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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 Center16 - 19 de Noviembre 2005
SIMPOSIO GENETICA Y CANCER MAMA
van’t Veer et al., van’t Veer et al.,
Nature 2002; 155,530-36Nature 2002; 155,530-36positivenegative
van’t Veer et al., van’t Veer et al.,
Nature 2002; 155,530-36Nature 2002; 155,530-36
Comparación de criterios clínico-patológicos (St. Gallen y NIH) vs perfil genético en recaída
(metástasis) y DFS (disease-free survival) en cáncer de mama
Metástasis DFS
N=34 N=44
St. Gallen 33 (97%) 31 (70%)
NIH 32 (94%) 40 (91%)
Perfil genético 31 (91%) 12 (27%)
van´t Veer et al.,Nature 2002, 415:530-535
– 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
MINDACT MINDACT Microarray In Node negative Microarray In Node negative
Disease may Avoid ChemotherapyDisease may Avoid ChemotherapyDESIGN UPDATE
New design-MINDACT_FINAL_ Feb2005
TRANSLATING MOLECULAR KNOWLEDGEINTO EARLY
BREAST CANCER MANAGEMENT
TRANSBIGTRANSBIG
TRANSBIG:TRANSBIG: International research network founded in 2004 International research network founded in 2004 EU supported Network of ExcellenceEU supported Network of Excellence
Aim: Aim: To integrate, strengthen and facilitate To integrate, strengthen and facilitate translational and clinical breast cancer research translational and clinical breast cancer research
Total cost:Total cost: € 24 million (EU contribution: € 7 million) € 24 million (EU contribution: € 7 million)
1st project:1st project: MINDACT clinical trial (Microarray for Node MINDACT clinical trial (Microarray for Node Negative Disease may Avoid Chemotherapy)Negative Disease may Avoid Chemotherapy)
TRANSBIG: PARTNERSTRANSBIG: PARTNERS
•
ChileChilean Cooperative Group
for Oncologic Research (GOCCHI) Australia/New
ZealandAustralian 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
RussiaCancer Research Centre
CanadaNational Cancer
Institute ofCanada (NCIC),Clinical Trials Group (CTG)
39 PARTNERS, 21 COUNTRIES39 PARTNERS, 21 COUNTRIES
= Third party countries likely to = Third party countries likely to participateparticipate
= Official partners= Official partners
TRANSBIG APPROACH: TRANSBIG APPROACH: TRANSLATIONAL RESEARCHTRANSLATIONAL RESEARCH
Gene analysis Gene analysis “translated““translated“ into tools into toolsto determine best clinical treatmentto determine best clinical treatment
« Tailors » treatment:« Tailors » treatment:individual patient individual tumour individual treatmentindividual patient individual tumour individual treatment
AVOIDS OVERTREATMENTAVOIDS OVERTREATMENT
TRANSBIG APPROACH: TRANSBIG APPROACH: TRANSLATIONAL RESEARCHTRANSLATIONAL RESEARCH
Gene analysis Gene analysis “translated““translated“ into tools into toolsto determine best clinical treatmentto determine best clinical treatment
« Tailors » treatment:« Tailors » treatment:individual patient individual tumour individual treatmentindividual patient individual tumour individual treatment
AVOIDS OVERTREATMENTAVOIDS OVERTREATMENT
WHAT IS MINDACT?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 individualAim:
Validate the hypothesis on 5000 women over 3 years
Outcome: • Save women from unnecessary treatment• Develop new areas of medical research
Assess clinical risk and genomic risk
MINDACT – 6000 patients
Clinical and Genomic
BOTH HIGH RISK
Clinical and Genomic
BOTH LOW RISK
Assess clinical risk and genomic risk
MINDACT – 6000 patients
N=330055%
N=60010%
Clinical and Genomic
BOTH HIGH RISK
Clinical and Genomic
BOTH LOW RISK
