%(33/100)、未发现C/C型;BAG-1 codon 324基因型频率分布C/C型占81%(81/100)、C/T型占19%(19/100),未发现T/T型。100例NSCLC患者化疗后,其中完全缓解(CR)、部分缓解(PR)、稳定(SD)和进展(PD)患者分别为0、31、41和28例。ERCC2/XPD C/A基因型多态性与化疗敏感性具有相关性(OR=3.53,95%CI=1.58-11.46,P<0.01);BAG-1 codon 324 C/C型患者与C/T型患者的化疗有效率差异有统计学意义(P=0.036),携带C/C基因型患者比C/T基因型患者化疗敏感(OR=2.67,95%CI=1.16-8.23,P<0.05);RAD51 codon 135G/C基因型患者是G/G基因型患者化疗敏感性的2.12倍(OR=2.12,95%CI=1.08-7.41,P<0.05)。结论:ERCC2/XPD、BAG-1 codon 324以及RAD 51 codon 135基因多态性可能与晚期NSCLC铂类药物化疗敏感性有关。     

ERCC1与XPD基因多态性对NSCLC化疗敏感性影响的研究进展

临床III-IV期NSCLC占肺癌的大多数,以铂类药物为基础联合第三代新药是晚期NSCLC的一线化疗方案,近年来多项研究表明,个体间化疗敏感性的不同可能与基因修复能力有关,本文主要对核苷酸切除修复系统的关键基因ERCC1、XPD的多态性与铂类药物化疗敏感性关系的最新研究成果做简要综述。     

ERCC2 rs1799793多态性与三阴性乳腺癌铂类化疗疗效的关系

背景与目的:DNA修复基因的多态性可以影响DNA损伤修复能力,从而影响患者的化疗疗效。切除修复交叉互补基因2(excision repair cross-complementing group 2,ERCC2)参与核苷酸切除修复和基因转录,在DNA损伤修复中起重要作用。本研究旨在初步探讨ERCC2单核苷酸多态性与三阴性乳腺癌铂类药物化疗疗效的关系。方法:全组患者中位年龄46岁,中位化疗周期数为4个周期。60例接受铂类药物化疗的晚期或局部晚期三阴性乳腺癌患者,收集其临床病理资料和随访信息,采用高通量MassARRAY时间飞行质谱生物芯片系统分析入组患者ERCC2基因候选位点的单核苷酸多态性,观察比较不同基因型与化疗疗效之间的关系。结果:接受含铂方案治疗的总体有效率为66.7%。60例中53例获得ERCC2 rs1799793位点检测结果,ERCC2rs1799793位点等位基因型有GG、GA 2种,频率分别为81.1%、18.9%。GG基因型患者化疗有效30例,无效13例;GA基因型患者化疗有效3例,无效7例。两组的化疗有效率分别为69.8%和30.0%,疗效差异有统计学意义(P=0.030),携带GG基因型的患者化疗敏感性高于携带GA基因型患者。结论:ERCC2基因rs1799793多态性与三阴性乳腺癌患者接受铂类药物化疗的临床疗效有关。     

