血液中的肺癌診斷課件

1、血液中的肺癌診斷方案洪群英 復(fù)旦大學(xué)附屬中山醫(yī)院 第2頁 2016 Roche肺癌篩查與初次評估診斷與鑒別診斷 H&E根據(jù)形態(tài)學(xué)分類 IHC亞型 (30%的病例需要）非小細(xì)胞肺癌小細(xì)胞肺癌腺癌鱗癌I/II期III/IV期I/II期III/IV期 EGFR+ ALK +所有分期TKI治療根據(jù)耐藥機(jī)制選擇后續(xù)治療策略手術(shù)療效監(jiān)控&耐藥機(jī)制分析影像TM組合（CEA, CYFRA21-1, NSE,ProGRP）根據(jù)最初主要升高的標(biāo)志物用血清學(xué)項目進(jìn)行療效監(jiān)測進(jìn)展監(jiān)測（影像、TM）若EGFR/ALK陰性監(jiān)測肺癌的動態(tài)檢測，將為全面理解疾病發(fā)展動態(tài)和異質(zhì)性提供窗口LDCTCTTM組合（CEA, CYFR

2、A21-1, NSE, SCC, ProGRP）臨床TNM分期BIOPSY頭顱MRI、骨掃描、腹部CT等？癌治療化學(xué)治療放療有效的個體化腫瘤診斷依賴于組織學(xué)診斷和血清/血漿診斷的互補(bǔ)第3頁 2016 Roche原發(fā)腫瘤（早期）晚期腫瘤早期復(fù)發(fā)檢測診斷預(yù)后預(yù)測治療監(jiān)測預(yù)后預(yù)測手術(shù)輔助治療內(nèi)科治療2內(nèi)科治療1組織學(xué)診斷02004006008001000血清/血漿診斷診斷預(yù)后預(yù)測預(yù)后預(yù)測動態(tài)時間+肺癌全程管理面臨的挑戰(zhàn)&羅氏診斷肺癌血清標(biāo)記物解決方案第4頁 2016 Roche是否存在高危風(fēng)險？是肺癌嗎？腫瘤類型是什么？能檢測復(fù)發(fā)嗎？治療有效嗎？80%的發(fā)現(xiàn)是良性的LDCTs數(shù)目增加 醫(yī)?；ㄙM(fèi)負(fù)擔(dān)增

3、加活檢并非適用于所有人混合組織類型復(fù)發(fā)的檢測可能延遲暴露于輻射隨訪費(fèi)用高可能無法發(fā)現(xiàn)病理類型轉(zhuǎn)換早期篩查結(jié)節(jié)管理診斷鑒別診斷I/II期手術(shù)化療和/或靶向治療生物標(biāo)志物界面*ProGRPCobas EGFR監(jiān)測平臺標(biāo)志物組合SCLCNSCLCProGRP標(biāo)志物組合血液中的肺癌診斷方案血清腫瘤標(biāo)記物：血液中的肺癌“足跡”footprintNSCLC最敏感的TM主要在鱗癌和腺癌中表達(dá)，但沒有明確相關(guān)的組織學(xué)類型CYFRA21-1 細(xì)胞角蛋白片段19(維持上皮細(xì)胞穩(wěn)定的結(jié)構(gòu)蛋白)用于SCLC的輔助診斷，但敏感性較低溶血樣本中存在假陽性NSE 神經(jīng)元特異性烯醇化酶(葡萄糖代謝酶)在NSCLC中占主導(dǎo)地位

4、主要在鱗狀細(xì)胞癌中表達(dá)SCC 鱗狀細(xì)胞癌抗原(糖蛋白，蛋白酶抑制劑)SCLC的首選TM，ProGRP與NSE互補(bǔ)腎功能衰竭中存在假陽性ProGRP 胃泌素釋放肽前體(神經(jīng)內(nèi)分泌激素)大多在腺癌中升高，在NSCLC中也升高在鱗癌中的濃度最低CEA 癌胚抗原Molina R. ProGRP: A new biomarker for small cell lung cancer. EJCMO 2009; 1: 25-32.R. Molina et al. Assessment of a combined panel of six serum tumor markers for lung cancer

