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Estudio TransBIG (MINDACT) Metodología y Objetivos Dr. Alejandro Corvalán R. Departamento Anatomía Patológica, Pontificia Universidad Católica de Chile.

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Presentation on theme: "Estudio TransBIG (MINDACT) Metodología y Objetivos Dr. Alejandro Corvalán R. Departamento Anatomía Patológica, Pontificia Universidad Católica de Chile."— Presentation transcript:

1 Estudio TransBIG (MINDACT) Metodología y Objetivos Dr. Alejandro Corvalán R. Departamento Anatomía Patológica, Pontificia Universidad Católica de Chile Grupo Oncológico Cooperativo Chileno de Investigación (GOCCHI) XIII Congreso Latinoamericano de Mastología VIII Congreso Chileno de Mastología Sheraton Santiago, Hotel & Convention Center de Noviembre 2005 SIMPOSIO GENETICA Y CANCER MAMA

2 van’t Veer et al., Nature 2002; 155, positive negative

3 van’t Veer et al., Nature 2002; 155,530-36

4 Comparación de criterios clínico-patológicos (St. Gallen y NIH) vs perfil genético en recaída (metástasis) y DFS (disease-free survival) en cáncer de mama MetástasisDFS N=34N=44 St. Gallen33 (97%)31 (70%) NIH 32 (94%)40 (91%) Perfil genético31 (91%)12 (27%) van´t Veer et al., Nature 2002, 415:

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6 –Estadio II o III de cancer de mama –Menores de 53 años –151 con linfonodos positivos –144 con linfonodos negativos Clasificación de 295 pacientes con carcinoma primario de mama usando perfil de expresión génica asociado a buen y mal pronóstico

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13 MINDACT Microarray In Node negative Disease may Avoid Chemotherapy DESIGN UPDATE DESIGN UPDATE New design-MINDACT_FINAL_ Feb2005

14 TRANSLATING MOLECULAR KNOWLEDGE INTO EARLY BREAST CANCER MANAGEMENT

15 TRANSBIG TRANSBIG: International research network founded in 2004 EU supported Network of Excellence Aim: To integrate, strengthen and facilitate translational and clinical breast cancer research Total cost:  € 24 million (EU contribution: € 7 million) 1st project: MINDACT clinical trial (Microarray for Node Negative Disease may Avoid Chemotherapy)

16 TRANSBIG: PARTNERS Chile Chilean Cooperative Group for Oncologic Research (GOCCHI) Australia/New Zealand Australian New Zealand Breast Cancer Trials Group (ANZ BCTG) European Union (Austria, Belgium, Denmark, France, Germany, Greece, Ireland, Italy, Luxemburg, The Netherlands, Portugal, Sweden and United Kingdom) + Turkey & Switzerland Russia Cancer Research Centre Canada National Cancer Institute of Canada (NCIC), Clinical Trials Group (CTG) 39 PARTNERS, 21 COUNTRIES = Third party countries likely to participate = Official partners

17 TRANSBIG APPROACH: TRANSLATIONAL RESEARCH Gene analysis “translated“ into tools to determine best clinical treatment « Tailors » treatment: individual patient individual tumour individual treatment AVOIDS OVERTREATMENT

18 TRANSBIG APPROACH: TRANSLATIONAL RESEARCH Gene analysis “translated“ into tools to determine best clinical treatment « Tailors » treatment: individual patient individual tumour individual treatment AVOIDS OVERTREATMENT

19 WHAT IS MINDACT? Study based on a 70-gene "genetic signature" identified by the Netherlands Cancer Institute Hypothesis: The analysis of thousands of tumours with the genetic signature can lead to better understanding of breast cancer and treatment required for the individual Aim: Validate the hypothesis on 5000 women over 3 years Outcome: Save women from unnecessary treatment Develop new areas of medical research

20 Assess clinical risk and genomic risk MINDACT – 6000 patients

21 Clinical and Genomic BOTH HIGH RISK Clinical and Genomic BOTH LOW RISK Assess clinical risk and genomic risk MINDACT – 6000 patients N= % N=600 10%

22 Clinical and Genomic BOTH HIGH RISK Clinical and Genomic BOTH LOW RISK Assess clinical risk and genomic risk MINDACT – 6000 patients N= % N=600 10% Chemotherapy ± 4350 patients No Chemotherapy ± 1650 patients

23 Clinical and Genomic BOTH HIGH RISK DISCORDANT Clinical and Genomic Risks Clinical and Genomic BOTH LOW RISK Assess clinical risk and genomic risk MINDACT – 6000 patients N= % Chemotherapy ± 4350 patients No Chemotherapy ± 1650 patients

24 Clinical and Genomic BOTH HIGH RISK DISCORDANT Clinical and Genomic Risks Clinical and Genomic BOTH LOW RISK Assess clinical risk and genomic risk Clinical HIGH RISK Genomic LOW RISK MINDACT – 6000 patients N= % Chemotherapy ± 4350 patients No Chemotherapy ± 1650 patients

25 Clinical and Genomic BOTH HIGH RISK DISCORDANT Clinical and Genomic Risks Clinical and Genomic BOTH LOW RISK Assess clinical risk and genomic risk Clinical HIGH RISK Genomic LOW RISK Genomic HIGH RISK Clinical LOW RISK MINDACT – 6000 patients N=420 20% N= % Chemotherapy ± 4350 patients No Chemotherapy ± 1650 patients

26 Clinical and Genomic BOTH HIGH RISK DISCORDANT Clinical and Genomic Risks Clinical and Genomic BOTH LOW RISK Assess clinical risk and genomic risk Clinical HIGH RISK Genomic LOW RISK RANDOMIZE decision-making MINDACT – 6000 patients Chemotherapy ± 4350 patients No Chemotherapy ± 1650 patients Genomic HIGH RISK Clinical LOW RISK

