Ⅰ-Ⅲ期NSCLC术后辅助化疗疗效的分子预测及预后研究
|
摘要
【目的】总结回顾Ⅰ-Ⅲ期可手术切除的NSCLC临床特点,术后治疗特点及生存规律;探索能够预测辅助化疗疗效、复发风险及预后的分子标记物;讨论复发后靶向治疗的特点与疗效,并寻找能预测靶向药物疗效的临床及分子特征,为建立NSCLC术后辅助治疗的个体化模式提供理论依据,为开展基于分子分型的前瞻性NSCLC术后辅助化疗的临床研究提供理论支持。
【方法】回顾性分析2000年1月至2007年12月在我院行手术治疗并至少在本院内进行1周期辅助化疗的病理及随访资料完整的Ⅰ-Ⅲ期NSCLC病例。对其临床特征、病理特征、治疗特点及其对生存规律的影响进行分析;复习全组病例的术后7项常规分子标记物的免疫组化染色标本与结果;收集全组病例的术后病理标本,利用免疫组化染色法检测ERCC1、RRM1、βtubulinⅢ、pERK1/2和pAKT1等5项指标蛋白水平的表达;收集全组病例中复发转移后应用TKI药物进行治疗的且疗效可以评价的亚组病例,从石蜡组织中提取基因组DNA,对EGFR18～21外显子及Kras 12、13密码子进行基因突变检测;采用SPSS 16.0软件包对上述研究中各组的临床特征、治疗特点和疗效以及生存规律进行单因素及多因素分析。
【结果】入选163例符合条件病例。各临床特征及治疗特征组基本规律分布,全组中位随访期37个月,截止本次随访终点2009年3月31日,出现47例(28.8%)死亡事件,中位生存期尚未达到;3年的总生存率为68.2%;疾病复发转移者86例,中位DFS为24.4个月。确诊时有症状,腺癌、较晚临床分期(特别是N2)、化疗＜4周期分别是DFS的独立不良预后因素。在复发转移亚组中男性、确诊时有症状、未使用TKI药物分别是OS的独立不良预后因素。TopⅡα高表达组较低表达组DFS明显延长(未到达,＞33.6个月vs 19.4个月,p=0.006);在TopⅡα低表达组中选用NVB较其他方案有更长的DFS(48.2个月vs15.7个月,p=0.043)。在化疗＜4周期分层中,ERCC1阳性组的DFS显著高于阴性组(33.0 vs9.6个月,p=0.046);而在化疗≥4周期层中,ERCC1阳性组的DFS却显著低于阴性组(18.6个月vs未到达,p=0.029);RRM1高表达组中应用NVB组的DFS较不含NVB组有延长趋势,但无统计学意义(p=0.077);βtubulinⅢ高表达组的中位DFS低于与低表达组(30.8 vs 47.4个月,p=0.057);pAKT1低表达组及pERK1/2高表达组均较各自对应组的DFS显著延长(34.2 vs 1 5.6个月,p=0.020和未到达vs 19.4个月,p=0.01),但2项指标均对辅助化疗药物无选择性;35例复发转移后应用TKI治疗组中,21例尚存活,中位生存期未到达,检测到的9例EGFR突变(19缺失突变8例,L858R1例)均显示临床获益,5例Kras 12密码子突变者均无效;除EGFR基因突变外,pAKT1高表达及吸烟是TKI获益的几率降低的独立预测因素;多因素生存分析仅提示吸烟是独立的预后因素。
【结论】标准的4周期术后辅助化疗方案对延长一般人群的DFS有益;TopⅡα、βtubulinⅢ、pAKT1、pERK1/2均是影响DFS的独立分子预测指标,可用于常规筛选潜在的能从辅助化疗明显获益的NSCLC人群;TopⅡα高表达者对辅助化疗敏感性高,低表达提示耐药可能,含NVB方案效果较好;ERCC1阴性者可予标准的4周期辅助化疗,具体方案的选择及阳性者的治疗原则有待更多研究;RRM1对治疗方案的选择显示了一定趋势,有待随访跟踪;EGFR外显子19和21突变提示TKI获益可能性大,而Kras突变提示TKI可能无效。除EGFR突变外,不吸烟及pAKT1的低表达可以作为评估潜在TKI获益人群的预测指标。
【Objective】To summarized clinical characters and features of treatments and survival in stageⅠ-Ⅲresected NSCLC patients,to explore subtential molecular predictors of therapeutic effect and recurrence risk,to discuss effect of target therapy on recurrence patients and to look for clinical and molecular predictors of TKI efficiency,to provide evidences for establishing individual postoperative adjuvant chemotherapy model and carrying out prospective clinical trials based molecular type in NSCLC patients.
【Methods】The cases who received surgery therapy in our hospital from Jan. 2000 to Dec.2007 and were diagnosed with stageⅠ-ⅢNSCLC were analyzed.Those who were lost of follow up or can't finish at least one cycle adjuvant chemotherapy were deleted.And immunohistochemistry(IHC) results of routine seven biomarkers of all cases were reviewed.Paraffin-embedded samples of all cases were collected to detect expression of ERCC1,RRM1,βtubulinⅢ,pERK1/2 and pAKT1 by IHC method.Those who received with TKI and can be evalued of effect after recurrence were picked up to further detect EGFR and Kras mutation from Paraffin-embedded samples;survival rate and disease free survival(DFS) were analyzed by SPSS 16.0 software.
【Results】163 cases were collected.The median follow up was 37 months. Untill the destinaion of study,there were only 47 cases dead,the median overall survival(OS) was not available.Three-year OS was 68.2%;and the median DFS was 24.4 months.Early symtoms,adenocarcinoma,N2 stage and less than 4 cycles chemotherapy predicted poor prognosis.The DFS in over-expression of TopⅡαgroup was significant longer than weak-expression group(not available vs 19.4 months,p=0.006).And in weak-expression group,the regimen with NVB had prolonged DFS(48.2 month vs15.7 months,p=0.043) compared with any other regimens.In less than 4 cycles chemotherapy strata,the DFS in positive group of ERCC1 was longer than negtive group(33.0 vs 9.6 months,p=0.046),on the contrary,the DFS in positive group of ERCC1 was shorter than negtive group in another chemotherapy cycle strata(18.6 months vs not available,p=0.029).The DFS in groups with weakexpression pAKT1 and with overexpression pERK1/2 was respectively longer than overexpression pAKT1 and negtive pERK1/2(34.2 vs 15.6 months,p=0.020 and not available vs 19.4 months,p=0.01).Both of them showed no selective in chemotherapy regimens.9 cases of EGFR mutation and 5 cases of Kras mutation was observed in 35 recurrence cases.And all patients with EGFR mutation have benefited from TKI,while 5 cases of Kras mutation were no response to TKI.Besides EGFR mutation,smoke and overexpression of pAKT1 were poor independent prognosis factors of efficiency of TKI.In COX proportional regression analysis of 35 recurrence cases,only smoke statue could impact overall survival.
【Conclusion】Routine 4 cycles adjuvant chemotherapy was approved to contribute to DFS for common patients.TopⅡα,βtubulinⅢ,pAKT1 and pERK1/2 were all independent prognosis factors of DFS,which may be used to select special patients who can benefit from adjuvant chemotherapy.All mutation of EGFR 19 and 21 exons have predict to benefit from TKI,while Kras mutation were the sign of no response to TKI.Besides EGFR mutation,smoke statu and expression of pAKT1 can be employed to predict TKI efficiency.
