晚期非小细胞肺癌组织ERCC1和BRCA1表达与铂类化疗敏感性临床研究

目的 吉西他滨联合顺铂是治疗晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的一线化疗方案,但其有效率仅20％～40％,其较低的化疗有效率与肿瘤耐药相关.研究NSCLC组织中切除修复交叉互补基因1(exeision repair cross-compietionl1,ERCC1)和乳腺癌易感基因1(breast cancer susceptibility gene-1,BRCA1)mRNA的表达及其与铂类化疗敏感性的关系.方法 应用实时荧光定量PCR技术检测2009-03-01-2011-04-16武汉钢铁(集团)公司第二职工医院收集的98例晚期NSCLC患者中ERCC1和BRCA1 mRNA的表达情况,分析其与含铂联合治疗方案化疗耐药性的关系.结果 检测98例患者中ERCC1和BRCA1 mRNA的相对表达量,其中位数分别为0.048和0.011,四分位间距IQR分别为0.0058和0.001.ERCC1 mRNA的高表达率为56.1％(55/98),其表达在不同性别、年龄、组织学类型及临床分期中差异无统计学意义,P＞0.05;BRCA1 mRNA的高表达率为64.3％(63/98),其表达在不同性别、年龄、组织学类型及临床分期中差异无统计学意义,P＞0.05.在ERCC1 mRNA低表达组GP方案化疗客观缓解率为48.8％(21/43),而在高表达组化疗客观缓解率为29.1％(16/55),两组之间比较差异有统计学意义,x2 =4.0,P=0.045;在BRCA1 mRNA低表达组GP化疗客观缓解率为57.1％(20/35),在高表达组GP化疗客观缓解率为28.6％(18/63),差异有统计学意义,x2 =7.74,P=0.005;ERCC1和BRCA1 rnRNA联合低表达组中GP化疗客观缓解率为70.4％(19/27),而其联合高表达组GP化疗客观缓解率仅为21.1％(8/38).结论 ERCC1、BRCA1 mRNA高表达患者在使用含铂化疗方案时疗效差,提示ERCC1和BRCA1 mRNA高表达NSCLC患者对铂类具有耐药性.ERCC1和BRCA1mRNA联合低表达患者在使用含铂方案化疗时有效率更高,提示应用ERCC1和BRCA1 mRNA联合检测时,患者可获得更大的益处.     

核苷酸切除修复交叉互补基因1 mRNA表达与非小细胞肺癌铂类化疗患者预后的相关性

目的 探讨核苷酸切除修复交叉互补基因1(ERCC1)mRNA表达与非小细胞肺癌(NSCLC)铂类化疗患者临床病理特征的关系及其预后意义.方法 采用实时荧光定量逆转录聚合酶链反应(RT-PCR)方法,检测NSCLC石蜡包埋组织中ERCC1 mRNA的表达水平,并比较其表达水平与NSCLC铂类化疗患者临床病理特征和生存时间之间的关系.结果 61例NSCLC患者中,ERCC1 mRNA的中位表达量为0.48.ERCC1 mRNA表达与NSCLC患者临床病理特征无关.ERCC1mRNA低表达(<0.35)患者经铂类药物化疗后的无进展生存时间为14.3个月,而高表达者为8.0个月,差异有统计学意义(P=0.028).ERCC1 mRNA低表达(<0.28)患者的总生存时间为28.4个月,而高表达者为12.9个月,差异有统计学意义(P=0.0064).Cox多因素回归分析显示,ERCC1 mRNA表达水平是影响NSCLC患者预后的独立因素.结论 ERCC1 mRNA的表达水平可以作为以铂类为基础药物化疗的NSCLC患者预后的独立预测因素,ERCC1 mRNA低表达的NSCLC患者经铂类化疗后,总生存时间明显延长,为制定NSCLC个体化的化疗方案提供了重要信息.     