5、. AJRCCM 2016NSCLCSCLC可用于肺癌的主要血清腫瘤標(biāo)志物血清腫瘤標(biāo)志物增高的鑒別診斷什么時候能采用血清腫瘤標(biāo)志物？時間手術(shù)原發(fā)腫瘤CTx2CTx1復(fù)發(fā)/轉(zhuǎn)移個體化基線值是解讀腫瘤標(biāo)志物動態(tài)改變的基礎(chǔ)治療對照在首程治療前開始腫瘤標(biāo)志物下降 - 到達(dá)半衰期后 - 有效手術(shù)或治療后每位患者應(yīng)確立個體基線值A(chǔ)dj CTx濃度個體化基線值02004006008001000“正?！敝祻?fù)發(fā)使腫瘤標(biāo)志物濃度上升，標(biāo)志物的上升速度預(yù)示腫瘤進(jìn)展和復(fù)發(fā)如果數(shù)值在參考范圍內(nèi)，每名患者的腫瘤標(biāo)志物無需“正?！?。第7頁 2016 RocheElecsys ProGRP（胃泌素釋放肽前體）在肺癌鑒別診斷中

6、的應(yīng)用組織學(xué)類型鑒別診斷明確鑒別SCLC和NSCLC第8頁 2016 RocheSCLC vs. NSCLC 以及 vs. 良性肺部疾病80pg/mlNSCLC隊列中特異度穩(wěn)定在95%臨界值SCLC vs. NSCLC鑒別診斷ProGRP可以作為獨(dú)立鑒別SCLC和NSCLC的診斷指標(biāo)背景：在歐洲和中國進(jìn)行多中心研究評估Elecsys 免疫分析檢測ProGRP方法：在3個歐洲國家和2個中國中心中評估肺癌檢測的方法結(jié)果：SCLC和NSCLC中ProGRP水平差異顯著，與種族、年齡、性別、吸煙狀態(tài)無顯著相關(guān)，中位ProGRP濃度在良性疾?。?38pg/mL ）、其它惡性疾?。?40pg/mL ）、或

7、NSCLC（ 39pg/mL ）中較低，除外慢性腎疾病3級（100pg/mL）。Clinica Chimica Acta 438 (2015) 388395鑒別診斷ProGRP在84 pg /mL，可以獨(dú)立作為NSCLC 和SCLC的鑒別診斷指標(biāo)，其敏感度為78%，特異度為95%EGFR-TKI治療前無病理診斷及基因狀態(tài)分析61歲女性患者言語不利伴多發(fā)骨痛3月胸部CT示右肺上葉腫塊4.5cmX3.0cm頭顱增強(qiáng)MRI示多發(fā)結(jié)節(jié)影，骨掃描示多發(fā)骨轉(zhuǎn)移外院擬診“肺癌腦骨轉(zhuǎn)移”予EGFR-TKI治療三月余，仍訴骨痛CEA 2.8 ng/mLCYFRA 6.1 ng/mLProGRP 155.7 pg

8、/mLNSE 235.2ng/mLProGRP有助于明確EGFR-TKI耐藥后轉(zhuǎn)化SCLC52歲女性患者肺腺癌患者經(jīng)EGFR-TKI治療耐藥后第二次活檢標(biāo)本顯示為SCLC，經(jīng)SCLC標(biāo)準(zhǔn)治療后療效好輔助診斷Watanabe S, et al. Lung Cancer. 2013 Nov;82(2):370-2.順鉑+培美曲塞6 x cycle厄洛替尼卡鉑依托泊苷2010.11CEA 23.5 ng/mLCYFRA 3.3 ng/mL2011.08CEA 11.9 ng/mLCYFRA 4.7 ng/mLProGRP 82.8 pg/mLNSE 19.9 ng/mL2012.07CEA 11.3