【方法】回顾性分析2000年1月至2007年12月在我院行手术治疗并至少在本院内进行1周期辅助化疗的病理及随访资料完整的Ⅰ-Ⅲ期NSCLC病例。对其临床特征、病理特征、治疗特点及其对生存规律的影响进行分析;复习全组病例的术后7项常规分子标记物的免疫组化染色标本与结果;收集全组病例的术后病理标本,利用免疫组化染色法检测ERCC1、RRM1、βtubulinⅢ、pERK1/2和pAKT1等5项指标蛋白水平的表达;收集全组病例中复发转移后应用TKI药物进行治疗的且疗效可以评价的亚组病例,从石蜡组织中提取基因组DNA,对EGFR18～21外显子及Kras 12、13密码子进行基因突变检测;采用SPSS 16.0软件包对上述研究中各组的临床特征、治疗特点和疗效以及生存规律进行单因素及多因素分析。
【结果】入选163例符合条件病例。各临床特征及治疗特征组基本规律分布,全组中位随访期37个月,截止本次随访终点2009年3月31日,出现47例(28.8%)死亡事件,中位生存期尚未达到;3年的总生存率为68.2%;疾病复发转移者86例,中位DFS为24.4个月。确诊时有症状,腺癌、较晚临床分期(特别是N2)、化疗＜4周期分别是DFS的独立不良预后因素。在复发转移亚组中男性、确诊时有症状、未使用TKI药物分别是OS的独立不良预后因素。TopⅡα高表达组较低表达组DFS明显延长(未到达,＞33.6个月vs 19.4个月,p=0.006);在TopⅡα低表达组中选用NVB较其他方案有更长的DFS(48.2个月vs15.7个月,p=0.043)。在化疗＜4周期分层中,ERCC1阳性组的DFS显著高于阴性组(33.0 vs9.6个月,p=0.046);而在化疗≥4周期层中,ERCC1阳性组的DFS却显著低于阴性组(18.6个月vs未到达,p=0.029);RRM1高表达组中应用NVB组的DFS较不含NVB组有延长趋势,但无统计学意义(p=0.077);βtubulinⅢ高表达组的中位DFS低于与低表达组(30.8 vs 47.4个月,p=0.057);pAKT1低表达组及pERK1/2高表达组均较各自对应组的DFS显著延长(34.2 vs 1 5.6个月,p=0.020和未到达vs 19.4个月,p=0.01),但2项指标均对辅助化疗药物无选择性;35例复发转移后应用TKI治疗组中,21例尚存活,中位生存期未到达,检测到的9例EGFR突变(19缺失突变8例,L858R1例)均显示临床获益,5例Kras 12密码子突变者均无效;除EGFR基因突变外,pAKT1高表达及吸烟是TKI获益的几率降低的独立预测因素;多因素生存分析仅提示吸烟是独立的预后因素。
【结论】标准的4周期术后辅助化疗方案对延长一般人群的DFS有益;TopⅡα、βtubulinⅢ、pAKT1、pERK1/2均是影响DFS的独立分子预测指标,可用于常规筛选潜在的能从辅助化疗明显获益的NSCLC人群;TopⅡα高表达者对辅助化疗敏感性高,低表达提示耐药可能,含NVB方案效果较好;ERCC1阴性者可予标准的4周期辅助化疗,具体方案的选择及阳性者的治疗原则有待更多研究;RRM1对治疗方案的选择显示了一定趋势,有待随访跟踪;EGFR外显子19和21突变提示TKI获益可能性大,而Kras突变提示TKI可能无效。除EGFR突变外,不吸烟及pAKT1的低表达可以作为评估潜在TKI获益人群的预测指标。
【Objective】To summarized clinical characters and features of treatments and survival in stageⅠ-Ⅲresected NSCLC patients,to explore subtential molecular predictors of therapeutic effect and recurrence risk,to discuss effect of target therapy on recurrence patients and to look for clinical and molecular predictors of TKI efficiency,to provide evidences for establishing individual postoperative adjuvant chemotherapy model and carrying out prospective clinical trials based molecular type in NSCLC patients.
【Methods】The cases who received surgery therapy in our hospital from Jan. 2000 to Dec.2007 and were diagnosed with stageⅠ-ⅢNSCLC were analyzed.Those who were lost of follow up or can't finish at least one cycle adjuvant chemotherapy were deleted.And immunohistochemistry(IHC) results of routine seven biomarkers of all cases were reviewed.Paraffin-embedded samples of all cases were collected to detect expression of ERCC1,RRM1,βtubulinⅢ,pERK1/2 and pAKT1 by IHC method.Those who received with TKI and can be evalued of effect after recurrence were picked up to further detect EGFR and Kras mutation from Paraffin-embedded samples;survival rate and disease free survival(DFS) were analyzed by SPSS 16.0 software.
【Results】163 cases were collected.The median follow up was 37 months. Untill the destinaion of study,there were only 47 cases dead,the median overall survival(OS) was not available.Three-year OS was 68.2%;and the median DFS was 24.4 months.Early symtoms,adenocarcinoma,N2 stage and less than 4 cycles chemotherapy predicted poor prognosis.The DFS in over-expression of TopⅡαgroup was significant longer than weak-expression group(not available vs 19.4 months,p=0.006).And in weak-expression group,the regimen with NVB had prolonged DFS(48.2 month vs15.7 months,p=0.043) compared with any other regimens.In less than 4 cycles chemotherapy strata,the DFS in positive group of ERCC1 was longer than negtive group(33.0 vs 9.6 months,p=0.046),on the contrary,the DFS in positive group of ERCC1 was shorter than negtive group in another chemotherapy cycle strata(18.6 months vs not available,p=0.029).The DFS in groups with weakexpression pAKT1 and with overexpression pERK1/2 was respectively longer than overexpression pAKT1 and negtive pERK1/2(34.2 vs 15.6 months,p=0.020 and not available vs 19.4 months,p=0.01).Both of them showed no selective in chemotherapy regimens.9 cases of EGFR mutation and 5 cases of Kras mutation was observed in 35 recurrence cases.And all patients with EGFR mutation have benefited from TKI,while 5 cases of Kras mutation were no response to TKI.Besides EGFR mutation,smoke and overexpression of pAKT1 were poor independent prognosis factors of efficiency of TKI.In COX proportional regression analysis of 35 recurrence cases,only smoke statue could impact overall survival.
【Conclusion】Routine 4 cycles adjuvant chemotherapy was approved to contribute to DFS for common patients.TopⅡα,βtubulinⅢ,pAKT1 and pERK1/2 were all independent prognosis factors of DFS,which may be used to select special patients who can benefit from adjuvant chemotherapy.All mutation of EGFR 19 and 21 exons have predict to benefit from TKI,while Kras mutation were the sign of no response to TKI.Besides EGFR mutation,smoke statu and expression of pAKT1 can be employed to predict TKI efficiency.
引文
1 Jemal A,Murray T,Ward E,et al.Cancer Statistics,2005.CA Cancer J Clin 2007;55:10—30.
2 Jemal A,Murray T,Ward E,et al.Cancer Statistics,2005.CA Cancer J Clin 2008;55:10—30.
3 Yang L,Parkin DM,Li LD,et al.Estimation and projection of the national profile of cancer mortality in China:1991-2005.Br J Cancer.2004 Jun 1;90(11):2157-66.
4 Pisters KM,Le Chevalier T.Adjuvant chemotherapy in completely resected non-small-cell lung cancer.J Clin Oncol 2005;23:3270—8.
5 Mountain CF.Revisions in the international system for staging lung cancer.Chest 1997;111:1710—7.
6 Non-small Cell Lung Cancer Collaborative Group.Chemotherapy in non-small cell lung cancer:a meta-analysis using updated data on individual patients from 52 randomized clinical trials.BMJ,1995,311:899-909.
7 Keller SM,Adak S,Wagner H,et al.Mediastinal lymph node dissection improves survival in patients with stages II and IIIa non-small cell lung cancer.Eastern Cooperative Oncology Group.Ann Thorac Surg.2000 Aug;70(2):358-65;discussion 365-6.
8 Waller D,Peake MD,Stephens RJ,et al.Chemotherapy for patients with non-small cell lung cancer:the surgical setting of the Big Lung Trial.Eur J Cardiothorac Surg 2004;26:173-82.
9 Scagliotti GV,Fossati R,Torri V,et al.Randomized study of adjuvant chemotherapy for completely resected stage Ⅰ,Ⅱ,or ⅢA non-small-cell Lung cancer.J Natl Cancer Inst 2603;95:1453-61.