非小细胞肺癌组织ERCC1表达及其与预后的相关性分析

目的:探讨ERCC1在非小细胞肺癌(NSCLC)组织中的表达及其预后的意义。方法:采用SP法检测129例手术切除NSCLC组织和10例癌旁正常肺组织中ERCC1表达情况,并进行预后随访。结果:在NSCLC组织中ERCC1表达阳性率为48.1%。ERCC1表达与年龄、性别、期别、病理类型均未见相关性,P均>0.05。ERCC1低、高表达者中位生存期为60、29个月,P=0.0001。分层分析发现Ⅰ期ER-CC1阳性表达的预后明显好于ER-CC1阴性表达,中位生存期分别为72和60个月,P=0.0165。而Ⅱ和ⅢA期ERCC1阴性表达较ERCC1阳性预后为好,Ⅱ期中位生存期分别为60和23个月,P=0.0000;ⅢA期中位生存期分别为46和15个月,P=0.0110。结论:NSCLC组织中存在ERCC1表达;ERCC1表达与患者的临床病理特征无明显相关性;ERCC1表达对Ⅰ期和Ⅱ～ⅢA期NSCLC术后生存具有双重效应;ERCC1表达状态是NSCLC患者独立预后因素之一。     

ERCC1β-tubulinⅢ与ⅢA-N2期非小细胞肺癌辅助化疗的临床研究

目的:探讨ERCC1、β-tubulin Ⅲ在ⅢA-N2期非小细胞肺癌中的表达与辅助化疗药物铂类、紫杉类的相关性,为非小细胞肺癌个体化辅助化疗提供依据.方法:应用免疫组化方法检测ERCC1、β-tubulin Ⅲ在89例手术完全切除并行含铂辅助化疗的ⅢA～N2期非小细胞肺癌中的表达.应用统计学软件SPSS 16.0行数据处理,回顾性分析ERCC1、β-tubulin Ⅲ的表达与患者预后的关系.结果:本组ⅢA～N2期非小细胞肺癌中ERCC1、β-tubulin Ⅲ阳性表达率分别为46.1%,53.9%.ERCC1表达阴性者在含铂化疗组有更长的无瘤生存期(P=0.000)和总生存期(P=0.000);β-tubulin Ⅲ表达阴性者在含紫杉类化疗药物组有更长的无瘤生存期(P=0.003)和总生存期(P=0.004).ERCC1和β-tubulin Ⅲ表达均阴性者在铂类联合紫杉类化疗组有更长的无瘤生存期(P=0.000)和总生存期(P=0.001).结论:ERCC1表达阳性、组织病理分化低、全肺切除是影响ⅢA～N2期非小细胞肺癌预后的危险因素.ERCC1的表达与铂类化疗相关,β-tubulin Ⅲ的表达与紫杉类化疗相关,表达阴性者预后较好;ERCC1、β-tubulin Ⅲ表达均阴性者在铂类联合紫杉类化疗组中预后最好.     

晚期非小细胞肺癌ERCC1和BRCA1的表达及与顺铂耐药性的临床研究

目的:探讨核苷酸切除修复交叉互补组1( excision repair cross complementation group 1,ERCC1)和乳腺癌易感基因(breast cancer susceptibility gene 1,BRCA1)在非小细胞肺癌( non-small cell lung cancer,NSCLC)中的表达及与顺铂耐药的关系.方法:应用免疫组织化学法检测81例NSCLC 患者标本ERCC1和BRCA1蛋白的表达,并与患者年龄、性别、组织病理学类型、临床分期、吸烟指数及含铂化疗方案疗效的关系进行分析.结果:ERCC1蛋白表达阳性率为35.80%,与患者的性别、年龄、临床分期及吸烟指数无关,ERCC1蛋白在腺癌中的表达高于鳞癌,差异有统计学意义(P＜0.05);ERCC1表达阳性组的化疗有效率(24.14%)低于阴性组(63.46%),差异有统计学意义(P＜0.05);ERCC1表达阳性组的中位生存期(median survival time,MST)(12.1个月)低于阴性组(20.6个月),差异有统计学意义(P<0.05).BRCA1蛋白表达阳性率为51.85%,与患者的性别、年龄、临床分期、组织学类型及吸烟指数无关;BRCA1表达阳性组化疗有效率(38.10%)低于阴性组(61.54%),差异有统计学意义(P＜0.05);BRCA1表达阳性组的MST(15.2个月)与阴性组(16.7个月)比较无明显差异.结论:ERCC1和BRCA1蛋白表达检测可预测NSCLC患者对铂类化疗药物的敏感性,有助于临床上NSCLC个体化化疗方案的制定.     

