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1、Department of Thoracic/Head&Neck Medical OncologyMutational Analysis in NSCLC Adenocarcinoma to Guide TherapyAnne S.Tsao,M.D.Associate ProfessorThe University of TexasThe University of TexasMD ANDERSON MD ANDERSON CANCER CENTERCANCER CENTERDirector,Mesothelioma ProgramDirector,Thoracic Chemo-XRT Pro
2、gramBackgroundEpidemiology HistologyMolecular ProfilingOutline:NSCLC EGFR mutantsIPASS EURTAC LUX LUNG 3EML 4 ALK,ROS 1CrizotinibUpcoming agents Lung Cancer During 2013,228,190 new cases and 159,480 deaths are expected in the United States Second most common cancer and leading cause of cancer deathA
3、merican Cancer Society.Cancer Facts and Figures 2013.Atlanta,GA:American Cancer Society;2013;Siegel.CA Cancer J Clin.61(4):212.Stage at DiagnosisLocalized(stage I/II)15%Distant(stage IV)56%Regional(stage III)22%5-Year Relative Survival Rateby Stage at Diagnosis Survival(%)LocalizedDistantRegional53%
4、24%4%01020304050607080901002004 WHO Classification of Lung TumorsNSCLC(87%)SCLC(13%)Adenocarcinoma(45%)SCC(33%)LCC(9%)Combined SCLCMixed subtypeAcinarPapillaryBACNonmucinousMucinousMixedSolidPapillaryClear cellSmall cellBasaloidLCNEC Combined LCNECClear cellBasaloidLymphoepithelioma-likeLCC with rha
5、bdoid phenotypeAmerican Cancer Society.Cancer Facts and Figures 2008.Atlanta:American Cancer Society;2008;Travis,ed.WHO Pathology&Genetics Tumours of the Lung,Pleura,Thymus and Heart.Lyon,France:IARC Press;2004;Kufe.Cancer Medicine 7.Hamilton,Ontario:BC Decker,Inc.;2006:1185;Georgoulias.Lancet.2001;
6、357:1478;Scagliotti.J Clin Oncol.2008;26(21):3543;Ciuleanu.Lancet.2009;374(9699):1432.Emerging data indicate that specific regimens show greater benefit depending on tumor histology.BAC=bronchioloalveolar carcinoma;LCC=large cell carcinoma;LCNEC=large cell neuroendocrine carcinoma;SCC=squamous cell
7、carcinoma;SCLC=small cell lung cancer;WHO=World Health Organization.Lung Cancer Mutation ConsortiumOrganization Headquarters:University of Colorado Paul Bunn,Principal Investigator 14 Sites:SPORE,P01,NCI Intramural Programs Plan:Genotype 1000 patients with advanced lung adenocarcinoma,2009-2011 Assa
8、y 10“driver”mutations in CLIA-certified laboratories:EGFR,KRAS,BRAF,HER2,AKT1,NRAS,PIK3CA,MEK1,EML4-ALK,MET ampJohnson et al on behalf of LCMC investigators,WLCC July 2011 Abstract#O16.01Kris et al.on behalf of LCMC investigators,ASCO June 2011 Abstract#CRA7506LCMC Objectives Characterize 1000 tumor
9、 specimens from patients with lung adenocarcinoma for KRAS,EGFR,BRAF,HER2,PIK3CA,AKT1,NRAS,MEK1,and EML4-ALK,and MET amplification To use the information in real time to either select erlotinib with EGFR mutations or recommend a clinical trial of an agent targeting the specific mutation identifiedJo
10、hnson et al on behalf of LCMC investigators,WLCC July 2011 Abstract#O16.01Kris et al.on behalf of LCMC investigators,ASCO June 2011 Abstract#CRA7506Lung Cancer Mutation ConsortiumIncidence of Mutations Detected(n=516)A driver mutation was found in 54%(280/516)oftumors completely tested (CI 50-59%)HE
11、R 2Johnson et al on behalf of LCMC investigators,WLCC July 2011 Abstract#O16.01Kris et al.on behalf of LCMC investigators,ASCO June 2011 Abstract#CRA7506Lung Cancer Mutation Consortium Conclusions An actionable driver mutation in 54%of patients with lung adenocarcinoma 23%KRAS mutations2%BRAF mutati
12、ons 18%EGFR mutations2%PIK3CA mutations 9%EML4-ALK EGFR mutations correlate with younger age,female gender,and never smokers KRAS mutations correlate with older age and smoking history Plans are underway to expand the scope of the LCMC when ARRA funding ends-LCMC 2.0Johnson et al on behalf of LCMC i
13、nvestigators,WLCC July 2011 Abstract#O16.01Kris et al.on behalf of LCMC investigators,ASCO June 2011 Abstract#CRA7506BackgroundEpidemiology HistologyMolecular ProfilingOutline:NSCLC EGFR mutantsIPASS EURTAC LUX LUNG 3EML 4 ALK,ROS 1CrizotinibUpcoming agents NSCLC PATIENTNon-SCCNeuroendocrinePlatinum
14、-etoposide;Switch Maintenance:pemetrexed,erlotinib AdenocarcinomaEGFR mutationEGFR wild-typeEGFR TKI1st or 2nd lineMaintenance(IPASS,BR.21,SATURN)EML 4 ALK or ROS 1crizotinibPlatinum-doublet-bevacizumabPlatinum-pemetrexed+bevacizumabNon-platinum or platinum based doubletSwitch Maintenance:pemetrexed
15、,erlotinib(E4599,AVAiL,Pointbreak,SATURN,JMEN)SCCAvoid pemetrexed or bevacizumabConsider 2nd line EGFR TKI or maintenance erlotinib(BR.21,SATURN)Tsao Algorithm:Histology and Molecular ProfilingEGFR mutationsFound in 10%-15%of all lung cancer patients and 85%who clinically respond to EGFR TKIsFound m
16、ore commonly in never-smokers,adenocarcinomas,BAC,women,AsiansPredominantly located in EGFR exons 19-21 EGFR mutations are not the same.There are sensitive mutations and acquired resistance mutations(T790M).85%of EGFR mutations are either deletion exon 19 or L858 mutation.Pao,Miller.J Clin Oncol.2005;23:2556-2568;Wu et al.J Thorac Oncol.2007;2:430-439.12-0012-02Patient with EGFR mutation deletion exon 19 Newly diagnosed3-16-073 months of erlotinib6-18-07Patient with L858 EGFR mutationEGFR T790M:
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