10 Smit EF,Van Meerbeeck JP,Lianes P,et al.Three-arm randomized study of two cisplatin-based regimens and paclitaxel plus gemcitabine in advanced non-small-cell lung cancer:a phase III trial of the European Organization for Research and Treatment of Cancer Lung Cancer Group-EORTC 08975.J Clin Oncol, 2003,21(21):3909-3917.
11 Strauss GM,Hernden J,Maddaus MA,et al.Adjuvant chemotherapy in Stage IB non-small cell lung cancer(NSCLC):update on Cancer and Leukemia Group B(CALGB)protocol 9633.J Clin Oncol 2006;24(18 Suppl):365s(abstr.#7007).
12 Arriagada R,Bergman B,Dunant A,et al.Cisplatinbased adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer.N Engl J Med 2004;350:351-60.
13 Winton TL,Livingstan R,Johnson D,et al.A prospective randomized trial of adjuvant vinorelbine(VNR)and cisplatin(CIS)in completely resected stage Ib and II non small cell lung cancer(NSCLC)Intergroup JBR10.N Engl J Med 2005;352:2589-97.
14 Douillard J,Rosell R,Delena M,et al.Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer(Adjuvant Navelbine International Trialist Association[ANITA]):a randomised controlled trial.Lancet Oncol 2006;7:719-27.
15 PORT Meta analysis Trialists Group.Postoperative radiotherapy in non small cell lung cancer:Systematic review and meta analysis of individual patient data from nine randomized controlled trials [J].Lancet,1998,352(9124):257-263.
16 Rube C,Phu Nguyen T,Fleckenstein J,et al.Postoperative radiotherapy in localized non small cell lung cancer.Lung Cancer,2001,33(Suppl 1):29-33.
17 Zeng-Rong N,Paterson J,Alpert L,et al.Elevated DNA repair capacity is associated with intrinsic resistance of lung cancer to chemotherapy.Cancer Res,1995,55(21):4760-4764.
18 Chang IY,Kim MH,Kim HB,et al.Small interfering RNA-induced suppression of ERCCl enhances sensitivity of human cancer cells to cisplatin.Biochem biophys Res Commun.2005,327(1):225-233.
19 Lord RV,Brabender J,Gandara D,et al.Low ERCCl expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer.Clin Cancer Res,2002;8(7):2286-2291.
20 Olaussen KA,Dunant D,Taranchon E,et al.DNA Repair by ERCCl in Non-Small-Cell Lung Cancer and Cisplatin-Based Adjuvant Chemotherapy.N Engl J Med,2006,355(10):983-991.
21 Rosell R,Danenberg KD,Alberola V,et al.Ribonucleotide reductase messenger RNA expression and survival in gemcitabine/cisplatin-treated advanced non-small-cell lung cancer patients.Clin Cancer Res,2004,10(4):1318-1325.
22 Seve P,Isaac S,tredan O,et al.Expression of class III beta-tubulin is predictive of patient outcome in patients with non-small cell lung cancer receiving vinorelbine-based chemotherapy.Clin Cancer Res 2005,11(15):5481.
23 Seve P,Lai R,Ding K,et al.Class III beta-tubulin expression and benefit from adjuvant cisplatin/vinorelbine chemotherapy in operable non-small cell lung cancer:analysis of NCIC JBR.10.Clin cancer Res,2007;13(3):994-999.
24 Peterson P,Park K,Fossella F,et al.Is pemetrexed more effective in adenocarcinoma and large cell lung cancer than in squamous cell carcinoma? A retrospective analysis of a phase III trial of pemetrexed vs docetaxel in previously treated patients with advanced non-small cell lung cancer.J Thor Oncol,2007,2(8Suppl 4):s851.
25 Goya T,Asamura H,Yoshimura H,et al.Prognosis of 6644 resected non-small cell lung cancers in Japan:a Japanese lung cancer registry study.Lung Cancer 2005;50:227-34.
26 Tsuboi M,Ohira T,Saji H,et al.The present status of postoperative adjuvant chemotherapy for completely resected non-small cell lung cancer.Ann Thorac Cardiovasc Surg,2007,13:73-77.
27 Schabel FM Jr.Surgical adjuvant chemotherapy of metastatic murine tumors.Cancer.1977 Jul;40(1 Suppl):558-68.
28 Pignon JP,Triboder GV,Scagliotti G,et al.Lung Adjuvant Cisplatin Evaluation(LACE):a pooled analysis of five randomized clinical trials including 4,584 patients.J Clin Oncol 2006;24(18 Suppl):366s(abstr.#7008).
29 Schiller JH,Harrington D,Belani CP,et al.Eastern Cooperative Oncology Group.Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.N Engl J Med.2002 Jan 10;346(2):92-8.
30 Kreuter M,Vansteenkiste J,Griesinger F,et al.Trial on refinement of early stage non-small cell lung cancer.Adjuvant chemotherapy with pemetrexed and cisplatin versus vinorelbine and cisplatin:the TREAT protocol.BMC Cancer.2007 May 8;7:77
31 Ciuleanu TE,Brodowicz T,Belani CP et al.Maintenance pemetrexed plus best supportive care(BSC)versus placebo plus BSC:A phase III study.J Clin Oncol 2008;26(15 suppl):426s.
32 Peng G,Zinner RG,Wang Y et al.Comparison of patient outcomes stratified by histology among pemetrexed(P)-treated patients(pts)with stage MB/TV non-small cell lung cancer(NSCLC)in two phase II trials.J Clin Oncol 2008;26(15 suppl):447s.
33 Hanna N,Shepherd FA,Fossella FV et al.Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy.J Clin Oncol 2004;22:1589-1597.
34 Scagliotti GV,Parikh P,von Pawel J et al.Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapynaive patients with advanced-stage non-small-cell lung cancer.J Clin Oncol 2008;26:3543-3551.
35 Scagliotti G,Hanna N,Fossella F,et al.The differential efficacy of pemetrexed according to NSCLC histology:a review of two Phase III studies.Oncologist.2009 Mar;14(3):253-63.Epub 2009 Feb 16.
36 Ceppi P,Volante M,Saviozzi S,et al.Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase.Cancer,2006,107(7):1589-1596.
37 Vargus SO,Leslie KO,Vacek PM,et al.Estrogen receptor related protein p29 in primary non small cell lung carcinoma:pathologyic and prognostic correlations.Cancer,1998,82(8):1495-1500.
38 Shepherd FA,Perira JR,Ciuleanu T et al.Erlotinib in previously treated non small cell lung cancer.N Engl J Med 2005;353:123-132.
39 Yang CH.EGFR tyrosine kinase inhibitors for the treatment of NSCLC in East Asia:present and future.Lung Cancer.2008 Jun;60 Suppl 2:S23-30.
40 Hirsch FR,Varella2Garcia M,Bunn PA J r,et al.Epidermal growth factor receptor in non-small cell lung carcinomas:correlation between gene copy number and protein expression and impact on prognosis.J Clin Oncol,2003,21(20):3798-3807.
41 Xue Q,Sano T,Kashiwabara K,et al.Aberrant expression of pRb,p16,p14ARF,MDM2,p21 and p53 in squamous cell carcinomas of lung.Jpn J Cancer Res,2001,92(3):285-292.
42 Bouchalova K,Trojanec R,Kol(?)r Z,Analysis of ERBB2 and TOP2A gene status using fluorescence in situ hybridization versus immunohistochemistry in localized breast cancer.Neoplasma.2006;53(5):393-401.
43 Franklin WA,Veve R,Hirsch FR,et al.Epidermal growth factor receptor family in lung cancer and premalignancy.Semin Oncol,2002,29(1 suppl 4):3-14.
44 Mendelsohn J,Baselga J.Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer.J Clin Oncol,2003,21(14):2787-2799.
45 Normanno N,Maiello MR,De Luca A.Epidermal growth factor receptor tyrosine kinase inhibitors(EGFR TKIs):simple drugs with a complex mechanism of action.J Cell Physiol,2003,194(1):13-19
46 Villaflor VM,Buchingham L,Gale M et al.EGFR mutations(muts),IHC and FISH status,and chromosome 7 gene copy number combined with pAkt expression as potential predictors of survival in non-small cell lung cancer(NSCLC)patients(pts)treated with Gefitinib(GEF).J Clin Oncol 2006;24(suppl):18s:7182a.
