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 .Ming Sound Tsao, MD, FRCPCMoleONTARIO CANCER INSTITUTE (OCI)PRINCESS MARGARET HOSPITAL .ONTARIO CA

2、NCER INSTITUTE (OCI)Objective:To report the results of 2 important clinical trials reported at 2004 American Society of Clinical OncologistMain message: Molecular Pathology will soon be an important component of pathological diagnosis in lung cancer.Objective:.Worlds cancer incidence and cancer deat

3、hsIncidence in thousands (% total)Deaths in thousands (% total)Lung1,305 (12.7%)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%).Worlds cancer incidence and c1999 WHO Pathological Classification of Lung Cancer.1999 WHO

4、 Pathological ClassifiNon-small Cell Lung CancerAdenocarcinomaSquamous cell carcinoma.Non-small Cell Lung CancerAdenNSCLC - Survival Rate and Proportion at Presentation vs. Clinical stageClinical StagePercentage of Patients5-year survival rateI36 %60 %II8 %39 %IIIA10 %23 %IIIB20 %5 %IV27 %2 regimens

5、 (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 Results731 patients randBR.21 Patient CharacteristicsErlotinib(N=488)Placebo(N=243)Median Age (yrs)62.259.5GenderMale65%66%Female35%34%ECOG PS

6、 (%)013%14%152%54%226%23%39%9%HistologyAdenocarcinoma50%49%Other50%51%.BR.21 Patient CharacteristicsEBR.21 Progression Free Survival*Adjusted for stratification factors Months _ Erlotinib, _ Placebo *HR 0.61, p=0.001.BR.21 Progression Free SurvivBR.21 Overall, Progression- Free and 1-year SurvivalEr

7、lotinib(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, Progression- FrBR.21 Overall Survival*Adjusted for stratification factors _ Erlotinib, _ Placebo *HR 0.72,

8、p=0.001Months31%22%.BR.21 Overall Survival*AdjustBR.21 Survival by Smoking HistoryMonths_ Erlotinib Non-Smoker_ Placebo Non-Smoker_ Erlotinib Smoker _ Placebo Smoker p=0.03* significant difference across the levels of the factor.BR.21 Survival by Smoking HistBR.21 SummaryThis is the first placebo co

9、ntrolled randomized trial to confirm that an oral tyrosine（酪氨酸） kinase inhibitor of EGFR can prolong survivalTreatment with erlotinib was associated with significantlylonger overall survivallonger progression free survivalimproved lung cancer-related symptomsimproved quality of lifeSurvival signific

10、antly better among non-smokers.BR.21 SummaryThis is the firstEGFR 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, Joh

11、nson BE, Meyerson M.Dana Farber Cancer Institute and Harvard UniversityScience April 29, 2004 Mutations（突變） (point mutation and deletions) were detected in exons（外顯子） 18, 19 and 21 in the kinase domain of EGFR gene. Mutations were found in:26% (15/68) of lung cancers from Japan 2% (1/61) of lung can

12、cers from USA Mutations among Japanese patients:14/15 were in adenocarcinoma8/14 (57%) women with adenocarcinoma had mutations Mutations were found in: all 5 patients who responded to gefitinib (Iressa) treatment at DFCI none of 4 patients who did not respond to gefitinib treatment . Mutations（突變） (

13、point mutationActivating Mutations in the Epidermal 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.

14、S.,Sara M.Haserlat,B.A., Jeffrey G.Supko,Ph.D.,Frank 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:

15、 8 of 9 lung cancer patients who were responsive to treatment 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.Activating Mutations in the Ep.International Associat

16、ion for the Study of Lung Cancer EGFR Summit Meeting HighlightsJuly 9-10, 2004, Baltimore, USA There are 18 mutations that have been described in exons 18-23. Rates of mutations varied according to countries:Adenocarcinoma in never smokers: 60% in tumors from Taiwan 62% from Japan 30 45% from USA (c

17、ompared to 2% overall) 80% from Hong Kong Adenocarcinoma of ever smoker from HK: 40% EGFR mutation 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.International Association for Future studies What are the best pred

18、ictors of benefits in patients treated with EGFR TKI? Mutation alone? Other gene or protein markers in the tumor or serum .Future studies What are the beFuture improvement in lung cancer diagnosis and treatment will be based on better understanding of the molecular pathology of lung cancer. Molecular diagnos