ERCC1和XRCC1多态性与进展期非小细胞肺癌对铂类化疗的敏感性

目的探讨DNA修复基因ERCC1 118C/T和XRCC1 Arg194Trp多态性与进展期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者铂类药物化疗敏感性的关系。方法采用PCR-RFLP技术检测149例经病理确诊的接受含铂两药方案化疗的NSCLC患者外周血ERCC1 118和XRCC1 194位点的基因型,并分析其与化疗疗效的关系。结果经2个周期化疗后,149例进展期NSCLC患者化疗有效率为32.9%。携带至少1个ERCC1 118T突变基因患者的化疗有效率至少是C/C野生型基因携带者的3倍(49.1%vs 23.4%,OR=3.156,95%CI:1.548～6.334,P=0.001)。携带至少1个XRCC1 194Trp突变基因患者的化疗有效率显著高于Arg/Arg基因型携带者(41.3%vs 23.2%,OR=2.326,95%CI:1.138～4.753,P=0.019)。ERCC1 118C/T和XRCC1 Arg194Trp 2个基因多态之间存在一定的联合作用,携带至少1个ERCC1 118 T突变基因同时又携带至少1个XRCC1 194Trp突变基因型者的化疗有效率明显高于同时携带ERCC1 118C/C和XRCC1 194Arg/Arg野生型基因者(66.7%vs 17.1%,OR=9.714,95%CI:3.104～30.406,P<0.001)。结论与单基因检测比较,2个基因的联合检测在预测铂类药物化疗敏感性中的价值更大。ERCC1 118和XRCC1 194基因多态联合与NSCLC患者对铂类药物化疗敏感性相关,ERCC1和XRCC1基因型的联合检测有可能成为预测铂类药物化疗敏感性的指标。     

碱基切除修复基因多态性与晚期非小细胞肺癌铂类药物化疗敏感性

目的:探讨DNA碱基切除修复通路中XRCC1 Arg399Gln和ADPRT Val762Ala基因多态性与晚期非小细胞肺癌(NSCLC)铂类药物化疗敏感性的关联,并与先前报道的XRCC1 T-77C、Argl94Trp联合分析其预测作用.方法:收集接受铂类药物为基础化疗的晚期NSCLC患者107例,用PCR-RFLP法检测基因型,分析各基因型与铂类药物化疗有效率的关联,并以非条件Logistic回归模型对患者年龄、性别、病理类型、临床分期和治疗方案进行校正.结果:对XRCC1 Arg399Gln多态性进行单因素分析时,发现携带至少1个Gln等位基因的患者的化疗有效率是携带Arg/Arg基因型者的0.42倍(95%CI:0.19-0.93),差异具有统计学意义;经多因素校正后发现携带至少1个Gln等位基因的患者的化疗有效率是携带Arg/Arg基因型者的0.52倍(95%CI:0.22-1.26),但差异不再具有统计学意义.对ADPRT Val762Ala多态性进行多因素分析时,发现携带至少1个Ala等位基因的患者的化疗有效率是携带Val/Val基因型者的1.57倍(95%CI:0.67-3.66).联合分析各患者4个多态性位点的铂类药物敏感基因型的总数目与铂类药物化疗有效率的关联,并经多因素分析校正后,发现携带3-4个铂类药物敏感基因型的患者的化疗有效率是具有0-2个铂类药物敏感基因型者的4.15倍(95%CI:1.54-11.19),差异具有统计学意义.结论:XRCC1 Arg399Gln多态性与铂类药物化疗敏感性的关系需进一步确认,似乎携带野生型Arg/Arg者对铂类药物化疗更敏感;但未能发现ADPRTVal762Ala多态性与铂类药物化疗敏感性存在明显关联;4个多态性位点联合分析的预测效能高于单个位点.     

DNA repair gene polymorphism associated with sensitivity of lung cancer to therapy

This study aimed to investigate association between single-nucleotide polymorphisms (SNPs) of excision repair cross-complementing gene 1 (ERCC1), excision repair cross-complementing gene 2 (ERCC2), and X-ray repair cross-complementing group 1 (XRCC1) with sensitivity of advanced non-small cell lung cancer (NSCLC) patients to platinum-based chemotherapy. A total of 89 NSCLC patients were recruited and treated with two cycles of platinum-based chemotherapy. DNA was extracted from peripheral lymphocytes for detection of SNPs of ERCC1 Asn118Asn, ERCC2 Lys751Gln, and XRCC1 Arg399Gln. The overall response rate of these patients was 29.2%. There was no statistically significant difference of treatment response between the wild genotypes and the variant genotypes for the ERCC1 Asn118Asn and ERCC2 Lys751Gln gene. The distributions of genotypes XRCC1 Arg399Gln differed significantly between the response and non-response groups (76.9 vs. 23.1%, P = 0.001). The XRCC1 399Arg/Arg genotype carriers had a higher response rate than that of the Gln genotype carriers (OR = 4.81, 95%CI = 1.778-13.013, P = 0.002). The combination of the favorable genotypes of ERCC1, ERCC2, and XRCC1 had a higher response rate compared to that of patients with other genotypes. The combined polymorphisms of ERCC1, ERCC2, and XRCC1 may be associated with sensitivity of NSCLC to platinum-based chemotherapy. Further studies will verify these SNPs as biomarkers for prediction of platinum-based chemotherapy responses of NSCLC patients.     

