晚期非小细胞肺癌内科治疗的个体化

晚期非小细胞肺癌内科治疗的个体化,同济大学附属上海市肺科医院 周彩存,晚期非小细胞肺癌的治疗现状,Platinum-based doublets improve overall survival Prolonged chemotherapy more than 3-4 cycles could not further improve efficacy Doublets plus avastin or cetuximab improve overall survival compared with doublets Chemotherapy could improve disease-related symptoms Chemotherapy has toxicities Advanced lung cancer could not be cured and our aim is to make it chronic disease,个体化治疗,Definition - 4R: Right agent, right dose, right patients and right timing - Biomarkers：predictive, prognostic - Purpose: improvement of efficacy of therapy Advantages？ -Informative treatment strategy -Better treatment outcome -Less risk of toxicities -Decrease in cost,我院开展的晚期NSCLC药物基因组学个体化研究,ERCC1 RRM1 BRCA1 SNP of DNA repair genes,ERCC1和XRCC3基因多态性在晚期接受含铂方案化疗病人中的疗效预测作用,Published in JJCO,研究方案及流程,2005.9月 to 2007.6月 IIIB/IV期 NSCLC Chemo-nave 重要脏器功能正常 无脑转移， 脊髓压迫,检测外周血白细胞 ERCC1 118和 XRCC3 241 单核 苷酸多态性,NP (N=53) GP(N=46) TP(N=31),DCR 85.4% PR 20% SD 65.4% PD 14.6%,1线化疗方案,N=130,Taqman 探针,Taqman探针结合实时荧光PCR方法与直接测序法一致,Figure 1 Real-time PCR reaction curves and sequencing profile of ERCC1 codon 118 (A )homozygous wide genotype.(B)heterozygous genotype.(C) homozygous variant genotype,Figure 2 Real-time PCR reaction curves and sequencing profile of XRCC3 coden 241(A) homozygous wide genotype.(B) heterozygous genotype.(C)homozygous variant genotype,ERCC1 118,XRCC3 241,基线特征及SNP分布,Genotyping Male Female Age Adeno Squam St IIIB St IV Total 56.9% 43.1% 61 62.3% 37.7% 30.8% 69.2% ERCC1 118 C/C 53.6% 46.4% 61 57.1% 42.9% 28.9% 71.1% 118 C/T+ T/T 63.0% 37% 60 71.7% 28.3% 34.8% 65.2% XRCC3 241 C/C 56.8% 43.2% 61 59.5% 40.5% 34.2% 65.8% 241 C/T+T/T 52.6% 47.4% 60 78.9% 21.1% 10.5% 89.5% Adeno=adenocarcinoma, Squam=squamous cell carcinoma, St= Stage,130例患者进入本研究,SNP与化疗疗效的关系,Genotyping Number PR SD PD Total 130 20% 65.4% 14.6% ERCC1 Wild-type 84 19% 65.5% 15.5% Mutant 46 21.7% 65.3% 13.0% XRCC3 Wild-type 111 19.8% 64% 16.2% Mutant 19 21.1% 77.6% 5.3%,ERCC1 118 C/T or T/T 者能明显从铂类治疗中生存获益,17.5m vs 13.5m， p =0.003,15 m vs 15.5m， p =0.57,多因素回归分析,ERCC1 mRNA表达水平对NSCLC一线接受含铂双药治疗的疗效预测作用,2006.11月 to 2008.11月 IIIB/IV期 NSCLC Chemo-nave 重要脏器功能正常 无脑转移， 脊髓压迫,化疗前通过FOB, 穿刺，活检等方 法获取肿瘤标本 检测ERCC1 mRNA 的表达,NP (N=43) GP(N=23) TP(N=24),DCR 80.6% PR 39.8% PD 19.4%,1线化疗方案,N=100,Accepted by,Taqman 探针,患者基线特征,ERCC1 mRNA的表达与临床特征之间的关系,Cutoff value of ERCC1:0.0012,PFS和OS单因素分析,ERCC1 mRNA的表达与PFS,OS的关系,P=0.446,P=0.022,6.4m vs 5.5m P=0.446,17m vs 11m P=0.022,总体生存多因素COX回归分析,RRM1 和BRCA1 mRNA表达水平对NSCLC一线接受含 铂双药治疗的疗效预测作用,2007.2月 to 2008.11月 IIIB/IV期 NSCLC Chemo-nave 重要脏器功能正常 无脑转移， 脊髓压迫,化疗前通过FOB, 穿刺，活检等方 法获取肿瘤标本 检测RRM1 及 BRCA1 mRNA 的表达,NP (N=40) GP(N=23) TP(N=26),DCR 79.6% PR 39.2% PD 19.4%,1线化疗方案,N=99,Taqman 探针,结果：基线特征,RRM1和BRCA1 mRNA与疗效之间的关系,健择组RRM1和BRCA1 mRNA与疗效之间的关系,抗微管组RRM1和BRCA1 mRNA与疗效间的关系,抗微管组BRCA1 mRNA表达水平与TTP间的关系,P=0.039,结 论,DNA修复基因ERCC1 118C/T或T/T多态性可以显著延长非小细胞肺癌患者