9、 ng/mLCYFRA 2.2 ng/mLProGRP 142.8 pg/mLNSE 29.2 ng/mLProGRP有助于明確腫瘤異質(zhì)性-158歲女性，體檢發(fā)現(xiàn)CEA升高約15ng/mlPET-CT：1.右肺中葉MT伴縱隔淋巴結(jié)、肝臟、胰尾部和多處骨骼轉(zhuǎn)移；左側(cè)腎上腺糖代謝增高，請隨訪除外轉(zhuǎn)移。2.右下腹和左側(cè)臀部皮下良性結(jié)節(jié)可能，轉(zhuǎn)移不除外，請結(jié)合臨床。經(jīng)支氣管鏡右肺中葉活檢病理為：低分化癌，傾向低分化腺癌。免疫組化：P63（弱+), P40(-), C-MET(+),Ki-67(80%陽性 )2016年11月12日起給予厄洛替尼治療。 治療。輔助診斷2016.112017.022017.

10、022016.11CEA 162.7 ng/mLCYFRA 10.8 ng/mLProGRP 5000 pg/mLNSE 242.6 ng/mL輔助診斷ProGRP有助于明確腫瘤異質(zhì)性-2差分化惡性腫瘤Ki-67（80%+）Syn +TTF-1 +全身多發(fā)皮下結(jié)節(jié)增多增大符合轉(zhuǎn)移性小細(xì)胞癌：CK(+),Ki-67(80%+),NapsinA(-),TTF-1(+),CD56(+),CHG(+),Syn(+),CD117(+),NSE(+),P40(-)SynElecsys ProGRP用于SCLC治療監(jiān)測以研究中一名患者為例ProGRP的動力學(xué)能實現(xiàn)有效治療監(jiān)測研究設(shè)計研究ProGRP與CT的

11、關(guān)系Korse et al; Clin Chim Acta.2015;438:388-95療效監(jiān)測V = 就診，PR = 部分緩解，SD = 疾病穩(wěn)定，PD = 疾病進(jìn)展采用標(biāo)準(zhǔn)化療的SCLC患者采用Elecsys ProGRP試劑盒分別檢測療前（基線）和療中的血清或血漿樣本的ProGRP水平根據(jù)RECIST標(biāo)準(zhǔn)完成治療反應(yīng)評估原發(fā)性肺癌診療規(guī)范(2015版)輔助診斷NSE和ProGRP是診斷SCLC的理想指標(biāo)CEA、SCC和CYFRA21-1水平升高有助于NSCLC的診斷一般推薦上述腫瘤標(biāo)志物聯(lián)合應(yīng)用，可提高鑒別SCLC和NSCLC的準(zhǔn)確率療效監(jiān)測治療前（包括手術(shù)前、化療前、放療前和分子靶向

12、治療前）需要進(jìn)行首次監(jiān)測，選擇對患者敏感的23種腫瘤標(biāo)志物作為治療后療效觀察的指標(biāo)?；颊咴诮邮苁状沃委熀?，根據(jù)腫瘤標(biāo)志物半衰期的不同可再次檢測。隨訪觀察治療后頭3年：每3個月檢測1次；35年： 每半年1次；5年以后：每年1次隨訪中若發(fā)現(xiàn)腫瘤標(biāo)志物明顯升高（高出首次隨訪值25%），應(yīng)在1個月內(nèi)復(fù)測1次，如果仍然升高，則提示可能復(fù)發(fā)或者存在轉(zhuǎn)移。中華腫瘤雜志2015 年 1 月第 37 卷第 1 期血液中的肺癌診斷方案液態(tài)活檢 ：Doing more with lessFigure 1 Various classes of tumour heterogeneity in adenocarcinom

