晚期非小细胞肺癌个体化治疗.pptx

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,0,晚期非小细胞肺癌个体化治疗,个体化治疗,定义,?,-,合适的药物，合适的剂量,合适的病人，合适的时间,-,涉及到寻找基因，基因组，和临床信息：准确地预测疾病,-,依赖于精确诊断方法和靶向治疗,-,不是剥夺病人治疗机会，而是，增加治疗成功率,可能优点有那些？,-,更加信息化治疗决策,-,较理想的治疗结果,-,减少副反应的风险,-,降低医疗费用,影响药物敏感性的因素,药物靶点的表型,taxane binding site on,tubulin,药物靶点的表达,不同,tubulin isoform,表达,药物,efflux,速度,P,糖蛋白的表达,药物代谢,肾脏清除速度,药物的生物依用度,药物运输增强可能克服药物的不敏感性,影响药物功能的细胞加工,细胞对,DNA,损伤的反应,Prognostic versus predictive biomarkers:they are not always the same,预后因子与预测因子,:,并不总是相同,预后因子,:,反映了疾病自然进程,(,如手术后生存期改变,),预测因子,:,反映 了治疗干预的作用,(,如,.,预测反应率和,/,或生存期：化疗或生物治疗后）,例如,:,乳癌的,HER2,状态,:,是预后差的因子，同时也是,truastuzumab,治疗受益的阳性预测因子,Factors used to individualized cancer treatment,Patients Factors,-age,sex,race,-PS,-Germline genetics,(SNP,CNV,mutation),-Co-morbidity,Tumor factors,-Size and stage,-Histopathology,-,生化功能,(PET scan),-,微环境,(,缺氧,血管生成）,-,蛋白表达,(IHC,蛋白组学,),-DNA,改变,(,突变,甲基化,),-RNA,表达,-,代谢产物,First line gefitinib for poor PS patients with EGFR mutations,入组条件,组织学或细胞学证实为,NSCLC,EGFR,突变：,19,外显子或,21,外显子,不能耐受化疗,20,74,岁：,PS 3,4,；,75,79,岁：,PS 2,4,；,80,岁：,PS 1,4,IIIB,IV,期，预计生存期,低BRCA1+高RRM2(32例）,Non-infmargin(1.,-依赖于精确诊断方法和靶向治疗,分期,XRCC1,与,XPD,突变数目,No.,MST(m),HR,95%CI,P,值,所有,0,1,2,3,26,40,24,13,20.4,16.6,11.0,6.8,1.0,0.75,1.38,2.72,0.41-1.38,0.73-2.63,1.31-5.67,0.009,III,期,0,1,2,3,16,22,11,7,35.0,25.9,15.2,6.3,1,1.34,3.27,4.28,0.58-3.1,1.28-8.40,1.47-12.51,0.004,IV,期,0,1,2,3,10,18,13,6,8.9,11.0,8.3,7.2,1,0.46,0.72,1.63,0.19-1.14,0.30-1.71,0.55-4.78,0.18,XPD,和,XRCC1,突变数目与,NSCLC,总体生存,Genetic polymorphisms correlate with OS in advanced NSCLC treated with taxol/carbo,药物基因组学,目标（前瞻性研究）,-,分析基因多态性与,PK/PD,参数间的关系,-,评价基因多态性与,OS,之间的关系,-119,例患者,基因型分析,-208,个基因的,5438,个,SNP,药物转运,/,代谢,Yamamoto et al.JCO 2008;8034a,结果,SNP,与,PK,、毒性和反应率无相关性,但,3,个,SNP,与生存期缩短相关,-SNP rs2267703 chr 7 TBXAS1 10,x10,5,-SNP rs4149525 chr 4 SUL T1E1 1.9x10,5,-SNP rs10999776 chr 10 SLC29A3 7.6x10,5,不明,-,这些,SNPs,是如何影响,OS,的,?,是不是只属于,carbo/taxol?,-,其它基因,SNP,的作用？,Predictive effects of ERCC1 and XRCC3 SNP on efficacy of platinum-based chemotherapy in advanced non-small cell lung cancer patients,Caicun Zhou,MD,Shengxiang Ren,MD,Songwen Zhou,MD,et alDepartment of Oncology,Shanghai Pulmonary Hospital,Tongji University,China,PASCO 2008,26(General Poster),The patients with ERCC1 118 C/T or T/T got better survival benefit from platinum-based chemotherapy,Phase III PC vs GC Trial:Study Design,R,N=1725,1,st,line treatment for advanced NSCLC,Primary endpoint:Overall