47 Nielsen DL,Andersson M,Kamby C.HER2-targeted therapy in breast cancer.Monoclonal antibodies and tyrosine kinase inhibitors.Cancer Treat Rev.2009 Apr;35(2):121-36.Epub 2008 Nov 12.Review.
48 Hung MC,Lau YK.Basic science of HER-2/neu:a review.Semin Oncol 1999;26(4 Suppl 12):51-9
49 Dei Tos AP.Hirsch FR,Langer CJ.The role of HER2/neu expression and trastuzumab in non-small cell lung cancer.Semin Oncol.2004;31(1 Suppl 1):75-82.
50 Langer CJ,Stephenson P,Thor A,et al.Trastuzumab in the Treatment of Advanced Non-Small-Cell Lung Cancer:Is There a Role? Focus on Eastern Cooperative Oncology Group Study 2598.J Clin Oncol.2004 Feb 23[Epub ahead of print]
51 Gatzemeier U,Groth G,Butts C,et al.Randomized phase II trial of gemcitabine-cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer.Ann Oncol.2004;15(1):19-27
52 Folkman J.Tumor angiogenesis:therapeutic implications.N Engl J Med 1971;285:1182-6.
53 Gasparini G Prognostic value of vascular endothelial growth factor in breast cancer.Oncologist 2000;5(Suppl 1):37-44.
54 Kabbinavar F,Hurwitz HI,Fehrenbacher L,et al.Phase II randomized trial comparing bevacizumab plus uorouracil(FU)/ leucovorin(LV)with FU/LV alone in patients with metastatic colorectal cancer.J Clin Oncol 2003;21:60-65.
55 Cui J,Dong BW,Liang P,et al.Construction and clinical significance of a predictive system for prognosis of hepatocellular carcinoma.World J Gastroenterol 2005;11:3027-33.
56 Ozdemir F,Akdogan R,Aydin F,et al.The effects of VEGF and VEGFR-2 on survival in patients with gastric cancer.J Exp Clin Cancer Res 2006;25(l):83-8.
57 Volm M,Koomagi R,Mattern J.Prognostic value of vascular endothelial growth factor and its receptor Flt-1 in squamous cell lung cancer.Int J Cancer 1997;74(l):64-8.
58 Giatromanolaki A,Koukourakis MI,Kakolyris S,et al.Vascular endothelial growth factor,wild-type p53,and angiogenesis in early operable non-small cell lung cancer.Clin Cancer Res 1998;4(12):3017-24.
59 Seto T,Higashiyama M,Funai H,et al.Prognostic value of expression of vascular endothelial growth factor and its flt-1 and KDR receptors in stage I non-small-cell lung cancer.Lung Cancer 2006;53(l):91-6.
60 Quantin X,Pujol JL,Lehmann M,et al.Immunohistochemical detection of p53 protein and prognosis of surgically resected non-small-cell lung cancer.Cancer Detect Prev.1997;21(5):418-25.
61 Rosenfeld MR,Malats N,Schramm L,et al.Serum anti-p53 antibodies and prognosis of patients with small-cell lung cancer.J Natl Cancer Inst.1997 Mar 5;89(5):381-5
62 Roth JA,Nguyen D,Lawrence DD,et al.Retro virus-mediated wild-type p53 gene transfer to tumors of patients with lung cancer.Nat Med.1996 Sep;2(9):985-91
63 Swisher SG,Roth JA,Nemunaitis J,et al.Adenovirus-mediated p53 gene transfer in advanced non-small-cell lung cancer.J Natl Cancer Inst.1999 May 5;91(9):763-71
64 Perry RR,Kang Y,Greaves B.Biochemical characterization of a mitomycin C resistant colon cancer cell line variant.Biochem Pharmacol.1993 Dec 3;46(11):1999-2005.
65 Ritchard KI,Messersmith H,Elavathil L,et al.HER-2 and topoisomerase II as predictors of response to chemotherapy.J Clin Oncol.2008 Feb 10;26(5):736-44
66 Wiesner FG,Magener A,Fasching PA,et al.Ki-67 as a prognostic molecular marker in routine clinical use in breast cancer patients.Breast.2009 Apr;18(2):135-41.
67 Bodey B,Bodey B Jr,Gr(?)ger AM,et al.Immunocytochemical detection of the p170 multidrug resistance(MDR)and the p53 tumor suppressor gene proteins in human breast cancer cells:clinical and therapeutical significance.Anticancer Res.1997 Mar-Apr;17(2B):1311-8.
68 Lee KH,Min HS,Han SW,et al.ERCCl expression by immunohistochemistry and EGFR mutations in resected non-small cell lung cancer.Lung Cancer.2008 Jun;60(3):401-7.Epub 2007 Nov 26.
69 Alberts WM.American College of Chest Physicians.Introduction:Diagnosis and management of lung cancer:ACCP evidence-based clinical practice guidelines.Chest 2003;123(1 suppl):1S—337S.
70 Simon GR,Sharma S,Cantor A,et al.ERCCl expression is a predictor of survival in resected patients with non-small cell lung cancer.Chest.2005 Mar;127(3):978-83
71 Rosell R,Cobo M,Isla D,et al.ERCCl mRNA-based randomized phase III trial of docetaxel doublets with cisplatin(cis)or gemcitabine(gem)in stage IV non-small-cell lung cancer(NSCLC)patients(p).ASCO 2005 Annual Meeting,Abstract No:7002.
72 Breen D,Barlesi F.The place of excision repair cross complementation 1(ERCCl)in surgically treated non-small cell lung cancer.Eur J Cardiothorac Surg.2008 May;33(5):805-11.
73 Olaussen KA,Dunant A,Fouret P,et al.DNA repair by ERCCl in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy.N Engl J Med.2006 Sep 7;355(10):983-91.
74 Zheng Z,Chen T,Li X,et al.DNA synthesis and repair genes RRM1 and ERCCl in lung cancer.N Engl J Med.2007 Feb 22;356(8):800-8
75 Simon G,Sharma A,Li X,et al.Feasibility and efficacy of molecular analysis-directed individualized therapy in advanced non-small-cell lung cancer.J Clin Oncol.2007 Jul l;25(19):2741-6
76 Bepler G,Sommers KE,Cantor A,et al.Clinical efficacy and predictive molecular markers of neoadjuvant gemcitabine and pemetrexed in resectable non-small cell lung cancer.J Thorac Oncol.2008 Oct;3(10):1112-8
77 Bepler G,Begum M,Simon GR.Molecular analysis-based treatment strategies for non-small cell lung cancer.Cancer Control.2008 Apr;15(2):130-9.
78 Brognard J,Clark AS,Ni Y,Dennis PA Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation.Cancer Res 2001;61:3986-97.
79 Brunet A,Bonni A,Zigmond MJ,et al Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.Cell 1999;96:857-68.
80 Rommel C,Clarke BA,Zimmermann S,et al Differentiation stage-specific inhibition of the Raf-MEK-ERK pathway by Akt.Science(Wash DC)1999;286:1738-41.
81 Okudela K,Hayashi H,Ito T,et al K-ras gene mutation enhances motility of immortalized airway cells and lung adenocarcinoma cells via Akt activation:possible contribution to non-invasive expansion of lung adenocarcinoma.Am J Pathol 2004;164:91-100.
82 David O,Jett J,LeBeau H,et al.Phospho-Akt overexpression in non-small cell lung cancer confers significant stage-independent survival disadvantage.Clin Cancer Res.2004 Oct 15;10(20):6865-71
83 Nakashio A,Fujita N,Rokudai S,et al.Prevention of phosphatidylinositol 3'-kinase-Akt survival signaling pathway during topotecan-induced apoptosis.Cancer Res 2000;60:5303-9.
84 Abou-Alfa GK,Schwartz L,Ricci S,et al.Phase II study of sorafenib in patients with advanced hepatocellular carcinoma.J Clin Oncol,2006,24(26):4293-4300.