Lack of Influence of XRCC1 and XPD Gene Polymorphisms on Outcome of Platinum-based Chemotherapy for Advanced Non Small Cell Lung Cancers

Purpose: Genetic polymorphisms of DNA repair genes are associated with differential enzyme activity andmay help explain interindividual differences in response rates after platinum-based chemotherapy for non smallcell lung cancers (NSCLCs). This study was conducted to assess relationships between X-ray repair crosscomplementing group1 (XRCC1) and xeroderma pigmentosum group D (XPD) genetic polymorphisms andoutcome in NSCLC patients. Methods: From March 1, 2005 to December 31, 2008, the polymerase chainreaction-restriction fragment length polymorphism method was applied to evaluate genetic polymorphisms ofthe XRCC1 codon399 (Arg/Gln) and XPD codon751 (Lys/Gln) DNA repair genes in 108 patients with stage IIIBand IV NSCLCs treated with platinum-based chemotherapy in the Department of Chemotherapy of JiangsuCancer Hospital and Research Institute. Results: Among the assessed NSCLC patients, the overall responserate of chemotherapy was 21.6%. No association was found with either of the genetic polymorphisms, althoughthe XRCC1 399Arg/Arg genotype was associated with a non-significant higher median survival time (29 monthsversus 21 months for the Arg/Gln genotype and 15 months for the Gln/Gln genotype, P=0.09). Conclusion: Ourresults suggested no influence of the XRCC1 codon399 (Arg/Gln) and XPD codon751 (Lys/Gln) geneticpolymorphisms on treatment response and survival in advanced NSCLC patients with platinum-basedchemotherapy.     

No evidence of an association of ERCC1 and ERCC2 polymorphisms with clinical outcomes of platinum-based chemotherapies in non-small cell lung cancer: a meta-analysis

Background

The nucleotide excision repair (NER) pathway modulates platinum-based chemotherapeutic efficacy by removing drug-induced DNA damage.

Methods

To summarize published data on the association between NER genes and responses to platinum-based chemotherapies in non-small cell lung cancer (NSCLC), we performed a meta-analysis of 17 published studies of ERCC1 C118T/C8092A and ERCC2 Lys751Gln/Asp312Asn polymorphisms, including 2097 cancer patients. Primary outcomes included objective response (TR) (i.e., complete response + partial response vs. stable disease + progressive disease), progression-free survival (PFS) and overall survival (OS). We calculated odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI) to estimate the risk or hazard.

Results

We found that none of the ERCC1 C118T/C8092A and ERCC2 Lys751Gln/Asp312Asn polymorphisms alone was statistically significantly associated with objective response, PFS and OS in NSCLC patients.

Conclusion

There is no evidence to support the use of NER ERCC1 C118T/C8092A and ERCC2 Lys751Gln/Asp312Asn polymorphisms as prognostic predictors of platinum-based chemotherapies in NSCLC.     

DNA Repair Gene Associated with Clinical Outcome ofEpithelial Ovarian Cancer Treated with Platinum-basedChemotherapy