ERCC1、RRM1和BRCA1在非小细胞肺癌中的表达及预后意义

目的:探讨DNA修复基因家族成员ERCC1、RRM1和BRCA1在非小细胞肺癌(NSCLC)中的表达及预后意义。方法:应用实时荧光定量PCR技术对32例肺癌及16例癌旁组织中ERCC1、RRM1和BRCA1基因的mRNA进行定量检测。用非参数检验、相关分析、Kap lan-M e ier生存曲线和COX多因素回归分析进行统计分析。结果:NSCLC中ERCC1、RRM1和BRCA1在癌组织内表达量显著高于癌旁组织,且在癌内表达具有正相关性;RRM1在肺鳞癌中高于腺癌,但在不同分期中表达无差异;ERCC1和BRCA1在不同病理类型和分期中表达均无差异;RRM1和BRCA1高表达组的生存期明显长于低表达组;COX多因素回归分析示RRM1表达是影响本组患者预后的独立因素。结论:NSCLC中,ERCC1、RRM1和BRCA1在肺癌组织中的表达显著高于癌旁组织,RRM1和BRCA1高表达组的生存期长于低表达组。RRM1和BRCA1可作为判断预后的一种指标。     

非小细胞肺癌组织VEGF-A和Survivin表达临床意义的研究

目的:探讨非小细胞肺癌(NSCLC)组织中血管内皮生长因子A(VEGF-A)和Survivin的表达情况及临床意义.方法:采用免疫组织化学SP法对48例术后NSCLC碏块进行免疫组织化学染色,检测VEGF-A、Survivin的表达水平,并分析NSCLC组织中VEGF-A、Survivin的表达水平与NSCLC的组织分型、淋巴结转移、临床病理分期的关系.结果:VEGF-A在NSCLC组织中的阳性表达率(68.75%)明显高于正常肺组织(6.25%),并与淋巴结转移有关(x2=11.95,P＜0.05).Survivin在NSCLC组织中的阳性表达率明显增加(54.17%),并且与有无淋巴结转移(x2=8.08,P＜0.05)及TNM分期(x2=5.19,P＜0.05)有关.两者在不同病理类型NSCLC组织中的表达差异无统计学意义.结论:VEGF-A、Survivin的表达可作为临床评估NSCLC的进展、转移、预后及治疗的重要检测指标.     

非小细胞肺癌组织MGMT蛋白的表达

目的:探讨DNA修复酶O6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)在非小细胞肺癌(NSCLC)组织中的表达及其与肺癌发生、发展的关系.方法:免疫组化SABC法检测120例NSCLC及癌旁组织中和30例肺炎MGMT的表达.结果:120例NSCLC组织中,MGMT蛋白的阳性表达率(33%,40/120)显著低于癌旁正常组织(63%,76/120),χ2=21.624,P<0.05;亦显著低于30例肺炎症组织(60%,18/30),χ2=7.196,P<0.05;MGMT蛋白的阳性表达与患者吸烟史、分化程度和淋巴结转移相关,P(0.05.结论:MGMT蛋白的表达与NSCLC的发生、发展相关,监测MG-MT蛋白可能对肺癌的辅助诊断有一定意义.     

