1、 Ming Sound Tsao,MD,FRCPCDepartment of Pathology,Princess Margaret HospitalDivision of Cellular and Molecular Biology,Ontario Cancer InstituteUniversity of TorontoMolecular Pathology of Lung Cancer.ONTARIO CANCER INSTITUTE(OCI)PRINCESS MARGARET HOSPITAL.Objective:lTo report the results of 2 importan
2、t clinical trials reported at 2004 American Society of Clinical Oncologist Main message:l Molecular Pathology will soon be an important component of pathological diagnosis in lung cancer.Worlds cancer incidence and cancer deathsIncidence in thousands(%total)Deaths in thousands(%total)Lung1,305(12.7%
3、)1,211(17.2%)Colon&rectum1,045(10.2%)608(6.7%)Breast1,032(10%)430(6.1%)Stomach973(9.5%)835(11.9%)Liver626(6.1%)611(8.7%).1999 WHO Pathological Classification of Lung Cancer.Months After TreatmentCumulative Proportion SurvivingStage IStage IIStage IIIaStage IIIbStage IV1008060402001224364860Months Af
4、ter TreatmentCumulative Proportion Surviving1008060402001224364860Stage IStage IIStage IIIaStage IIIbStage IVAdenocarcinomaSquamous cell carcinoma.NSCLC-Survival Rate and Proportion at Presentation vs.Clinical stageClinical StagePercentage of Patients5-year survival rateI36%60%II8%39%IIIA10%23%IIIB2
5、0%5%IV27%2 regimens(9)Only single agent in young patient(2)CT or RT given within 2-4 weeks,concurrent CT(5)Biochemical abnormalities(4)Symptomatic CNS metastases(2).BR.21 Patient CharacteristicsErlotinib(N=488)Placebo(N=243)Median Age(yrs)62.259.5GenderMale65%66%Female35%34%ECOG PS(%)013%14%152%54%2
6、26%23%39%9%HistologyAdenocarcinoma50%49%Other50%51%.BR.21 Progression Free Survival*Adjusted for stratification factors SUMMARY STATISTICS:Log-Rank test for equality of groups:p=0.0000Wilcoxon test for equality of groups:p=0.0000Survival rate at 12 months for OSI-774:8%-%C.I.(5%,10%)Survival rate at
7、 12 months for Placebo:2%-%C.I.(0%,4%)Hazard Ratio of Placebo/OSI-774:1.572-95%C.I.(1.337,1.848)OSI-774PlaceboPercentage020406080100Time(months)#At Risk(OSI-774)#At Risk(Placebo)0.0488243 5.01533410.052615.08120.010Months _ Erlotinib,_ Placebo *HR 0.61,p=0.001.BR.21 Overall,Progression-Free and 1-ye
8、ar SurvivalErlotinib(N=488)Placebo(N=243)HR*Log Rank PProgression Free Survival2.2 m1.8 m0.610.001Overall Survival 6.7m4.7m0.720.001I-year survival31%22%*Adjusted for stratification factors.BR.21 Overall Survival*Adjusted for stratification factors SUMMARY STATISTICS:Log-Rank test for equality of gr
9、oups:p=0.0018Wilcoxon test for equality of groups:p=0.0143Survival rate at 12 months for OSI-774:31%-%C.I.(27%,35%)Survival rate at 12 months for Placebo:22%-%C.I.(16%,27%)Hazard Ratio of Placebo/OSI-774:1.309-95%C.I.(1.105,1.551)OSI-774PlaceboPercentage020406080100Time(months)#At Risk(OSI-774)#At R
10、isk(Placebo)0.048824310.01885920.012430.000 _ Erlotinib,_ Placebo *HR 0.72,p=0.001Months31%22%.BR.21 Survival by Smoking HistoryMonthsSUMMARY STATISTICS:Log-Rank test for equality of groups:p=0.0000Smoked/OSI-774Smoked/PlaceboNever Smoked/OSI-774Never Smoked/PlaceboPercentage020406080100Time(months)
11、#At Risk(Smoked/OSI-774)#At Risk(Smoked/Placebo)#At Risk(Never Smoked/OSI-774)#At Risk(Never Smoked/Placebo)0.03581871044210.01164663920.0734030.00000_ Erlotinib Non-Smoker_ Placebo Non-Smoker_ Erlotinib Smoker _ Placebo Smoker p=0.03*significant difference across the levels of the factor.BR.21 Summ