13、a of the lung腫瘤的動態(tài)檢測，將為全面理解異質(zhì)性和腫瘤的發(fā)展動態(tài)提供窗口Mitsudomi, T. et al. (2013Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2013.22基因分型指導(dǎo)的個體化治療對指導(dǎo)用藥至關(guān)重要肺腺癌人群經(jīng)驅(qū)動基因篩選分類檢測結(jié)果指導(dǎo)用藥TKI治療過程中動態(tài)監(jiān)測理解單個病人耐藥機(jī)制變化血液中的腫瘤標(biāo)志物游離循環(huán) DNA (cfDNA)循環(huán)腫瘤細(xì)胞 (CTCs)外泌體Tissue is still the issue：我們需要非侵入性的，更簡便的活檢方法液態(tài)活檢應(yīng)用場景：組織標(biāo)本不足組織標(biāo)本中缺少腫瘤細(xì)胞難以

14、穿刺獲取組織標(biāo)本需要動態(tài)監(jiān)測ctDNA應(yīng)用于腫瘤早期診斷，復(fù)發(fā)，和耐藥監(jiān)測早期診斷復(fù)發(fā)耐藥動態(tài)監(jiān)測 Luis A. Diaz Jr and Alberto Bardelli J Clin Oncol 32:579-586. 2014Crowley, E. et al. Nat. Rev. Clin. Oncol. 10, 472484 (2013)來源：在細(xì)胞凋亡過程中產(chǎn)生的DNA片段釋放入血（CfDNA）；cfDNA片段長度通常是160-180bp；來源于腫瘤細(xì)胞的DNA片段是ctDNA；原發(fā)灶，轉(zhuǎn)移灶，和CTC都可能釋放出游離DNActDNA檢測技術(shù)與敏感性McLarty et al MO

15、J Cell Science & Report 2015ARMs and Cobas Methods：敏感性： 50 70；特異性： 95100AURA3 plasma ctDNA analysis : 在50%組織檢測T790m的患者血漿中，檢測到T790m ( cobas EGFR Mutation Test (RMS)*Percent agreement of the cobas plasma test with the cobas tissue test. Positive percent agreement and negative percent agreement are use

16、d here as measures of test sensitivity and specificity, respectively, and calculated with invalid results excluded.CI, confidence interval; Ex19del, Exon 19 deletion.Plasma ctDNA test results, n Tissue T790M positive (n=399)Tissue Ex19del positive (n=427)Tissue L858R positive (n=253)Plasma positive1

17、84273139Plasma negative1756067No plasma test / invalid37 / 391 / 347 / 0Percent agreement using tissue test as reference, % (95% CI)*T790MEx19delL858RPositive percent agreement (sensitivity)51 (46, 57)82 (77, 86)68 (61, 74) Negative percent agreement (specificity)77 (71, 83)98 (96, 100)99 (98, 100)O

18、verall concordance61 (57, 65)89 (86, 91)88 (85, 90)51% sensitivity and 77% specificity for T790M detection using cobas tissue test as referenceHigh sensitivity and specificity is observed for Exon 19 deletion and L858RPatients with tissue sample available at screening (n=756)abstract MA08.03, presen

19、ted by WU YL at WCLC 2016AURA3: 血漿檢測T790m陽性患者接受osimertinib治療的療效與組織檢測陽性者一致Tick marks indicate censored data. PFS is defined as time from randomisation until date of objective disease progression or death. Progression included deaths in the absence of RECIST progression. Osimertinib administered 80 mg

20、 orally once daily. Platinum-pemetrexed group treatment consisted of: pemetrexed 500 mg/m2 + carboplatin AUC5 or cisplatin 75 mg/m2 Q3W for up to 6 cycles + optional maintenance pemetrexed for patients whose disease had not progressed after 4 cycles of platinum-pemetrexed. RECIST v1.1 assessments pe

21、rformed every 6 weeks until objective disease progression.*PFS adjusted for ethnicity. All patients were selected using a tumour tissue test for EGFR T790M (by cobas EGFR Mutation Test) from a biopsy after disease progression prior to study entry; Response did not require confirmation per RECIST v1.