ERCC1、RRM1在非小细胞肺癌中的表达及其意义

 【摘要】　目的　探讨ERCC1和RRM1在非小细胞肺癌（NSCLC）中的表达及其与NSCLC浸润、转移和预后的关系。方法　采用免疫组织化学法检测59例NSCLC和20例癌旁正常组织中ERCC1和RRM1的表达情况。结果　NSCLC组织中ERCC1和RRM1的阳性表达率（44.07 %、5.00 %）均明显高于癌旁正常组织（5.00 %、0）（χ2＝10.134、19.211,均P＜0.05）。在NSCLC组织中ERCC1低表达组的中位生存期为29个月,明显短于高表达组33个月 （χ2＝5.277,P＝0.022）,RRM1低表达组的中位生存期为35个月,显著长于高表达组26个月（χ2＝9.376,P＝0.002）。结论　ERCC1和RRM1在NSCLC中高表达;二者可能与NSCLC的发生、发展及预后密切相关。     

ERCC1 and BRCA1 mRNA expressions are associated with clinical outcome of non-small cell lung cancer treated with platinum-based chemotherapy

We conducted a perspective study to investigate whether the expression of excision repair cross-complementing 1 (ERCC1), xeroderma pigmentosum group G (XPG), breast cancer 1 (BRCA1), and ribonucleotide reductase M1 (RRM1) is correlated with clinical outcome of non-small cell lung cancer (NSCLC). Patients with histologically confirmed inoperable stages IIIB and IV NSCLC were collected and followed up until January 2012. Relative cDNA quantification for ERCC1, XPG, BRCA1, and RRM1 was performed using a fluorescence-based, real-time detection method. Cox regression analysis indicated that a high level of ERCC1 was associated with shorter overall survival (OS) and progression-free survival (PFS) times when compared with low expression, with adjusted hazard ratios (HRs) (95 % confidence interval (CI)) of 2.25 (1.18–4.39) and 2.63 (1.33–5.25), respectively. High expression of BRCA1 was correlated with shorter OS and PFS times when compared with low expression, and the adjusted HRs (95 % CI) were 3.29 (1.72–6.39) and 5.94 (2.80–13.06), respectively. Moreover, we found a significant correlation between BRCA1 expression and age (χ ²?=?4.14, P?=?0.04) and stage (χ ²?=?5.26, P?=?0.02). Our results suggest that ERCC1 and BRCA1 mRNA expressions are associated with PFS and OS in advanced NSCLC patients treated with platinum-based chemotherapy.     

Randomised study of adjuvant chemotherapy for completely resected p-stage I-IIIA non-small cell lung cancer

We evaluated the therapeutic usefulness of adjuvant chemotherapy in patients with completely resected non-small cell lung cancer (NSCLC). We also examined the relation between DNA ploidy pattern and the response to chemotherapy. A total of 267 patients with NSCLC (pathologically documented stage I, II, or IIIA) underwent complete resection, and DNA ploidy pattern was analysed. Patients with stage I disease (n=172) were randomly assigned to receive surgery alone (group A) or surgery followed by adjuvant chemotherapy (UFT (oral anti-cancer drug, a combination of Uracil and Tegaful) 400 mg day-1 for 1 year after surgery; group B). Stage II or IIIA disease patients (n=95) were randomly assigned to surgery alone (group C) or surgery followed by chemotherapy (two 28-day courses of cisplatin 80 mg m-2 on day 1 plus vindesine 3 mg m-2 on days 1 and 8, followed by UFT 400 mg day-1 for at least 1 year; group D). Eight-year overall survival rate in patients with stage I disease was 74.2% (95% confidence interval (CI): 64.4-84.0%) in group B and 57.6% (95% CI: 46.4-68.8%) in group A (P=0.045 by log-rank test). In patients with stage II and IIIA disease, no difference was found between groups C and D. Analysis according to DNA ploidy pattern revealed no difference between the groups. Postoperative chemotherapy with UFT was suggested to be useful in patients with completely resected stage I NSCLC. No difference was seen in relation to DNA pattern in any treatment group.     