Assess clinical risk and genomic risk
MINDACT – 6000 patients
N=330055%
N=60010%
Chemotherapy± 4350 patients
No Chemotherapy± 1650 patients
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=210035%
Chemotherapy± 4350 patients
No Chemotherapy± 1650 patients
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=168080%
Chemotherapy± 4350 patients
No Chemotherapy± 1650 patients
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=42020%
N=168080%
Chemotherapy± 4350 patients
No Chemotherapy± 1650 patients
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
RANDOMIZEdecision-making
MINDACT – 6000 patients
Chemotherapy± 4350 patients
No Chemotherapy± 1650 patients
Genomic HIGH RISK Clinical LOW RISK
Clinical and Genomic
BOTH HIGH RISK
Clinical and Genomic
BOTH LOW RISK
Assess clinical risk and genomic risk
RANDOMIZEdecision-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
Clinical and Genomic
BOTH HIGH RISK
Clinical and Genomic
BOTH LOW RISK
Assess clinical risk and genomic risk
RANDOMIZEdecision-making
Use genomic riskUse clinical riskLow riskHigh risk
MINDACT – 6000 patients
N=84080%
N=21020%
Chemotherapy± 4350 patients
No Chemotherapy± 1650 patients
DISCORDANT Clinical and
Genomic Risks
Clinical HIGH RISK Genomic LOW RISK
Genomic HIGH RISK Clinical LOW RISK
Clinical and Genomic
BOTH HIGH RISK
Clinical and Genomic
BOTH LOW RISK
Assess clinical risk and genomic risk
RANDOMIZEdecision-making
Use genomic riskUse clinical riskHigh risk Low risk
MINDACT – 6000 patients
N=21020%
N=84080%
Chemotherapy± 4350 patients
No Chemotherapy± 1650 patients
DISCORDANT Clinical and
Genomic Risks
Clinical HIGH RISK Genomic LOW RISK
Genomic HIGH RISK Clinical LOW RISK
Clinical and Genomic
BOTH HIGH RISK
Clinical and Genomic
BOTH LOW RISK
Assess clinical risk and genomic risk
RANDOMIZEdecision-making
Use genomic riskUse clinical riskHigh risk Low risk
MINDACT – 6000 patients
N=84080%
Chemotherapy± 4350 patients
No Chemotherapy± 1650 patients
Low riskHigh riskN=84080%
N=21020%
N=21020%
N=42020%
N=168080%
N=330055%
N=60010%
DISCORDANT Clinical and
Genomic Risks
Clinical HIGH RISK Genomic LOW RISK
Genomic HIGH RISK Clinical LOW RISK
PRIMARY TESTPRIMARY TEST• Dataset: the patients who have a low risk gene prognosis Dataset: the patients who have a low risk gene prognosis
signature and high risk clinical-pathologic criteria, and who signature and high risk clinical-pathologic criteria, and who were randomized to receive no chemotherapy. were randomized to receive no chemotherapy. Expected size: Expected size: 840840
• Null hypothesis: Null hypothesis: 5-year DMFS = 92%5-year DMFS = 92% will be tested. will be tested. • Assuming:Assuming:
– 3 years accrual3 years accrual– 6 years total duration (3 to 6 years follow up per patient)6 years total duration (3 to 6 years follow up per patient)– two-sided test at 95% confidence leveltwo-sided test at 95% confidence level– true true 5-year DMFS = 95%5-year DMFS = 95%
• This test has This test has 80% power80% power
TRANSBIG : STANDARDITRANSBIG : STANDARDISSATION/ VALIDATION PHASEATION/ VALIDATION PHASE
Jules Bordet InstituteBrussels
Gustave Roussy Institute
Paris
NKI Radcliffe HospitalOxford
Karolinska Institute
Stockholm
KEY QUESTIONS TO BE ANSWEREDKEY QUESTIONS TO BE ANSWEREDKEY QUESTIONS TO BE ANSWEREDKEY 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
ReproducibilityReproducibility
Are results reproducible acrossAre results reproducible acrosslaboratories laboratories
and platforms?and platforms?
