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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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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. - PowerPoint PPT Presentation

Text of 基于外周血 EGFR 突变检测临床意义的深度思考

  • EGFR

  • 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 deletionL858RTime from randomization (months)HR (95% CI) = 0.377 (0.255, 0.560) 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%)

    66401862074154210615604812162024GefitinibC/PPatients at risk :643013510471720004839048121620240.00.20.40.60.81.0Probability of progression-free survivalGefitinib (n=64) Carboplatin/paclitaxel (n=47) MonthsMonths0.00.20.40.60.81.0Probability of progression-free survival

  • Median OSHR n (months)(95% CI)21727.022.731.3SLOG Study:Survival in patients with EGFR mutation+ disease1.00.80.60.40.20Probability of PFS012243648Time (months)Median PFSHR n (months)(95% CI)21714.011.316.71.00.80.60.40.20Probability of OS012243648Time (months)14.027.0Rosell R, et al. N Eng J Med 2009;361:95867

  • Randomized Study on Japanese Population with EGFR Mutation: NEJGSG002Kobayashi K, et al. 2009 ASCO Abstract 8016.HR=0.357 95% CI: 0.252-0.507, P
  • DocetaxelCisplatinGefitinibChemotherapy- nave stage IIIb/IV NSCLC; EGFR mutation (Exon 19 or 21); PS 02; Age 18y;Progression Free Survival R A N D O M I S E1:1Primary endpoint: PFSSecondary endpoint: OS; ORR; QOL; SafetyWJTOG 3405Progression Free SurvivalOverall Survival

  • EGFRDNA(10)DNA DNACTCCTC: NSCLC-74/:MALDI-MS/DNA

  • EGFR ()?EGFR?

    /DNA EGFR:

  • Finding EGFR Mutation in Plasma DNA by PCR: Spanish Study

    CR = complete response; PR = partial response; SD = stable disease; PD = progressive diseaseRosell R, et al. N Eng J Med2009;361:95867*Evaluated in the serum of 164 patientsEvaluated in 197 patients

    False Negative Rate

    Response (all patients) n (%)CR24 (12.2)PR115 (58.4)CR / PR139 (70.6)SD38 (19.3)PD20 (10.2)SD / PD58 (29.4)

    ValueErlotinib therapy, n (%) First-line Second- or third-line 113 (52.1) 104 (47.9)EGFR mutation, n (%) del 19 L858R 135 (62.2) 82 (37.8)EGFR mutation in serum, n (%)* del 19 L858R Not detected 64 (39.0) 33 (20.1) 67 (40.9)

  • 230 pts with tumor samples for EGFR mutation analysisDHPLC performed in plasma102 pts received gefitinib (second line)

    Bai and Wang JCO 27:2653, 2009

  • DNAEGFRFalse negativeRate=18.8%False PositiveRate=20.2%=Bai and Wang JCO 27:2653, 2009

  • IPASS: Japanese PopulationPatients recruited in Japan (n=233)cfDNA extracted from pre-dose serum samplesDNA extracted from paraffin-embedded archival tumor tissueEGFR mutations detected by ARMSEGFR M+: 1/21 mutationsa (n=46)EGFR M-: 0/21 mutations (n=148)EGFR M unknownc: (n=39)EGFR 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 cfDNAand/orESMO 2009cfDNATumor tissue5 patients had a known mutation result by tumor tissue but not cfDNA108 patients had a known mutation result by cfDNA but not by tumor tissue86 patients had a known mutation status by both tumor tissue and cfDNA

  • IPASS:Comparison of EGFR mutation statusin cfDNA and tumor samplescfDNA, n EGFR M+ EGFR M- Total

    2229 51

    0 3535EGFR M+EGFR M-

    226486TotalTumor tissue, nPatients 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%) concordanceJapanese ITT populationFalse PositiveRate=0%False negativeRate=57.7%

  • Plasma DNA as Predictive Biomarker in IPASS (Japanese Subgroup)Treatment by subgroup interaction test, p=0.0448Japanese ITT population; Cox analysisHR
  • /DNA EGFR

  • Wang, et al Clin.Can.Res. 2010,

  • IEGFR?

  • 2009 WCLC, Okimi et al

  • ,,65,(IIb)32007.8 Iressa 2009.5 Iressa21

  • IIEGFR?

  • 44%EGFR-28%35.7%28.6%

  • III

  • Comparison of Somatic Gene Mutation Analysis MethodsJimeno et al. JCO 2008

    MethodPrincipleSensitivity(MT/WT; %)TurnaroundDisadvantagesDirect SequencingNon-mutation-specific determination of test case nucleotide sequence and comparison with normal sequence20-50Slow turnaround (4 days to 2 weeks from paraffin)Poorly quantitativeInsensitiveProlonged turnaroundAllele specific probePolymerase chain reaction/selective detection10Rapid (

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