survival(non-inferiority),Secondary endpoints:RR,Response duration,PFS,TTP,TTF,Tox,Scagliotti et al.WCLC 2007:PRS-03.,Pemetrexed 500 mg/m,2,+Cisplatin 75 mg/m,2,Gemcitabine 1250 mg/m,2,d 1,8+Cisplatin 75 mg/m,2,Q 3 weeks x 6 cycles,PC better,Non-infmargin(1.176),1.6,1.0,0.5,Hazard ratio,GC better,0.81 0.70;0.94,0.68 0.48;0.97,1.3 1.0,1.50,ADENO(847 pts),LARGE CELL(153 pts),SQUAMOUS(473 pts),UNKNOWN(252 pts),0.94 0.84;1.05,OVERALL(1725 pts),Scagliotti et al.WCLC 2007:PRS-03.,Overall Survival,ERCC1,既是预后因子，又是含铂方案化疗的受益预测因子,ERCC1,决定了顺铂引起,DNA,损伤后,DNA,修复,DNA,损伤和,DNA,修复之间的平衡决定顺铂处理后细胞是死亡还是生存？,ERCC1 mRNA,表达是预后因子（,Simon Chest 2005),ERCC1 mRNA,水平预测含铂方案的反应率（,58%vs 37%,p=0.03),和生存期（,p=0.009,Lord.CCR 2002),Phase III study of ERCC1 guided treatment in advanced NSCLC,Customizing platinum chemotherapy:response by ERCC1 profiling,多因素分析,Cobos,Gandara,Rosell.JCO 2007,Odds Ratio,（,85%CI,）,P,值,治疗组别,对照组,1,基因组,低表达组,高表达组,1.59,（,1.3,2.47,）,1.77,（,1.07,2.92,）,1.41,（。,082,2.43,）,0.02,0.03,0.22,ECOG PS 1,0,1,1.83,（,1.17,2.85,）,0.008,低,ERCC1,表达,Doc/cis,N=28,高ERCC1,表达,Doc/Gem or Cis,N=16,P,值,Response,SD,PD,8(28.6),2(7.1),8(50),3(18.8),NS,Response,CR+PR,SD+PD,18(64.3),10(35.7),5(31.3),11(68.8),0.06,中,位生存期,(mos,95%CI),Not reached,9.59(6.13-13.04),0.07,Median TTP(mos,95%CI),9.22(5.50-12.95),3.27(1.20-5.35),0.06,根据,ERCC1 mRNA,，个体化化疗,:,老年人结果,Prospective evaluation of RRM1 as a predictor of response to gem/carbo in NSCLC,MADe IT,Simon et al.ASCO 2007,MADeIT,13208,MADeIT,12621,GCb+,13303,PCb+,E4599,PCb+A,E1594,(all),Median Survival,13.3m,6.7m,10.6m,12.3m,8.0m,12-m Survival,59%,38%,43%,52%,33%,CR/PR,44%,24%,19%,35%,19%,Jco 2007;25:June 20,BRCA1 mRNA in Gem/Cis-Treated Stage IIIA N2 NSCLC,BRCA1 Functions,TC-NER,HR,NHEJ,Mitotic spindle assembly,JNK pathway,BRCA1,是预测因子也是预后因子,BRCA1 mRNA,N,MS,95%CI,P,0.28-0.61,15,NR,-,0.012,0.61-2.37,28,37.80,10.6-65,2.37-10.43,12,12.70,0-28.8,Time(months),Probability,BRCA1 mRNA expression,2.37-10.43,0.61-2.37,0.28-0.61,60,50,40,30,20,10,0,1.0,.9,.8,.7,.6,.5,.4,.3,.2,.1,SLA-Trial of customized treatment based on EGFR mutations and BRCA1 mRNA expression:ancillary analysis of Abraxax and RAP 90 expression,多中心前瞻性试验,188,例,120,例组织,93,例资料,BRCA1,复合物：铂类与抗微管类药物,RAP80,：进一步改善个体化,预先制定的其它分子分析,Rosell et al.JCO 2008;8073a,BRCA1,RAP 80,MST/TTP,P,低,低,中,高,10,5,5,NR,NR,6,0.16,高,低,中,高,3,10,2,8,4,0.003,低,低,中,高,3,10,8,2,8,4,0.003,肿瘤组织,BRCA1,RRM1,和,RRM2 mRNA,表达与多烯紫杉醇,/,吉西他滨一线晚期,NSCLC,的疗效,102,例未治疗过晚期,NSCLC,接受,/G,一线化疗,回顾性分析肿瘤组织内,BRCA1,RRM1,和,RRM2 mRNA,C.Papadaki,M.Trypaki,A.Koutsopoulos,et