MULTI-CENTER EXTERNAL VALIDATION STUDY MULTI-CENTER EXTERNAL VALIDATION STUDY OF THE AMSTERDAM 70-GENE PROGNOSTIC OF THE AMSTERDAM 70-GENE PROGNOSTIC SIGNATURE IN NODE NEGATIVE UNTREATED SIGNATURE IN NODE NEGATIVE UNTREATED
BREAST CANCERBREAST CANCER
INTERIM ANALYSISINTERIM ANALYSIS
MJ Piccart, S Loi, L Van’t Veer, M Saghastchian-d’Assignies, A Glas, P Ellis, A MJ Piccart, S Loi, L Van’t Veer, M Saghastchian-d’Assignies, A Glas, P Ellis, A Harris, J Bergh, Harris, J Bergh, R Lidereau, R Lidereau, D Sgroi, E Rutgers, G Viale, C Sotiriou, M Delorenzi, J D Sgroi, E Rutgers, G Viale, C Sotiriou, M Delorenzi, J
Bogaerts, P Therasse, M Amakrane, F Cardoso, M Buyse Bogaerts, P Therasse, M Amakrane, F Cardoso, M Buyse on behalf of the TRANSBIG CONSORTIUMon behalf of the TRANSBIG CONSORTIUM
Partially funded by the European Commission’s Framework VI ProgrammePartially funded by the European Commission’s Framework VI Programme
SABCS, Dec. 8, 2004SABCS, Dec. 8, 2004
PATIENT POPULATIONS : GENE PATIENT POPULATIONS : GENE SIGNATURE RISKSSIGNATURE RISKS
Validation series N = 291
Validation series N = 291
Original Amsterdam series N = 151
Original Amsterdam series N = 151
High riskHigh risk(n=182)(n=182)
63%63%
Low riskLow risk(n=109)(n=109)
37%37%High riskHigh risk
(n=91)(n=91)
60%60%
Low riskLow risk(n=60)(n=60)
40%40%
CLINICAL RISK CLASSIFICATIONSCLINICAL RISK CLASSIFICATIONS
Validation Validation seriesseries
Amsterdam Amsterdam seriesseries
1. St Gallen criteria1. St Gallen criteria
2. Nottingham Prognostic Index2. Nottingham Prognostic Index
3. Adjuvant ! Online (P. Ravdin)3. Adjuvant ! Online (P. Ravdin)
Threshold for Clinical Low RiskThreshold for Clinical Low Risk==
Predicted 10-year survival probabilityPredicted 10-year survival probabilityat least equal to x % with x varying from 60% to 95%at least equal to x % with x varying from 60% to 95%
If x=90% Low risk: n=45 (15%)If x=90% Low risk: n=45 (15%) High risk: n=246 (85%)High risk: n=246 (85%)
ADJUVANT! ONLINE FOR BREAST CANCERADJUVANT! ONLINE FOR BREAST CANCER
Amsterdamgene-expression
prognostic signature
N=78
Level 5 and 4Level 5 and 4
IndependentIndependentvalidation study on validation study on
archive materialarchive material
• Other populationsOther populations
• Internal + external Internal + external
quality assurancequality assurance
Level 3Level 3
High powered clinical trial specifically
addressing the gene signature’s
utilityMINDACT
Level 1Level 1
Levels of evidence for biomarkers studiesLevels of evidence for biomarkers studies
E.U. GRANT, 6E.U. GRANT, 6thth Framework Programme Framework Programme
@
The TRANSBIG consortium is grateful to the European The TRANSBIG consortium is grateful to the European Community for the support it has provided under its Community for the support it has provided under its
Framework Programme VI. Framework Programme VI.
The European Community is not responsible for any of The European Community is not responsible for any of the views presented here, nor is it liable for any use that the views presented here, nor is it liable for any use that
may be made of the information contained herein.may be made of the information contained herein.
GRACIAS