85 Galleges Ruiz MI,Floor K,Steinberg SM,et al.Combined assessment of EGFR pathway-related molecular markers and prognosis of NSCLC patients.Br J Cancer.2009 Jan 13;100(1):145-52.
86 Cappuzzo F,Ligorio C,J(a|¨)nne PA,et al.Prospective study of gefitinib in epidermal growth factor receptor fluorescence in situ hybridization-positive/ phospho-Akt-positive or never smoker patients with advanced non-small-cell lung cancer:the ONCOBELL trial.J Clin Oncol.2007 Jun 1;25(16):2248-55.
87 Engelman JA,Zejnullahu K,Mitsudomi T,et al.MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling.Science.2007 May 18;316(5827):1039-43.Epub 2007 Apr 26.
88 She QB,Solit DB,Ye Q,et al.The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells.Cancer Cell.2005 Oct;8(4):287-97.
89 Berns K,Horlings HM,Hennessy BT,et al.A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer.Cancer Cell.2007 Oct;12(4):395-402.
90 Sos ML,Koker M,Weir BA,et al.PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR.Cancer Res.2009 Apr 15;69(8):3256-61.Epub 2009 Apr 7.
91 Kim ES,Salgia R.MET Pathway as a Therapeutic Target.J Thorac Oncol.2009Apr;4(4):444-7.
92 Wang Y,Zhang XR,HX,et al.Establishment of a model to assess the clinical efficacy of Gefitinib in treatment of non -small cell lung cancer.Natl Med J China,2007,87(43):3069-3073.
1 Jemal A,Murray T,Ward E,et al.Cancer Statistics,2005.CA Cancer J Clin 2007;55:10-30.
2 Jemal A,Murray T,Ward E,et al.Cancer Statistics,2005.CA Cancer J Clin 2008;55:10-30.
3 Goya T,Asamura H,Yoshimura H,et al.Prognosis of 6644 resected non-small cell lung cancers in Japan:a Japanese lung cancer registry study.Lung Cancer 2005;50:227-34.
4 Mountain CF.Revisions in international system for staging lung cancer.Chest 1997;111:1710-7.
5 Non-small Cell Lung Cancer Collaborative Group.Chemotherapy in non-small cell lung cancer:a meta-analysis using updated data on individual patients from 52 randomized clinical trials.BMJ,1995,311:899-909.
6 Scagliotti GV,Fossati R,Torri V,et al.Randomized study of adjuvant chemotherapy for completely resected stage 1,II,or IIIA non-small-cell Lung cancer.J Natl Cancer Inst 2003;95:1453-61.
7 Waller D,Peake MD,Stephens RJ,et al.Chemotherapy for patients with non-small cell lung cancer:the surgical setting of the Big Lung Trial.Eur J Cardiothorac Surg 2004;26:173-82.
8 Arriagada R,Bergman B,Dunant A,et al.Cisplatinbased adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer.N Engl J Med 2004;350:351-60.
9 Winton TL,Livingstan R,Johnson D,et al.A prospective randomized trial of adjuvant vinorelbine(VNR)and cisplatin(CIS)in completely resected stage Ib and II non small cell lung cancer(NSCLC)Intergroup JBR10.N Engl J Med 2005;352:2589-97.
10 Douillard J,Rosell R,Delena M,et al.Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer(Adjuvant Navelbine International Trialist Association[ANITA]):a randomised controlled trial.Lancet Oncol 2006;7:719-27.
11 Strauss GM,Hernden J,Maddaus MA,et al.Adjuvant chemotherapy in Stage IB non-small cell lung cancer(NSCLC):update on Cancer and Leukemia Group B(CALGB)protocol 9633.J Clin Oncol 2006;24(18 Suppl):365s(abstr.#7007).
12 Pignon JP,Triboder GV,Scagliotti G,et al.Lung Adjuvant Cisplatin Evaluation(LACE):a pooled analysis of five randomized clinical trials including 4,584 patients.J Clin Oncol 2006;24(18 Suppl):366s(abstr.#7008).
13 Kreuter M,Vansteenkiste J,Griesinger F,et al.Trial on refinement of early stage non-small cell lung cancer.Adjuvant chemotherapy with pemetrexed and cisplatin versus vinorelbine and cisplatin:the TREAT protocol.BMC Cancer.2007 May 8;7:77.
14 Paik S.Development and clinical utility of a 21-gene recurrence score prognostic assay in patients with early breast cancer treated with tamoxifen 。 Oncologist.2007 Jun;12(6):631-5
15 Chen HY,Yu SL,Chen CH,et al.A five-gene signature and clinical outcome in non-small-cell lung cancer.N Engl J Med.2007 Jan 4;356(1):11-20.
16 Anguiano A,Potti A.Genomic signatures individualize therapeutic decisions in non-small-cell lung cancer.Expert Rev Mol Diagn.2007 Nov;7(6):837-44.
17 Brock MV,Hooker CM,Ota-Machida E,et al.DNA methylation markers and early recurrence in stage I lung cancer.N Engl J Med.2008 Mar 13;358(11):1118-28.
18 Simon GR,Sharma S,Cantor A,et al.ERCCl expression is a predictor of survival in resected patients with non-small cell lung cancer.Chest.2005 Mar;127(3):978-83
19 Cobo M,Isla D,Sanchez J,et al.ERCCl mRNA-based randomized phase Ⅲ trial of docetaxel doublets with cisplatin or gefhcitabine in stage Ⅳ non-small-cell lung cancer patients.Lung 2005;49(supplS32).
20 Rosell R,Danenberg KD,Alberola V,et al.Ribonucleotide reductase messenger RNA expression and survival in gemcitabine/cisplatin-treated advanced non-small-cell lung cancer patients.Clin Cancer Res,2004,10(4):1318-1325.
21 Seve P,Isaac S,tredan O,et al.Expression of class Ⅲ beta-tubulin is predictive of patient outcome in patients with non-small cell lung cancer receiving vinorelbine-based chemotherapy.Clin Cancer Res 2005,11(15):5481.
22 Save P,Lai R,Ding K,et al.Class Ⅲ beta-tubulin expression and benefit from adjuvant cisplatin/vinorelbine chemotherapy in operable non-small cell lung cancer:analysis of NCIC JBR.10.Clin cancer Res,2007;13(3):994-999.
23 Peterson P,Park K,Fossella F,et al.Is pemetrexed more effective in adenocarcinoma and large cell lung cancer than in squamous cell carcinoma? A retrospective analysis of a phase III trial of pemetrexed vs docetaxel in previously treated patients with advanced non-small cell lung cancer.J Thor Oncol,2007,2(8Suppl 4):s851.
24 Rosell CR,Jassem E,Skrzypski M,et al.A prognostic model based on BRCA1 mRNA expression:a new determinant of outcome in early non-small-cell lung cancer.Euro J Cancer.2007,5(4):Suppl,358.Abs6506.
25 Ritchard KI,Messersmith H,Elavathil L,et al.HER-2 and topoisomerase II as predictors of response to chemotherapy.J Clin Oncol.2008 Feb 10;26(5):736-44.
26 Wang Y,Zhang XR,HX et al.Establishment of a model to assess the clinical efficacy of Gefitinib in treatment of non-small cell lung cancer.Natl Med J China,2007,87(43):3069-3073.
2 Jemal A,Murray T,Ward E,et al.Cancer Statistics,2005.CA Cancer J Clin 2008;55:10—30.
3 Yang L,Parkin DM,Li LD,et al.Estimation and projection of the national profile of cancer mortality in China:1991-2005.Br J Cancer.2004 Jun 1;90(11):2157-66.
4 Pisters KM,Le Chevalier T.Adjuvant chemotherapy in completely resected non-small-cell lung cancer.J Clin Oncol 2005;23:3270—8.
5 Mountain CF.Revisions in the international system for staging lung cancer.Chest 1997;111:1710—7.
6 Non-small Cell Lung Cancer Collaborative Group.Chemotherapy in non-small cell lung cancer:a meta-analysis using updated data on individual patients from 52 randomized clinical trials.BMJ,1995,311:899-909.