22、1; HR, hazard ratio; ORR, objective response rate; PFS, progression-free survival; Q3W, once every 3 weeks; RECIST, Response Evaluation Criteria In Solid Tumors.Tumour T790M-positive (intent-to-treat)*Plasma T790M-positive statusOsimertinibPlatinum-pemetrexedPFS HR (95% CI)0.42 (0.29, 0.61) Median P

23、FS, months (95% CI)8.2 (6.8, 9.7) 4.2 (4.1, 5.1)ORR, % (95% CI)77 (68, 84)39 (27, 53)OsimertinibPlatinum-pemetrexedPFS HR (95% CI)0.30 (0.23, 0.41)*, p0.001Median PFS, months (95% CI)10.1 (8.3, 12.3)4.4 (4.2, 5.6) ORR, % (95% CI)71 (65, 76)31 (24, 40)No. at riskOsimertinib1.00.80.60.40.200369121518M

24、onths2791402409316244881750713100Osimertinib (n=279)Platinum-pemetrexed (n=140)No. at riskOsimertinibPlatinum-pemetrexedPlatinum-pemetrexed1.00.80.60.40.20036912151811656953963133552025100MonthsOsimertinib (n=116)Platinum-pemetrexed (n=56)Probability of progression-free survivalProbability of progre

25、ssion-free survivalProbability of progression-free survival血漿檢測T790m陽性患者接受osimertinib治療的ORR與組織檢測陽性者一致（77% VS 71%）Best percentage change in target lesion size is the maximum reduction from baseline or the minimum increase. *Represents imputed values: if it is known that the patient has died, has new

26、lesions or progression of assessments, best change will be imputed as 20%; All patients were selected using a tumour tissue test for EGFR T790M (by cobas EGFR Mutation Test) from a biopsy after disease progression prior to study entry.150-251251007550250-50-75Best change from baseline in target lesi

27、on size (%)*-100Tumour T790M positive (intent-to-treat)Osimertinib (n=279)ORR 71% (95% CI 65, 76)Plasma T790M positiveOsimertinib (n=116)ORR 77% (95% CI 68, 84)150-251251007550250-50-75Best change from baseline in target lesion size (%)-100*abstract MA08.03, presented by WU YL at WCLC 2016 在50%組織檢測T

28、790m的患者血漿中，檢測到T790m 血漿檢測T790m陽性患者接受osimertinib治療的療效與組織檢測陽性者一致組織與血漿檢測T790m檢測率的差異，提示有必要在血漿檢測陰性的患者中考慮再次組織活檢AURA3 plasma ctDNA analysisabstract MA08.03, presented by WU YL at WCLC 2016cobas EGFR Mutation Test (RMS)Primary endpointProgression-free survival (PFS)Secondary endpointsObjective response rateO

29、verall survival (OS)Location of progressionSafetyEGFR mutation analysis in serumQuality of lifeECOG = Eastern Cooperative Oncology Group; PS = performance status; PD = progressive disease*Cisplatin 75mg/m2 d1 / docetaxel 75mg/m2 d1; cisplatin 75mg/m2 d1 / gemcitabine 1250mg/m2 d1,8;carboplatin AUC6

30、d1 / docetaxel 75mg/m2 d1; carboplatin AUC5 d1 / gemcitabine 1000mg/m2 d1,8Stage IIIB/IV NSCLCEGFR exon 19 deletion or exon 21 L858R mutation (DNA sequencing/Genescan and Taqman)ChemonaiveECOG PS 02Measurable or evaluable diseaseRPDErlotinib 150 mg/dayPDStratificationMutation typeECOG PS (0 vs 1 vs

31、2)Platinum-based doublet chemotherapy q3wks x 4 cycles*評估應(yīng)用cfDNA作為EGFR狀態(tài)的診斷替代樣本，以及經(jīng)cfDNA檢測的EGFR狀態(tài)與臨床轉(zhuǎn)歸的關(guān)系A(chǔ)ssociation of EGFR L858R Mutation in Circulating Free DNA With Survival in the EURTAC Trial cfDNA檢測的EGFR L858R突變狀態(tài)與OS的關(guān)系：EURTAC 分析JAMA Oncol. 2015;1(2):149-157. 97例血液樣本可供進(jìn)行突變狀態(tài)分析（組織/血液）：19del（56