早期非小细胞肺癌完全切除术后的辅助治疗

外科手术切除是早期非小细胞肺癌的标准治疗方式,文献报道外科可以提供给早期肺癌病人最佳的治愈率。然而,标准的肺叶切除或全肺切除及纵隔淋巴结清扫后IA期病人的5年生存率为68.5%,IB期为66.6%,许多病人死于癌转移[1]。而肺段切除则较多发生局部复发     

Postoperative adjuvant therapy for completely resected early-stage non-small cell lung cancer

Consensus on adjuvant therapy for completely resected non-small cell lung cancer until 2002 was as follows. (1) There was no significant impact of postoperative adjuvant chemotherapy based on meta-analysis and previous clinical trials. (2) Confirmatory studies are necessary in large-scale prospective clinical trials. However, recent mega trials have introduced epoch-making changes for postoperative adjuvant chemotherapy in clinical practice since ASCO 2003. The effectiveness of UFT in N0 patients was confirmed. Patients with completely resected stage I non-small cell lung cancer, especially T2N0 adenocarcinoma, will benefit from adjuvant chemotherapy with UFT. The results of the International Adjuvant Lung Trial (IALT) have confirmed the meta-analysis in 1995. Also, both the JBR10 and Cancer and Leukemia Group B (CALGB) 9633 studies have also confirmed positive IALT results of the benefit for postoperative platinum-based chemotherapy in completely resected non-small cell lung cancer. Adjuvant chemotherapy for pathological stage IB to II, completely resected non-small cell lung cancer is standard care based on clinical trials. UFT showed the strongest evidence for IB in Japan. Platinum doublet chemotherapy with third-generation anticancer agents is also recommended. Adjuvant chemotherapy should be offered as standard care to patients after completely resected early stage non-small cell lung cancer. However, there is no evidence of the feasibility and efficacy for adjuvant chemotherapy with the platinum-based regimen in Japan. Careful management should be necessary in such treatment.The ASCO-JSCO Joint Symposium was held in Kyoto, Japan, on October 29, 2004.     

Polymorphisms in ERCC1 gene could predict clinical outcome of platinum-based chemotherapy for non-small cell lung cancer patients

We analyzed the role of three common single-nucleotide polymorphisms (SNPs) of ERCC1 in predicting the tumor responses and the survival of non-small cell lung cancer (NSCLC) patients who received platinum-based chemotherapy. One hundred ninety-two patients who were identified as stage IV or IIIB/A NSCLC were collected between January 2008 and December 2009. ERCC1 rs11615, rs3212986, and rs2298881 were selected and genotyped by MassARRAY® Analyzer 4 system. One hundred three (53.65 %) patients showed a CR and PR to chemotherapy, and 81 (42.19 %) patients died from NSCLC with the median OS of 35.82?±?15.19 months. Multivariate regression analysis showed that rs11615 TT genotype and T allele were associated with optimal response to chemotherapy, and rs3212986 AA and A allele were correlated with better response to chemotherapy. Cox regression showed that patients carrying the rs11615 TT genotype and T allele and the rs3212986 AA genotype and A allele were significantly associated with higher risk of death from NSCLC. In conclusion, ERCC1 rs11615 and rs3212986 polymorphism were associated with a poor response to chemotherapy and shorter survival time of advanced NSCLC. ERCC1 rs11615 and rs3212986 polymorphisms may be helpful for designing individualized cancer treatment for NSCLC patients.     