27 Clinical and Genomic BOTH HIGH RISK Clinical and Genomic BOTH LOW RISK Assess clinical risk and genomic risk RANDOMIZE decision-making Use genomic riskUse clinical risk MINDACT – 6000 patients Chemotherapy ± 4350 patients No Chemotherapy ± 1650 patients DISCORDANT Clinical and Genomic Risks Clinical HIGH RISK Genomic LOW RISK Genomic HIGH RISK Clinical LOW RISK

28 Clinical and Genomic BOTH HIGH RISK Clinical and Genomic BOTH LOW RISK Assess clinical risk and genomic risk RANDOMIZE decision-making Use genomic riskUse clinical risk Low riskHigh risk MINDACT – 6000 patients N=840 80% N=210 20% Chemotherapy ± 4350 patients No Chemotherapy ± 1650 patients DISCORDANT Clinical and Genomic Risks Clinical HIGH RISK Genomic LOW RISK Genomic HIGH RISK Clinical LOW RISK

29 Clinical and Genomic BOTH HIGH RISK Clinical and Genomic BOTH LOW RISK Assess clinical risk and genomic risk RANDOMIZE decision-making Use genomic riskUse clinical risk High riskLow risk MINDACT – 6000 patients N=210 20% N=840 80% Chemotherapy ± 4350 patients No Chemotherapy ± 1650 patients DISCORDANT Clinical and Genomic Risks Clinical HIGH RISK Genomic LOW RISK Genomic HIGH RISK Clinical LOW RISK

30 Clinical and Genomic BOTH HIGH RISK Clinical and Genomic BOTH LOW RISK Assess clinical risk and genomic risk RANDOMIZE decision-making Use genomic riskUse clinical risk High riskLow risk MINDACT – 6000 patients N=840 80% Chemotherapy ± 4350 patients No Chemotherapy ± 1650 patients Low riskHigh risk N=840 80% N=210 20% N=210 20% N=420 20% N= % N= % N=600 10% DISCORDANT Clinical and Genomic Risks Clinical HIGH RISK Genomic LOW RISK Genomic HIGH RISK Clinical LOW RISK

31 PRIMARY TEST Dataset: the patients who have a low risk gene prognosis signature and high risk clinical-pathologic criteria, and who were randomized to receive no chemotherapy. Expected size: 840Dataset: the patients who have a low risk gene prognosis signature and high risk clinical-pathologic criteria, and who were randomized to receive no chemotherapy. Expected size: 840 Null hypothesis: 5-year DMFS = 92% will be tested.Null hypothesis: 5-year DMFS = 92% will be tested. Assuming:Assuming: –3 years accrual –6 years total duration (3 to 6 years follow up per patient) –two-sided test at 95% confidence level –true 5-year DMFS = 95% This test has 80% powerThis test has 80% power

32 TRANSBIG : STANDARDISATION/ VALIDATION PHASE Jules Bordet Institute Brussels Gustave Roussy Institute Paris NKIRadcliffe Hospital Oxford Karolinska Institute Stockholm KEY QUESTIONS TO BE ANSWERED Validation Is the prognostic value of the 70 gene signature confirmed ? Transferability Is the 70 gene signature transferable onto the Affymetrix platform? Collection of frozen samples of BC patients with  5 year f-up Node (-) = 400 Collection of frozen samples of BC patients with  5 year f-up Node (-) = 400 Reproducibility Are results reproducible across laboratories and platforms?

33 MULTI-CENTER EXTERNAL VALIDATION STUDY OF THE AMSTERDAM 70-GENE PROGNOSTIC SIGNATURE IN NODE NEGATIVE UNTREATED BREAST CANCER INTERIM ANALYSIS MJ Piccart, S Loi, L Van’t Veer, M Saghastchian-d’Assignies, A Glas, P Ellis, A Harris, J Bergh, R Lidereau, D Sgroi, E Rutgers, G Viale, C Sotiriou, M Delorenzi, J Bogaerts, P Therasse, M Amakrane, F Cardoso, M Buyse on behalf of the TRANSBIG CONSORTIUM Partially funded by the European Commission’s Framework VI Programme SABCS, Dec. 8, 2004

34 PATIENT POPULATIONS : GENE SIGNATURE RISKS Validation series N = 291 Validation series N = 291 Original Amsterdam series N = 151 Original Amsterdam series N = 151 High risk (n=182)63% Low risk (n=109)37% High risk (n=91)60% Low risk (n=60)40%

35 CLINICAL RISK CLASSIFICATIONS Validation series Amsterdam series 1. St Gallen criteria 2. Nottingham Prognostic Index 3. Adjuvant ! Online (P. Ravdin)

36 Threshold for Clinical Low Risk = Predicted 10-year survival probability at least equal to x % with x varying from 60% to 95% If x=90% Low risk: n=45 (15%)High risk: n=246 (85%) ADJUVANT! ONLINE FOR BREAST CANCER

37 Amsterdam gene-expression prognostic signature N=78 Level 5 and 4 Independent validation study on archive material Other populations Other populations Internal + external quality assurance Internal + external quality assurance Level 3 High powered clinical trial specifically addressing the gene signature’s utility MINDACT Level 1 Levels of evidence for biomarkers studies E.U. GRANT, 6 th Framework Programme

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39 The TRANSBIG consortium is grateful to the European Community for the support it has provided under its Framework Programme VI. The European Community is not responsible for any of the views presented here, nor is it liable for any use that may be made of the information contained herein.

40 GRACIAS


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