7 Keller SM,Adak S,Wagner H,et al.Mediastinal lymph node dissection improves survival in patients with stages II and IIIa non-small cell lung cancer.Eastern Cooperative Oncology Group.Ann Thorac Surg.2000 Aug;70(2):358-65;discussion 365-6.
8 Waller D,Peake MD,Stephens RJ,et al.Chemotherapy for patients with non-small cell lung cancer:the surgical setting of the Big Lung Trial.Eur J Cardiothorac Surg 2004;26:173-82.
9 Scagliotti GV,Fossati R,Torri V,et al.Randomized study of adjuvant chemotherapy for completely resected stage Ⅰ,Ⅱ,or ⅢA non-small-cell Lung cancer.J Natl Cancer Inst 2603;95:1453-61.
10 Smit EF,Van Meerbeeck JP,Lianes P,et al.Three-arm randomized study of two cisplatin-based regimens and paclitaxel plus gemcitabine in advanced non-small-cell lung cancer:a phase III trial of the European Organization for Research and Treatment of Cancer Lung Cancer Group-EORTC 08975.J Clin Oncol, 2003,21(21):3909-3917.
11 Strauss GM,Hernden J,Maddaus MA,et al.Adjuvant chemotherapy in Stage IB non-small cell lung cancer(NSCLC):update on Cancer and Leukemia Group B(CALGB)protocol 9633.J Clin Oncol 2006;24(18 Suppl):365s(abstr.#7007).
12 Arriagada R,Bergman B,Dunant A,et al.Cisplatinbased adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer.N Engl J Med 2004;350:351-60.
13 Winton TL,Livingstan R,Johnson D,et al.A prospective randomized trial of adjuvant vinorelbine(VNR)and cisplatin(CIS)in completely resected stage Ib and II non small cell lung cancer(NSCLC)Intergroup JBR10.N Engl J Med 2005;352:2589-97.
14 Douillard J,Rosell R,Delena M,et al.Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer(Adjuvant Navelbine International Trialist Association[ANITA]):a randomised controlled trial.Lancet Oncol 2006;7:719-27.
15 PORT Meta analysis Trialists Group.Postoperative radiotherapy in non small cell lung cancer:Systematic review and meta analysis of individual patient data from nine randomized controlled trials [J].Lancet,1998,352(9124):257-263.
16 Rube C,Phu Nguyen T,Fleckenstein J,et al.Postoperative radiotherapy in localized non small cell lung cancer.Lung Cancer,2001,33(Suppl 1):29-33.
17 Zeng-Rong N,Paterson J,Alpert L,et al.Elevated DNA repair capacity is associated with intrinsic resistance of lung cancer to chemotherapy.Cancer Res,1995,55(21):4760-4764.
18 Chang IY,Kim MH,Kim HB,et al.Small interfering RNA-induced suppression of ERCCl enhances sensitivity of human cancer cells to cisplatin.Biochem biophys Res Commun.2005,327(1):225-233.
19 Lord RV,Brabender J,Gandara D,et al.Low ERCCl expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer.Clin Cancer Res,2002;8(7):2286-2291.
20 Olaussen KA,Dunant D,Taranchon E,et al.DNA Repair by ERCCl in Non-Small-Cell Lung Cancer and Cisplatin-Based Adjuvant Chemotherapy.N Engl J Med,2006,355(10):983-991.
21 Rosell R,Danenberg KD,Alberola V,et al.Ribonucleotide reductase messenger RNA expression and survival in gemcitabine/cisplatin-treated advanced non-small-cell lung cancer patients.Clin Cancer Res,2004,10(4):1318-1325.
22 Seve P,Isaac S,tredan O,et al.Expression of class III beta-tubulin is predictive of patient outcome in patients with non-small cell lung cancer receiving vinorelbine-based chemotherapy.Clin Cancer Res 2005,11(15):5481.
23 Seve P,Lai R,Ding K,et al.Class III beta-tubulin expression and benefit from adjuvant cisplatin/vinorelbine chemotherapy in operable non-small cell lung cancer:analysis of NCIC JBR.10.Clin cancer Res,2007;13(3):994-999.
24 Peterson P,Park K,Fossella F,et al.Is pemetrexed more effective in adenocarcinoma and large cell lung cancer than in squamous cell carcinoma? A retrospective analysis of a phase III trial of pemetrexed vs docetaxel in previously treated patients with advanced non-small cell lung cancer.J Thor Oncol,2007,2(8Suppl 4):s851.
25 Goya T,Asamura H,Yoshimura H,et al.Prognosis of 6644 resected non-small cell lung cancers in Japan:a Japanese lung cancer registry study.Lung Cancer 2005;50:227-34.
26 Tsuboi M,Ohira T,Saji H,et al.The present status of postoperative adjuvant chemotherapy for completely resected non-small cell lung cancer.Ann Thorac Cardiovasc Surg,2007,13:73-77.
27 Schabel FM Jr.Surgical adjuvant chemotherapy of metastatic murine tumors.Cancer.1977 Jul;40(1 Suppl):558-68.
28 Pignon JP,Triboder GV,Scagliotti G,et al.Lung Adjuvant Cisplatin Evaluation(LACE):a pooled analysis of five randomized clinical trials including 4,584 patients.J Clin Oncol 2006;24(18 Suppl):366s(abstr.#7008).
29 Schiller JH,Harrington D,Belani CP,et al.Eastern Cooperative Oncology Group.Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.N Engl J Med.2002 Jan 10;346(2):92-8.
30 Kreuter M,Vansteenkiste J,Griesinger F,et al.Trial on refinement of early stage non-small cell lung cancer.Adjuvant chemotherapy with pemetrexed and cisplatin versus vinorelbine and cisplatin:the TREAT protocol.BMC Cancer.2007 May 8;7:77
31 Ciuleanu TE,Brodowicz T,Belani CP et al.Maintenance pemetrexed plus best supportive care(BSC)versus placebo plus BSC:A phase III study.J Clin Oncol 2008;26(15 suppl):426s.
32 Peng G,Zinner RG,Wang Y et al.Comparison of patient outcomes stratified by histology among pemetrexed(P)-treated patients(pts)with stage MB/TV non-small cell lung cancer(NSCLC)in two phase II trials.J Clin Oncol 2008;26(15 suppl):447s.
33 Hanna N,Shepherd FA,Fossella FV et al.Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy.J Clin Oncol 2004;22:1589-1597.
34 Scagliotti GV,Parikh P,von Pawel J et al.Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapynaive patients with advanced-stage non-small-cell lung cancer.J Clin Oncol 2008;26:3543-3551.
35 Scagliotti G,Hanna N,Fossella F,et al.The differential efficacy of pemetrexed according to NSCLC histology:a review of two Phase III studies.Oncologist.2009 Mar;14(3):253-63.Epub 2009 Feb 16.
36 Ceppi P,Volante M,Saviozzi S,et al.Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase.Cancer,2006,107(7):1589-1596.
37 Vargus SO,Leslie KO,Vacek PM,et al.Estrogen receptor related protein p29 in primary non small cell lung carcinoma:pathologyic and prognostic correlations.Cancer,1998,82(8):1495-1500.
38 Shepherd FA,Perira JR,Ciuleanu T et al.Erlotinib in previously treated non small cell lung cancer.N Engl J Med 2005;353:123-132.
39 Yang CH.EGFR tyrosine kinase inhibitors for the treatment of NSCLC in East Asia:present and future.Lung Cancer.2008 Jun;60 Suppl 2:S23-30.
40 Hirsch FR,Varella2Garcia M,Bunn PA J r,et al.Epidermal growth factor receptor in non-small cell lung carcinomas:correlation between gene copy number and protein expression and impact on prognosis.J Clin Oncol,2003,21(20):3798-3807.
41 Xue Q,Sano T,Kashiwabara K,et al.Aberrant expression of pRb,p16,p14ARF,MDM2,p21 and p53 in squamous cell carcinomas of lung.Jpn J Cancer Res,2001,92(3):285-292.
42 Bouchalova K,Trojanec R,Kol(?)r Z,Analysis of ERBB2 and TOP2A gene status using fluorescence in situ hybridization versus immunohistochemistry in localized breast cancer.Neoplasma.2006;53(5):393-401.