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。     

Role of ERCC1 variants in response to chemotherapy and clinical outcome of advanced non-small cell lung cancer

Excision repair cross-complementation group 1 (ERCC1) and xeroderma pigmentosum-F (XPF) in the nucleotide excision repair pathway have been effectively repairing DNA damage induced by chemotherapeutic agents. We conducted a cohort study to assess the associations of ERCC1 and XPF polymorphisms with response to platinum-based chemotherapy and clinical outcome of non-small-cell lung cancer (NSCLC). One hundred eighty-seven NSCLC cases treated with platinum-based chemotherapy were prospectively analyzed. The predictive value of four SNPs in ERCC1 and two SNPs in XPF in patient's response and survival related to platinum-based chemotherapy were analyzed using χ ² tests, Kaplan-Meier method, log-rank test, and Cox proportional hazards regression. The overall chemotherapy response rate for treatment was 51.18 %. One hundred eighty-seven patients were followed up, and the median survival time is 17.6 months (ranged from 1 to 50 months). A total of 106 patients (56.68 %) died from NSCLC during the follow-up period. Carriers of the rs3212986 AA and A allele had a borderline significantly lower response rate to the chemotherapy. In the Cox proportional hazards model, patients carrying the ERCC1 rs3212986 AA genotype were significantly associated with increased risk of death from NSCLC when compared with those with CC genotype as a reference variable. This study reported that variants in ERCC1 can be used as a prognostic maker to platinum-based chemotherapy in NSCLC patients.     

The future of adjuvant chemotherapy for resected non-small cell lung cancer

Non-small cell lung cancer is a frequent type of cancer, with approximately 1.2 million cases per year expected worldwide. A total of 20-30% of patients with early stage non-small cell lung cancer are amenable to radical surgery, although only 40-50% of these patients are cured. An improvement in survival has never been demonstrated for postoperative radiotherapy. However, a major step forward is several recent large randomized studies that have demonstrated improved survival with postoperative chemotherapy. This review covers the historic data on adjuvant chemotherapy for non-small cell lung cancer, meta-analyses, modern studies with cisplatin-based or other chemotherapy, implications for current clinical practice and guidelines, some practical recommendations and, finally, the questions for future studies.     

The future of adjuvant chemotherapy for resected non-small cell lung cancer

Non-small cell lung cancer is a frequent type of cancer, with approximately 1.2 million cases per year expected worldwide. A total of 20–30% of patients with early stage non-small cell lung cancer are amenable to radical surgery, although only 40–50% of these patients are cured. An improvement in survival has never been demonstrated for postoperative radiotherapy. However, a major step forward is several recent large randomized studies that have demonstrated improved survival with postoperative chemotherapy. This review covers the historic data on adjuvant chemotherapy for non-small cell lung cancer, meta-analyses, modern studies with cisplatin-based or other chemotherapy, implications for current clinical practice and guidelines, some practical recommendations and, finally, the questions for future studies.     

Pharmacogenetic role of ERCC1 genetic variants in treatment response of platinum-based chemotherapy among advanced non-small cell lung cancer patients

The excision repair cross-complementation group 1 (ERCC1) plays an essential role in DNA repair and has been linked to resistance to platinum-based anticancer drugs among advanced non-small cell lung cancer (NSCLC) patients. We systematically evaluate whether ERCC1 Asn118Asn and C8092A genetic variants are associated with treatment response of platinum chemotherapy. We preformed a meta-analysis using ten eligible cohort studies (including 11 datasets) with a total of 1,252 NSCLC patients to summarize the existing data on the association between the ERCC1 Asn118Asn and C8092A polymorphisms and response to platinum regiments. Odds ratio or hazard ratio with 95% confidence interval were calculated to estimate the correlation. We found that neither ERCC1 C8092A polymorphism nor Asn118Asn variant is associated with different response of platinum-based treatment among advanced NSCLC patients. Additionally, these two genetic variants are not related to treatment response in either Caucasian patients or Asian patients. Our meta-analysis indicates that the ERCC1 Asn118Asn and C8092A polymorphisms may not be good prognostic biomarkers for platinum-based chemotherapy in patients with stage III-IV NSCLC.