32、/47），L858R（41/29）JAMA Oncol. 2015;1(2):149-157. 組織和血漿同時檢出19Del接受厄洛替尼治療OS達(dá)到34.4月，顯著優(yōu)于化療組 19.9月（p0.001）組織和血漿同時檢出L858R接受厄洛替尼治療OS達(dá)到13.7月，顯著優(yōu)于化療組 12.6月（p0.001）中位隨訪時間49.4m（截止到2013年9月）Overall Survival According to Epidermal Growth Factor (EGFR) Mutation Status in Tissue and in Circulating Free DNA (cfDNA)：

33、A, In all 97 patients according to type of mutation in tissue. B, In all 97 patients according to type of mutation in cfDNA 在全組97例中，組織檢測19Del患者OS顯著優(yōu)于L858R（24.9m vs 17.7m，P=0.006），cfDNA檢測出19del患者OS同樣顯著優(yōu)于L858R（30.3m vs 13.7m，P0.001）OS=24.9mOS=17.7mOS=30.3mOS=13.7mOverall Survival According to Epiderma

34、l Growth Factor (EGFR) Mutation Status in Tissue and in Circulating Free DNA (cfDNA)：C, In the 40 patients with mutations detected in cfDNA who received erlotinib, according to type of mutation in cfDNA. D, In the 41 patients with the L858R mutation in tissue according to the EGFR L858R mutation in

35、cfDNA (detected vs not detected). 接受厄洛替尼治療的患者中（N=40），cfDNA檢測出19del患者OS顯著優(yōu)于L858R（34.4m vs 13.7m，P=0.01）；在41例L858R組織檢測陽性患者中，cfDNA檢測陽性患者OS最短（13.7m）OS=13.7mOS=34.4m血清cfDNA檢測L858R和19DEL能夠作為療效預(yù)測因子組織/血清cfDNA檢測19del患者，能夠從厄洛替尼治療中獲得長達(dá)34.4個月的長期生存組織/血清cfDNA檢測L858R患者，生存時間較短，這一結(jié)果提示有必要對這部分亞組人群探索聯(lián)合治療的必要性Association

36、 of EGFR L858R Mutation in Circulating Free DNA With Survival in the EURTAC Trial cfDNA檢測的EGFR L858R突變狀態(tài)與OS的關(guān)系：EURTAC 分析該研究中使用的檢測為TaqManThe ASSESS study 大型的，歐洲和日本多中心，非干預(yù)性研究，評估ctDNA在EGFR檢測中的真實世界應(yīng)用Patients Patients were enrolled from Japan (n=300), France (n=145), Germany (n=346), Italy (n=259), Nethe

37、rlands (n=27), Spain (n=158), Sweden (n=17), UK (n=59) Inclusion criteria Patients with newly diagnosed, locally advanced (stage IIIA / B) / metastatic chemotherapy-nave NSCLC not suitable for curative treatmenta or Recurrent disease after surgical resection with / without adjuvant chemotherapy Samp

38、les Provision of tumor and plasma samples for EGFR mutation testing Clinical guidelines recommend2: Mutation test turnaround time within 2 weeks Sensitive testing methods (10% tumor cell content) Immunohistochemistry to establish histological lineage No specific recommendations for blood testing Con

39、cordance between EGFR mutation status obtained via tissue / cytology and blood (plasma)-based testing Secondary (included) EGFR mutation testing practices (tumor samples tested according to local practices) aIncluding surgery and chemoradiotherapy ctDNA, circulating free tumor-derived DNA; WHO, Worl

