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基于外周血 EGFR 突变检测临床意义的深度思考

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). Exon 19 deletion. L858R. Gefitinib (n=66) Carboplatin/paclitaxel (n=74). Gefitinib (n=64) Carboplatin/paclitaxel (n=47). 1.0. 1.0.

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基于外周血 EGFR 突变检测临床意义的深度思考

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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

  2. IPASS Study:Progression-free survival by EGFR mutation type (ITT population) Exon 19 deletion L858R Gefitinib (n=66)Carboplatin/paclitaxel (n=74) Gefitinib (n=64)Carboplatin/paclitaxel (n=47) 1.0 1.0 HR (95% CI) = 0.377 (0.255, 0.560) No. events gefitinib, 46 (69.7%)No. events C/P, 65 (87.8%) HR (95% CI) = 0.553 (0.352, 0.868)No. events gefitinib, 48 (75.0%)No. events C/P, 40 (85.1%) 0.8 0.8 0.6 0.6 Probability of progression-free survival Probability of progression-free survival 0.4 0.4 0.2 0.2 0.0 0.0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Months Months Patients at risk : Gefitinib 66 61 40 18 6 2 0 64 48 30 13 5 1 0 C/P 74 56 15 4 2 1 0 47 39 17 2 0 0 0 Time from randomization (months) Post-hoc Cox analysis with covariatesp-values not calculated due to small patient numbers

  3. SLOG Study:Survival in patients with EGFR mutation+ disease Median PFS HR n (months) (95% CI) 217 14.0 11.3–16.7 Median OS HR n (months) (95% CI) 217 27.0 22.7–31.3 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 Probability of OS Probability of PFS 14.0 27.0 0 12 24 36 48 0 12 24 36 48 Time (months) Time (months) Rosell R, et al. N Eng J Med 2009;361:958–67

  4. Randomized Study on Japanese Population with EGFR Mutation: NEJGSG002 HR=0.357 95% CI: 0.252-0.507, P<0.001 Kobayashi K, et al. 2009 ASCO Abstract 8016.

  5. 生物标记物检测的采样情况 • 不可评估的主要原因包括： • 取样困难 • 样本量不足 • 只有细胞学样本 • 样本取材于肿瘤外的其他部位 1217 随机患者(100%) 1038 同意检测生物标记物 (85%) 683 提供样本 (56%) 可评估的: EGFR 突变: 437 (36%) EGFR 基因表达数目: 406 (33%) EGFR 表达: 365 (30%)

  6. WJTOG 3405 • Chemotherapy- • naïve stage IIIb/IV • NSCLC; • EGFR mutation • (Exon 19 or 21); • PS 0–2; • Age ≥18y; R A N D O M I S E Gefitinib Progression Free Survival Docetaxel Cisplatin 1:1 Progression Free Survival Overall Survival • Primary endpoint: PFS • Secondary endpoint: OS; ORR; QOL; Safety

  7. 外周血EGFR突变检测 血浆/血清游离DNA • 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: NSCLC循环肿瘤 细胞-中位数74个/微升 • CTC 蛋白组学:MALDI-MS

  8. 血清/血浆游离DNA EGFR突变研究:争议的问题 • 外周血EGFR突变检测与组织的一致性 (敏感性与特异性)? • 外周血EGFR突变检测能否预测疗效与生存?

  9. Finding EGFR Mutation in Plasma DNA by PCR: Spanish Study ‡Evaluated in 197 patients False Negative Rate *Evaluated in the serum of 164 patients CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease Rosell R, et al. N Eng J Med 2009;361:958–67

  10. 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

  11. 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% 吻合度：78% = Bai and Wang JCO 27:2653, 2009

  12. IPASS: Japanese Population Patients recruited in Japan (n=233) DNA extracted from paraffin-embedded archival tumor tissue cfDNA extracted from pre-dose serum samples and/or EGFR mutations detected by ARMS cfDNA Tumor tissue EGFR M+: 1/29 mutationsb (n=56) EGFR M-: 0/29 mutations (n=35) EGFR M unknownc: (n=142) EGFR M+: 1/21 mutationsa (n=46) EGFR M-: 0/21 mutations (n=148) EGFR M unknownc: (n=39) Comparison of cfDNA vs tumor tissue EGFR mutations based on 22 mutations analyzed for cfDNA ESMO 2009 • 5 patients had a known mutation result by tumor tissue but not cfDNA • 108 patients had a known mutation result by cfDNA but not by tumor tissue • 86 patients had a known mutation status by both tumor tissue and cfDNA

  13. IPASS:Comparison of EGFR mutation statusin cfDNA and tumor samples Patients with known cfDNA and tumorEGFR mutation status (n=86) Tumor tissue, n EGFR M+ EGFR M- Total cfDNA, n EGFR M+ EGFR M- Total 22 29 51 22 64 86 0 35 35 False Positive Rate=0% False negative Rate=57.7% • 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 ITT population

  14. Plasma DNA as Predictive Biomarker in IPASS (Japanese Subgroup) EGFR M+ EGFR M- 1.0 1.0 HR (95% CI) = 0.29 (0.14, 0.60) p=0.0009 HR (95% CI) = 0.88 (0.61, 1.28) p=0.5013 0.8 0.8 0.6 0.6 Probability of progression-free survival 0.4 0.4 0.2 0.2 0.0 0.0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Months Months Patients at risk: Gefitinib 24 21 4 2 0 0 70 36 14 7 1 0 12 23 22 15 4 1 0 0 0 78 54 24 7 1 1 0 C/P Gefitinib 70 51 (72.9) C/P 78 67 (85.9) n Events, n (%) Gefitinib 24 15 (62.5) C/P 22 19 (86.4) n Events, n (%) Treatment by subgroup interaction test, p=0.0448 Japanese ITT population; Cox analysis HR <1 implies a lower risk of progression/death on gefitinib

  15. 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。

  16. Wang, et al Clin.Can.Res. 2010,

  17. 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 原发灶与转移灶的异质性

  18. 2009 WCLC, Okimi et al

  19. 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。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

  20. 深度思考（II） • 治疗对EGFR突变状态有无影响?

  21. 化疗前后EGFR突变的改变-来自北京肿瘤医院的报道化疗前后EGFR突变的改变-来自北京肿瘤医院的报道 疗前 35.7% 疗后 28.6% 疗前 44% 疗后 28%

  22. 深度思考（III） • 什么是最佳的检测方法？

  23. Comparison of Somatic Gene Mutation Analysis Methods Jimeno et al. JCO 2008

  24. 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!

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