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1、,基于外周血EGFR突变检测临床意义的深度思考,王 洁 北京大学临床肿瘤学院 北京肿瘤医院,IPASS Study:Progression-free survival by EGFR mutation type (ITT population),Post-hoc Cox analysis with covariates p-values not calculated due to small patient numbers,Exon 19 deletion,L858R,Time from randomization (months),HR (95% CI) = 0.377 (0.255, 0.
2、560) No. events gefitinib, 46 (69.7%) No. events C/P, 65 (87.8%),Gefitinib (n=66) Carboplatin/paclitaxel (n=74),HR (95% CI) = 0.553 (0.352, 0.868) No. events gefitinib, 48 (75.0%) No. events C/P, 40 (85.1%),66,40,18,6,2,0,74,15,4,2,1,0,61,56,0,4,8,12,16,20,24,Gefitinib,C/P,Patients at risk :,64,30,1
3、3,5,1,0,47,17,2,0,0,0,48,39,0,4,8,12,16,20,24,0.0,0.2,0.4,0.6,0.8,1.0,Probability of progression-free survival,Gefitinib (n=64) Carboplatin/paclitaxel (n=47),Months,Months,0.0,0.2,0.4,0.6,0.8,1.0,Probability of progression-free survival,Median OS HR n (months) (95% CI) 217 27.0 22.731.3,SLOG Study:S
4、urvival in patients with EGFR mutation+ disease,1.0 0.8 0.6 0.4 0.2 0,Probability of PFS,0 12 24 36 48,Time (months),Median PFS HR n (months) (95% CI) 217 14.0 11.316.7,1.0 0.8 0.6 0.4 0.2 0,Probability of OS,0 12 24 36 48,Time (months),14.0,27.0,Rosell R, et al. N Eng J Med 2009;361:95867,Randomize
5、d Study on Japanese Population with EGFR Mutation: NEJGSG002,Kobayashi K, et al. 2009 ASCO Abstract 8016.,HR=0.357 95% CI: 0.252-0.507, P0.001,生物标记物检测的采样情况,Docetaxel Cisplatin,Gefitinib,Chemotherapy- nave stage IIIb/IV NSCLC; EGFR mutation (Exon 19 or 21); PS 02; Age 18y;,Progression Free Survival,R
6、 A N D O M I S E,1:1,Primary endpoint: PFS Secondary endpoint: OS; ORR; QOL; Safety,WJTOG 3405,Progression Free Survival,Overall Survival,外周血EGFR突变检测,患者血浆中有足够的游离DNA(是正常人的10倍)。 血浆中的游离DNA主要由凋亡和坏死的肿瘤细胞产 生，其遗传学特性与肿瘤基因组DNA相似。,CTC,CTC: NSCLC循环肿瘤 细胞-中位数74个/微升,蛋白组学:MALDI-MS,血浆/血清游离DNA,外周血EGFR突变检测与组织的一致性 (敏感
7、性与特异性)? 外周血EGFR突变检测能否预测疗效与生存?,血清/血浆游离DNA EGFR突变研究:争议的问题,Finding EGFR Mutation in Plasma DNA by PCR: Spanish Study,CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease,Rosell R, et al. N Eng J Med 2009;361:95867,*Evaluated in the serum of 164 patients,Evaluated
8、 in 197 patients,False Negative Rate,北京肿瘤医院的研究,230 pts with tumor samples for EGFR mutation analysis DHPLC performed in plasma 102 pts received gefitinib (second line),Bai and Wang JCO 27:2653, 2009,吻合度：78%,血浆DNA与原发瘤中EGFR突变的吻合度,False negative Rate=18.8%,False Positive Rate=20.2%,=,Bai and Wang JCO 2
9、7:2653, 2009,IPASS: Japanese Population,Patients recruited in Japan (n=233),cfDNA extracted from pre-dose serum samples,DNA extracted from paraffin-embedded archival tumor tissue,EGFR mutations detected by ARMS,EGFR M+: 1/21 mutationsa (n=46) EGFR M-: 0/21 mutations (n=148) EGFR M unknownc: (n=39),E
10、GFR M+: 1/29 mutationsb (n=56) EGFR M-: 0/29 mutations (n=35) EGFR M unknownc: (n=142),Comparison of cfDNA vs tumor tissue EGFR mutations based on 22 mutations analyzed for cfDNA,and/or,ESMO 2009,cfDNA,Tumor tissue,5 patients had a known mutation result by tumor tissue but not cfDNA 108 patients had
11、 a known mutation result by cfDNA but not by tumor tissue 86 patients had a known mutation status by both tumor tissue and cfDNA,IPASS:Comparison of EGFR mutation status in cfDNA and tumor samples,cfDNA, n EGFR M+ EGFR M- Total,22 29 51,0 35 35,EGFR M+,EGFR M-,22 64 86,Total,Tumor tissue, n,Patients
12、 with known cfDNA and tumor EGFR mutation status (n=86),No false positive results Specificity and positive predictive value 100% 29/51 (56.9%) of tumor EGFR M+ were cfDNA EGFR M- (false negatives) Sensitivity 43.1% (22/51), negative predictive value 54.7% (35/64) 57/86 (66.3%) concordance,Japanese I
13、TT population,False Positive Rate=0%,False negative Rate=57.7%,Plasma DNA as Predictive Biomarker in IPASS (Japanese Subgroup),Treatment by subgroup interaction test, p=0.0448,Japanese ITT population; Cox analysis HR 1 implies a lower risk of progression/death on gefitinib,0,0.0,0.2,0.4,0.6,0.8,1.0,
14、Probability of progression-free survival,4,8,12,16,20,24,0,0.0,0.2,0.4,0.6,0.8,1.0,4,8,12,16,20,24,HR (95% CI) = 0.29 (0.14, 0.60) p=0.0009,HR (95% CI) = 0.88 (0.61, 1.28) p=0.5013,EGFR M+,EGFR M-,24,12,4,2,0,0,22,4,1,0,0,0,21,15,Gefitinib,C/P,70,23,14,7,1,0,78,24,7,1,1,0,36,54,n Events, n (%),C/P 2
15、2 19 (86.4),n Events, n (%),C/P 78 67 (85.9),Patients at risk:,Months,Months,Gefitinib 24 15 (62.5),Gefitinib 70 51 (72.9),血清/血浆游离DNA EGFR突变临床预测意义研究,以上三组研究对外周血分析而言均为回顾性研究 且检测方法、病人基线条件不一。但结果显示若利用更加敏感的 检测方法，假阳性率较低。需前瞻性研究验证。,Wang, et al Clin.Can.Res. 2010,深度思考（I）,外周血与组织EGFR突变检测结果不一致的原因? 肿瘤组织内的异质性 原发灶与转
16、移灶的异质性,2009 WCLC, Okimi et al,患者,女,65岁,右下肺周围型低分化腺癌术后(IIb)3年肺内、脑转移。,2007.8 Iressa 治疗前 2009.5 Iressa治疗21个月后,深度思考（II）,治疗对EGFR突变状态有无影响?,疗前 44%,化疗前后EGFR突变的改变-来自北京肿瘤医院的报道,疗后 28%,疗前 35.7%,疗后 28.6%,深度思考（III）,什么是最佳的检测方法？,Comparison of Somatic Gene Mutation Analysis Methods,Jimeno et al. JCO 2008,未来方向,积极开展以外周血分子标志严格分层的前瞻多中心研究 建立规范化标准化系列分子检测平台 探索新的治疗靶基因及相关药物,THANKS!,