Objective: The nucleotide excision repair (NER) and base excision repair (BER) pathways, two DNA repairpathways, are related to platinum resistance in cancer treatment. In this paper, we studied the association betweensingle nucleotide polymorphisms (SNPs) of involved genes and response to platinum-based chemotherapy inepithelial ovarian cancer. Method: Eight SNPs in XRCC1 (BER), XPC and XPD (NER) were assessed in 213patients with epithelial ovarian cancer using polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) and primer-introduced restriction analysis-polymerase chain reaction (PIRA-PCR) techniques.Results: The median progression-free survival (PFS) of patients carrying the Lys/Lys and Lys/Gln+Gln/Glngenotype of the XPC Lys/Gln polymorphism were 25 and 12 months, respectively (P=0.039); and the mean overallsurvival (OS) of patients was 31.1 and 27.8 months, respectively (P=0.048). Cox’s multivariate analysis suggestedthat patients with epithelial ovarian cancer with the Gln allele had an increased risk of death (HR=1.75; 95%CI=1.06-2.91) compared to those with the Lys/Lys genotype. There are no associations between the XPC PAT+/-,XRCC1 Arg194Trp, Arg280His, Arg399Gln, and XPD Asp312Asn, Lys751Gln polymorphisms and the survivalof patients with epithelial ovarian cancer when treated with platinum-based chemotherapy. Conclusion: Ourresults indicated that the XPC Lys939Gln polymorphism may correlate with clinical outcome of patients withepithelial ovarian cancer when treated with platinum-based chemotherapy in Northern China.     

Predictive value of ERCC1 and XPD polymorphism in patients with advanced non-small cell lung cancer receiving platinum-based chemotherapy: a systematic review and meta-analysis

The published data on the predictive value of polymorphism of ERCC1 and XPD in patients with advanced non-small cell lung cancer receiving platinum-based chemotherapy are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Relevant studies were identified by searching the Medline, Embase, CNKI and American Society of Clinical Oncology abstract databases. Inclusion criteria were patients with advanced NSCLC, received platinum-based chemotherapy, evaluation of polymorphism of ERCC1 and XPD and overall response rate (ORR). A total of 12 studies were included in this meta-analysis. For studies evaluating ERCC1 polymorphism at codon 118, the ORR for the wild-type C/C genotype versus the heterozygous C/T and T/T genotype was 2.17 (95% confidence interval (CI), 1.43–3.33; P = 0.000). For studies evaluating XPD Asp312Asn and XPD Lys751Gln, the pooled OR was 1.33 (95% CI, 0.92–1.91; P = 0.13) and 1.02 (95% CI, 0.72–1.45; P = 0.915), respectively. The results indicated that platinum-based chemotherapy sensitivity was significantly associated with polymorphism of ERCC1 C118T. However, XPD Asp312Asn and XPD Lys751Gln were not predictive makers for platinum-based chemotherapy in patients with advanced NSCLC.     

DNA repair gene ERCC1 and XPD polymorphisms predict glioma susceptibility and prognosis

Aims: We conducted a case-control study in a Chinese population to clarify the association betweenpolymorphisms in ERCC1 and XPD and susceptibility and survival of glioma. Methods: A total of 393 cases and410 controls were selected from March 2007 to December 2011. Genotyping of ERCC1 and XPD was conductedby TaqMan assays using the ABI Prism 7911HT Sequence Detection System. All analyses were performed usingthe STATA statistical package. Results: Polymorphisms in ERCC1 118C/T, ERCC1 8092C/A and XPD Asp312Asnshowed no statistically significant difference between glioma cases and controls. However, individuals with theXPD 751Gln/Gln genotype had an increased risk of developing glioma compared with those with the Lys/Lysgenotype (adjusted OR=1.64, 95% CI: 1.06-2.89). The ERCC1 118T/T genotype was associated with significantlyhigher median survival than the ERCC1 C/C genotype (HR=0.67, 95%CI=0.35-0.96). In addition, individualswith XPD 751Gln/Gln had a lower median survival time than XPD Lys/Lys carriers (HR=0.54, 95%CI=0.37-0.93). Conclusion: In conclusion, we observed that the XPD 751Gln/Gln genotype is associated with gliomasusceptibility, and ERCC1 118 T/T and XPD 751Gln/Gln genotypes confer a significantly better prognosis.     

Correlation of CDA, ERCC1, and XPD polymorphisms with response and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients.

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-na?ve, 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)Gln 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 > or =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.