40、d Health Organization 1. Reck et al. 2015; 2. Lindeman 2013 WCLC大樣本真實世界驅(qū)動基因檢測實踐將ctDNA應(yīng)用于真實世界EGFR檢測Martin Reck , et al . Journal of Thoracic Oncology, Volume 11, Issue 10, 2016, 16821689ASSESS，大型的，歐洲和日本多中心，非干預(yù)性研究，評估ctDNA在EGFR檢測中的真實世界應(yīng)用結(jié)果 ：組織與血漿檢測方法CharacteristicConcordance RateSensitivitySpecificityP

41、PVNPVn/n (%)95% CIn/n (%)95% CIn/n (%)95% CIn/n (%)95% CIn/n (%)95% CIOverall (n= 1162)1035 of 1162 (89)87.190.887 of 189 (46)38.853.4948 of 973 (97)96.298.387 of 112 (78)68.885.0948 of 1050 (90)88.392.0Japan (n= 281)227 of 281 (81)75.785.234 of 86 (40)29.250.7193 of 195 (99)96.399.934 of 36 (94)81.

42、399.3193 of 245 (79)73.183.7Europe (n= 881)808 of 881 (92)89.793.453 of 103 (51)41.461.4755 of 778 (97)95.698.153 of 76 (70)58.179.8755 of 805 (94)91.995.4Qiagen therascreen EGFR RGQ PCR Kit (n= 138)131 of 138 (95)89.897.916 of 22 (73)49.889.3115 of 116 (99)95.310016 of 17 (94)71.399.9115 of 121 (95

43、)89.598.2Roche cobas EGFR Mutation Test (n= 23)22 of 23 (96)78.199.93 of 4 (75)19.499.419 of 19 (100)82.41003 of 3 (100)29.210019 of 20 (95)75.1100Cycleave (n= 190)161 of 190 (85)78.889.529 of 57 (51)37.364.4132 of 133 (99)95.910029 of 30 (97)82.899.9132 of 160 (83)75.588.0PNA-LNA PCR Clampa (n= 91)

44、76 of 91 (84)74.390.515 of 29 (52)32.570.661 of 62 (98)91.310015 of 16 (94)69.899.861 of 75 (81)70.789.4EGFR突變狀態(tài)在組織/細(xì)胞學(xué)標(biāo)本與血漿標(biāo)本之間的一致性（有配對組織/細(xì)胞學(xué)標(biāo)本）PPV, positive predictive value; NPV, negative predictive value; CI, confidence interval; RGQ, Rotor-Gene Q; PCR, polymerase chain reaction; PNA-LNA, peptid

45、e nucleic acid-locked nucleic acid; ctDNA, circulating free tumor-derived DNA.aPNA-LNA PCR Clamp concordance data using optimized ctDNA extraction procedure血漿ctDNA能夠作為分子病理檢測的可靠標(biāo)本（與組織/細(xì)胞學(xué)突變狀態(tài)匹配度89%），血漿ctDNA陽性可以作為TKI治療指征78%PPV（positive predict value)可能是由于組織學(xué)標(biāo)本的假陰性而非血漿標(biāo)本的假陽性引起；腫瘤異質(zhì)性（小活檢標(biāo)本），檢測方法的敏感性，都可能

46、導(dǎo)致假陰性的出現(xiàn)在真實世界中，檢測的敏感性還可能受到分期/疾病分化狀態(tài)的影響WCLC大樣本真實世界驅(qū)動基因檢測實踐將ctDNA應(yīng)用于真實世界EGFR檢測The ASSESS study CTONG1405 (BENEFIT Study)A Single-arm, Open, Multicenter Study Evaluating Efficacy and Safety of First- line Gefitinib Treatment in Metastatic Lung Adenocarcinoma Patients with Sensitizing EGFR Mutation Determined by ddPCR in Plasma cell-free DNA1.Stage IV adenocarnoma； 2.age18-75；PS 0-2 ；cf-DNA EGFRmutation by ddPCR；Tumor sampleavailable；gefitinib 250mg/dPDPI: Jie Wang and Yi-long Wu. 14 sites The primary endpoint : objective response rate