43 Franklin WA,Veve R,Hirsch FR,et al.Epidermal growth factor receptor family in lung cancer and premalignancy.Semin Oncol,2002,29(1 suppl 4):3-14.
44 Mendelsohn J,Baselga J.Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer.J Clin Oncol,2003,21(14):2787-2799.
45 Normanno N,Maiello MR,De Luca A.Epidermal growth factor receptor tyrosine kinase inhibitors(EGFR TKIs):simple drugs with a complex mechanism of action.J Cell Physiol,2003,194(1):13-19
46 Villaflor VM,Buchingham L,Gale M et al.EGFR mutations(muts),IHC and FISH status,and chromosome 7 gene copy number combined with pAkt expression as potential predictors of survival in non-small cell lung cancer(NSCLC)patients(pts)treated with Gefitinib(GEF).J Clin Oncol 2006;24(suppl):18s:7182a.
47 Nielsen DL,Andersson M,Kamby C.HER2-targeted therapy in breast cancer.Monoclonal antibodies and tyrosine kinase inhibitors.Cancer Treat Rev.2009 Apr;35(2):121-36.Epub 2008 Nov 12.Review.
48 Hung MC,Lau YK.Basic science of HER-2/neu:a review.Semin Oncol 1999;26(4 Suppl 12):51-9
49 Dei Tos AP.Hirsch FR,Langer CJ.The role of HER2/neu expression and trastuzumab in non-small cell lung cancer.Semin Oncol.2004;31(1 Suppl 1):75-82.
50 Langer CJ,Stephenson P,Thor A,et al.Trastuzumab in the Treatment of Advanced Non-Small-Cell Lung Cancer:Is There a Role? Focus on Eastern Cooperative Oncology Group Study 2598.J Clin Oncol.2004 Feb 23[Epub ahead of print]
51 Gatzemeier U,Groth G,Butts C,et al.Randomized phase II trial of gemcitabine-cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer.Ann Oncol.2004;15(1):19-27
52 Folkman J.Tumor angiogenesis:therapeutic implications.N Engl J Med 1971;285:1182-6.
53 Gasparini G Prognostic value of vascular endothelial growth factor in breast cancer.Oncologist 2000;5(Suppl 1):37-44.
54 Kabbinavar F,Hurwitz HI,Fehrenbacher L,et al.Phase II randomized trial comparing bevacizumab plus uorouracil(FU)/ leucovorin(LV)with FU/LV alone in patients with metastatic colorectal cancer.J Clin Oncol 2003;21:60-65.
55 Cui J,Dong BW,Liang P,et al.Construction and clinical significance of a predictive system for prognosis of hepatocellular carcinoma.World J Gastroenterol 2005;11:3027-33.
56 Ozdemir F,Akdogan R,Aydin F,et al.The effects of VEGF and VEGFR-2 on survival in patients with gastric cancer.J Exp Clin Cancer Res 2006;25(l):83-8.
57 Volm M,Koomagi R,Mattern J.Prognostic value of vascular endothelial growth factor and its receptor Flt-1 in squamous cell lung cancer.Int J Cancer 1997;74(l):64-8.
58 Giatromanolaki A,Koukourakis MI,Kakolyris S,et al.Vascular endothelial growth factor,wild-type p53,and angiogenesis in early operable non-small cell lung cancer.Clin Cancer Res 1998;4(12):3017-24.
59 Seto T,Higashiyama M,Funai H,et al.Prognostic value of expression of vascular endothelial growth factor and its flt-1 and KDR receptors in stage I non-small-cell lung cancer.Lung Cancer 2006;53(l):91-6.
60 Quantin X,Pujol JL,Lehmann M,et al.Immunohistochemical detection of p53 protein and prognosis of surgically resected non-small-cell lung cancer.Cancer Detect Prev.1997;21(5):418-25.
61 Rosenfeld MR,Malats N,Schramm L,et al.Serum anti-p53 antibodies and prognosis of patients with small-cell lung cancer.J Natl Cancer Inst.1997 Mar 5;89(5):381-5
62 Roth JA,Nguyen D,Lawrence DD,et al.Retro virus-mediated wild-type p53 gene transfer to tumors of patients with lung cancer.Nat Med.1996 Sep;2(9):985-91
63 Swisher SG,Roth JA,Nemunaitis J,et al.Adenovirus-mediated p53 gene transfer in advanced non-small-cell lung cancer.J Natl Cancer Inst.1999 May 5;91(9):763-71
64 Perry RR,Kang Y,Greaves B.Biochemical characterization of a mitomycin C resistant colon cancer cell line variant.Biochem Pharmacol.1993 Dec 3;46(11):1999-2005.
65 Ritchard KI,Messersmith H,Elavathil L,et al.HER-2 and topoisomerase II as predictors of response to chemotherapy.J Clin Oncol.2008 Feb 10;26(5):736-44
66 Wiesner FG,Magener A,Fasching PA,et al.Ki-67 as a prognostic molecular marker in routine clinical use in breast cancer patients.Breast.2009 Apr;18(2):135-41.
67 Bodey B,Bodey B Jr,Gr(?)ger AM,et al.Immunocytochemical detection of the p170 multidrug resistance(MDR)and the p53 tumor suppressor gene proteins in human breast cancer cells:clinical and therapeutical significance.Anticancer Res.1997 Mar-Apr;17(2B):1311-8.
68 Lee KH,Min HS,Han SW,et al.ERCCl expression by immunohistochemistry and EGFR mutations in resected non-small cell lung cancer.Lung Cancer.2008 Jun;60(3):401-7.Epub 2007 Nov 26.
69 Alberts WM.American College of Chest Physicians.Introduction:Diagnosis and management of lung cancer:ACCP evidence-based clinical practice guidelines.Chest 2003;123(1 suppl):1S—337S.
70 Simon GR,Sharma S,Cantor A,et al.ERCCl expression is a predictor of survival in resected patients with non-small cell lung cancer.Chest.2005 Mar;127(3):978-83
71 Rosell R,Cobo M,Isla D,et al.ERCCl mRNA-based randomized phase III trial of docetaxel doublets with cisplatin(cis)or gemcitabine(gem)in stage IV non-small-cell lung cancer(NSCLC)patients(p).ASCO 2005 Annual Meeting,Abstract No:7002.
72 Breen D,Barlesi F.The place of excision repair cross complementation 1(ERCCl)in surgically treated non-small cell lung cancer.Eur J Cardiothorac Surg.2008 May;33(5):805-11.
73 Olaussen KA,Dunant A,Fouret P,et al.DNA repair by ERCCl in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy.N Engl J Med.2006 Sep 7;355(10):983-91.
74 Zheng Z,Chen T,Li X,et al.DNA synthesis and repair genes RRM1 and ERCCl in lung cancer.N Engl J Med.2007 Feb 22;356(8):800-8
75 Simon G,Sharma A,Li X,et al.Feasibility and efficacy of molecular analysis-directed individualized therapy in advanced non-small-cell lung cancer.J Clin Oncol.2007 Jul l;25(19):2741-6
76 Bepler G,Sommers KE,Cantor A,et al.Clinical efficacy and predictive molecular markers of neoadjuvant gemcitabine and pemetrexed in resectable non-small cell lung cancer.J Thorac Oncol.2008 Oct;3(10):1112-8
77 Bepler G,Begum M,Simon GR.Molecular analysis-based treatment strategies for non-small cell lung cancer.Cancer Control.2008 Apr;15(2):130-9.
78 Brognard J,Clark AS,Ni Y,Dennis PA Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation.Cancer Res 2001;61:3986-97.
79 Brunet A,Bonni A,Zigmond MJ,et al Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.Cell 1999;96:857-68.
80 Rommel C,Clarke BA,Zimmermann S,et al Differentiation stage-specific inhibition of the Raf-MEK-ERK pathway by Akt.Science(Wash DC)1999;286:1738-41.