al.,J Clin Oncol,26:2008(May 20 suppl;abstr 8112),Response in gem/doc-treated stage IV NSCLC according to BRCA1 mRNA levels,CR+PR,P,单因素,OR,多因素,OR,BRCA1,T1,T2,T3,27.6%,13.8%,58.6%,0.002,0.31,0.13,1,0.03,0.001,0.54,0.22,1,0.40,0.05,RRM1,T1,T2,T3,41.4%,31%,27.6%,0.56,1,0.65,0.58,0.43,0.32,1,1.43,0.95,0.62,0.94,RRM2,T1,T2,T3,72.4%,24.1%,3.4%,0.001,1,0.13,0.02,0.001,0.001,1,0.20,0.02,0.02,低,BRCA1+,高,RRM1(n=18),高,BRCA1+,和低,RRM2(n=31):RR(p,低,BRCA1+,高,RRM2(32,例）,低,RRM1+RRM2(n=29):RR(p=0.001),和,TTP(p=0.002),高,RRM1+,高,RRM2,高,BRCA1+,低,RRM1+,低,RRM2(n=17):RR(p=0.007),和,TTP,低,BRCA1+,高,RRM1+,高,RRM2(n=14),-其它基因SNP的作用？,102例未治疗过晚期NSCLC,接受/G一线化疗,-不是剥夺病人治疗机会，而是，增加治疗成功率,First line gefitinib for poor PS patients with EGFR mutations,Rosell et al.,SLA-Trial of customized treatment based on EGFR mutations and BRCA1 mRNA expression:ancillary analysis of Abraxax and RAP 90 expression,-涉及到寻找基因，基因组，和临床信息：准确地预测疾病,Predictive effects of ERCC1 and XRCC3 SNP on efficacy of platinum-based chemotherapy in advanced non-small cell lung cancer patients,PASCO 2008;,Survival in Doc/Cis treated stage IV NSCLC pts with PS 0 according to ERCC1 C8092A SNP,PASCO 2006,DNA损伤和DNA修复之间的平衡决定顺铂处理后细胞是死亡还是生存？,-这些 SNPs是如何影响 OS的?,JCO 2008;8034a,个体治疗是否能进一步改善疗效?,-208个基因的5438个SNP药物转运/代谢,应用中困境,相关性不是,100%,多基因的影响，环境影响,需要建立微小样本检测方法,多为回顾性研究,根据,分法，可能意义更多,Personalized medicine in lung cancer,个体治疗是否能进一步改善疗效,?,-,更加有科学的治疗决策,Yes,-,更好的疗效,yes,-,减少治疗不利因素,-yes,-,降低治疗费用,could save time,-Importantly,this approach is feasible,-,随着更多靶向治疗的开发,个体化治疗将在治疗决策中发挥重要作用,-,我们将需要更多的组织，更多的分子病理,谢谢大家,个体化治疗,定义,?,-,合适的药物，合适的剂量,合适的病人，合适的时间,-,涉及到寻找基因，基因组，和临床信息：准确地预测疾病,-,依赖于精确诊断方法和靶向治疗,-,不是剥夺病人治疗机会，而是，增加治疗成功率,可能优点有那些？,-,更加信息化治疗决策,-,较理想的治疗结果,-,减少副反应的风险,-,降低医疗费用,Efficacy,CR 3%,PR 62%,SD 24%,PD 7%,NE 3%,PFS 6.5m,1YS 63%;PS 1-2 vs PS 3-4:no difference,Survival in Doc/Cis treated stage IV NSCLC pts with PS 0 according to ERCC1 C8092A SNP,Taron et al.PASCO 2006,P=0.05,Predictive effects of ERCC1 and XRCC3 SNP on efficacy of platinum-based chemotherapy in advanced non-small cell lung cancer patients,Caicun Zhou,MD,Shengxiang Ren,MD,Songwen Zhou,MD,et alDepartment of Oncology,Shanghai Pulmonary Hospital,Tongji University,China,PASCO 2008,26(General Poster),Phase III study of ERCC1 guided treatment in advanced NSCLC,MADeIT,13208,MADeIT,12621,GCb+,13303,PCb+,E4599,PCb+A,E1594,(all),Median Survival,13.3m,6.7m,10.6m,12.3m,8.0m,12-m Survival,59%,38%,43%,52%,33%,CR/PR,44%,24%,19%,35%,19%,Jco 2007;25:June 20,