12、ary This is the first placebo controlled randomized trial to confirm that an oral tyrosine（酪氨酸）kinase inhibitor of EGFR can prolong survival Treatment with erlotinib was associated with significantlyllonger overall survivalllonger progression free survivallimproved lung cancer-related symptomslimpro
13、ved quality of life Survival significantly better among non-smokers.EGFR Mutations in Lung Cancer:Correlation with Clinical Response to Gefitinib Therapy.Paez JG,Janne PA,Lee JC,Tracy S,Greulich H,Gabriel S,Herman P,Kaye FJ,Lindeman N,Boggon TJ,Naoki K,Sasaki H,Fujii Y,Eck MJ,Sellers WR,Johnson BE,M
14、eyerson M.Dana Farber Cancer Institute and Harvard UniversityScience April 29,2004 Mutations（突变）(point mutation and deletions)were detected in exons（外显子）18,19 and 21 in the kinase domain of EGFR gene.Mutations were found in:l26%(15/68)of lung cancers from Japanl 2%(1/61)of lung cancers from USA Muta
15、tions among Japanese patients:l14/15 were in adenocarcinomal8/14(57%)women with adenocarcinoma had mutations Mutations were found in:l all 5 patients who responded to gefitinib(Iressa)treatment at DFCIl none of 4 patients who did not respond to gefitinib treatment.Activating Mutations in the Epiderm
16、al Growth Factor Receptor Underlying Responsiveness of Non Small-Cell Lung Cancer to GefitinibThomas J.Lynch,M.D.,Daphne W.Bell,Ph.D.,Raffaella Sordella,Ph.D.,Sarada Gurubhagavatula,M.D.,Ross A.Okimoto,B.S.,Brian W.Brannigan,B.A.,Patricia L.Harris,M.S.,Sara M.Haserlat,B.A.,Jeffrey G.Supko,Ph.D.,Fran
17、k G.Haluska,M.D.,Ph.D.,David N.Louis,M.D.,David C.Christiani,M.D.,Jeff Settleman,Ph.D.,and Daniel A.Haber,M.D.,Ph.D.Massachusetts General Hospital and Harvard Medical SchoolNEW ENGLAND JOURNAL OF MEDICINE,MAY 20 ISSUE EGFR mutations were found in:8 of 9 lung cancer patients who were responsive to tr
18、eatment with Iressa 0 of 7 lung cancer patients who were non-responsive All 8 tumors were adenocarcioma 5 of 8 were from women non-smokers Mutations were not found in 95 non-lung cancer tumors.International Association for the Study of Lung Cancer EGFR Summit Meeting HighlightsJuly 9-10,2004,Baltimo
19、re,USA There are 18 mutations that have been described in exons 18-23.Rates of mutations varied according to countries:lAdenocarcinoma in never smokers:60%in tumors from Taiwan 62%from Japan 30 45%from USA(compared to 2%overall)80%from Hong Kongl Adenocarcinoma of ever smoker from HK:40%EGFR mutatio
20、n and Ras mutations are mutually（相互）exclusive排斥 In Korea where women rarely smoke,response to Iressa is seen in up to 60%of patients.Future studies What are the best predictors of benefits in patients treated with EGFR TKI?l Mutation alone?l Other gene or protein markers in the tumor or serum.Future
21、 improvement in lung cancer diagnosis and treatment will be based on better understanding of the molecular pathology of lung cancer.Molecular diagnosis will play increasingly important roles in future management of lung cancer patients.Final Comments.Acknowledgement Laboratory personnel:l Liu Ni l Z
22、hu Chang-Qil Davina Lau Past visiting fellows:l Fiona Blackhall(Manchester)l Mu Xiao-yan(Shandong)l Lu Ming(Beijing)Dr.Frances Shepherd(Medical oncologist and current President of IASLC)Thoracic surgeons at Toronto General Hospital/Princess Margaret Hospital National Cancer Institute of Canada Clinical Trial Group and staffs.感谢亲观看此幻灯片，此课件部分内容来源于网络，感谢亲观看此幻灯片，此课件部分内容来源于网络，如有侵权请及时联系我们删除，谢谢配合！如有侵权请及时联系我们删除，谢谢配合！