81 Okudela K,Hayashi H,Ito T,et al K-ras gene mutation enhances motility of immortalized airway cells and lung adenocarcinoma cells via Akt activation:possible contribution to non-invasive expansion of lung adenocarcinoma.Am J Pathol 2004;164:91-100.
82 David O,Jett J,LeBeau H,et al.Phospho-Akt overexpression in non-small cell lung cancer confers significant stage-independent survival disadvantage.Clin Cancer Res.2004 Oct 15;10(20):6865-71
83 Nakashio A,Fujita N,Rokudai S,et al.Prevention of phosphatidylinositol 3'-kinase-Akt survival signaling pathway during topotecan-induced apoptosis.Cancer Res 2000;60:5303-9.
84 Abou-Alfa GK,Schwartz L,Ricci S,et al.Phase II study of sorafenib in patients with advanced hepatocellular carcinoma.J Clin Oncol,2006,24(26):4293-4300.
85 Galleges Ruiz MI,Floor K,Steinberg SM,et al.Combined assessment of EGFR pathway-related molecular markers and prognosis of NSCLC patients.Br J Cancer.2009 Jan 13;100(1):145-52.
86 Cappuzzo F,Ligorio C,J(a|¨)nne PA,et al.Prospective study of gefitinib in epidermal growth factor receptor fluorescence in situ hybridization-positive/ phospho-Akt-positive or never smoker patients with advanced non-small-cell lung cancer:the ONCOBELL trial.J Clin Oncol.2007 Jun 1;25(16):2248-55.
87 Engelman JA,Zejnullahu K,Mitsudomi T,et al.MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling.Science.2007 May 18;316(5827):1039-43.Epub 2007 Apr 26.
88 She QB,Solit DB,Ye Q,et al.The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells.Cancer Cell.2005 Oct;8(4):287-97.
89 Berns K,Horlings HM,Hennessy BT,et al.A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer.Cancer Cell.2007 Oct;12(4):395-402.
90 Sos ML,Koker M,Weir BA,et al.PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR.Cancer Res.2009 Apr 15;69(8):3256-61.Epub 2009 Apr 7.
91 Kim ES,Salgia R.MET Pathway as a Therapeutic Target.J Thorac Oncol.2009Apr;4(4):444-7.
92 Wang Y,Zhang XR,HX,et al.Establishment of a model to assess the clinical efficacy of Gefitinib in treatment of non -small cell lung cancer.Natl Med J China,2007,87(43):3069-3073.
1 Jemal A,Murray T,Ward E,et al.Cancer Statistics,2005.CA Cancer J Clin 2007;55:10-30.
2 Jemal A,Murray T,Ward E,et al.Cancer Statistics,2005.CA Cancer J Clin 2008;55:10-30.
3 Goya T,Asamura H,Yoshimura H,et al.Prognosis of 6644 resected non-small cell lung cancers in Japan:a Japanese lung cancer registry study.Lung Cancer 2005;50:227-34.
4 Mountain CF.Revisions in international system for staging lung cancer.Chest 1997;111:1710-7.
5 Non-small Cell Lung Cancer Collaborative Group.Chemotherapy in non-small cell lung cancer:a meta-analysis using updated data on individual patients from 52 randomized clinical trials.BMJ,1995,311:899-909.
6 Scagliotti GV,Fossati R,Torri V,et al.Randomized study of adjuvant chemotherapy for completely resected stage 1,II,or IIIA non-small-cell Lung cancer.J Natl Cancer Inst 2003;95:1453-61.
7 Waller D,Peake MD,Stephens RJ,et al.Chemotherapy for patients with non-small cell lung cancer:the surgical setting of the Big Lung Trial.Eur J Cardiothorac Surg 2004;26:173-82.
8 Arriagada R,Bergman B,Dunant A,et al.Cisplatinbased adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer.N Engl J Med 2004;350:351-60.
9 Winton TL,Livingstan R,Johnson D,et al.A prospective randomized trial of adjuvant vinorelbine(VNR)and cisplatin(CIS)in completely resected stage Ib and II non small cell lung cancer(NSCLC)Intergroup JBR10.N Engl J Med 2005;352:2589-97.
10 Douillard J,Rosell R,Delena M,et al.Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer(Adjuvant Navelbine International Trialist Association[ANITA]):a randomised controlled trial.Lancet Oncol 2006;7:719-27.
11 Strauss GM,Hernden J,Maddaus MA,et al.Adjuvant chemotherapy in Stage IB non-small cell lung cancer(NSCLC):update on Cancer and Leukemia Group B(CALGB)protocol 9633.J Clin Oncol 2006;24(18 Suppl):365s(abstr.#7007).
12 Pignon JP,Triboder GV,Scagliotti G,et al.Lung Adjuvant Cisplatin Evaluation(LACE):a pooled analysis of five randomized clinical trials including 4,584 patients.J Clin Oncol 2006;24(18 Suppl):366s(abstr.#7008).
13 Kreuter M,Vansteenkiste J,Griesinger F,et al.Trial on refinement of early stage non-small cell lung cancer.Adjuvant chemotherapy with pemetrexed and cisplatin versus vinorelbine and cisplatin:the TREAT protocol.BMC Cancer.2007 May 8;7:77.
14 Paik S.Development and clinical utility of a 21-gene recurrence score prognostic assay in patients with early breast cancer treated with tamoxifen 。 Oncologist.2007 Jun;12(6):631-5
15 Chen HY,Yu SL,Chen CH,et al.A five-gene signature and clinical outcome in non-small-cell lung cancer.N Engl J Med.2007 Jan 4;356(1):11-20.
16 Anguiano A,Potti A.Genomic signatures individualize therapeutic decisions in non-small-cell lung cancer.Expert Rev Mol Diagn.2007 Nov;7(6):837-44.
17 Brock MV,Hooker CM,Ota-Machida E,et al.DNA methylation markers and early recurrence in stage I lung cancer.N Engl J Med.2008 Mar 13;358(11):1118-28.
18 Simon GR,Sharma S,Cantor A,et al.ERCCl expression is a predictor of survival in resected patients with non-small cell lung cancer.Chest.2005 Mar;127(3):978-83
19 Cobo M,Isla D,Sanchez J,et al.ERCCl mRNA-based randomized phase Ⅲ trial of docetaxel doublets with cisplatin or gefhcitabine in stage Ⅳ non-small-cell lung cancer patients.Lung 2005;49(supplS32).
20 Rosell R,Danenberg KD,Alberola V,et al.Ribonucleotide reductase messenger RNA expression and survival in gemcitabine/cisplatin-treated advanced non-small-cell lung cancer patients.Clin Cancer Res,2004,10(4):1318-1325.
21 Seve P,Isaac S,tredan O,et al.Expression of class Ⅲ beta-tubulin is predictive of patient outcome in patients with non-small cell lung cancer receiving vinorelbine-based chemotherapy.Clin Cancer Res 2005,11(15):5481.
22 Save P,Lai R,Ding K,et al.Class Ⅲ beta-tubulin expression and benefit from adjuvant cisplatin/vinorelbine chemotherapy in operable non-small cell lung cancer:analysis of NCIC JBR.10.Clin cancer Res,2007;13(3):994-999.
23 Peterson P,Park K,Fossella F,et al.Is pemetrexed more effective in adenocarcinoma and large cell lung cancer than in squamous cell carcinoma? A retrospective analysis of a phase III trial of pemetrexed vs docetaxel in previously treated patients with advanced non-small cell lung cancer.J Thor Oncol,2007,2(8Suppl 4):s851.
24 Rosell CR,Jassem E,Skrzypski M,et al.A prognostic model based on BRCA1 mRNA expression:a new determinant of outcome in early non-small-cell lung cancer.Euro J Cancer.2007,5(4):Suppl,358.Abs6506.
25 Ritchard KI,Messersmith H,Elavathil L,et al.HER-2 and topoisomerase II as predictors of response to chemotherapy.J Clin Oncol.2008 Feb 10;26(5):736-44.
26 Wang Y,Zhang XR,HX et al.Establishment of a model to assess the clinical efficacy of Gefitinib in treatment of non-small cell lung cancer.Natl Med J China,2007,87(43):3069-3073.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |