estudio transbig (mindact) metodología y objetivos dr. alejandro corvalán r. departamento...

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

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


BOTH LOW RISK



N=330055%

N=60010%


BOTH HIGH RISK


BOTH LOW RISK



N=330055%

N=60010%

Chemotherapy± 4350 patients

No Chemotherapy± 1650 patients


BOTH HIGH RISK

DISCORDANT Clinical and

Genomic Risks


BOTH LOW RISK



N=210035%




BOTH HIGH RISK


Genomic Risks


BOTH LOW RISK


Clinical HIGH RISK Genomic LOW RISK


N=168080%




BOTH HIGH RISK


Genomic Risks


BOTH LOW RISK



Genomic HIGH RISK Clinical LOW RISK


N=42020%

N=168080%




BOTH HIGH RISK


Genomic Risks


BOTH LOW RISK



RANDOMIZEdecision-making






BOTH HIGH RISK


BOTH LOW RISK



Use genomic riskUse clinical risk





Genomic Risks




BOTH HIGH RISK


BOTH LOW RISK



Use genomic riskUse clinical riskLow riskHigh risk


N=84080%

N=21020%




Genomic Risks




BOTH HIGH RISK


BOTH LOW RISK



Use genomic riskUse clinical riskHigh risk Low risk


N=21020%

N=84080%




Genomic Risks




BOTH HIGH RISK


BOTH LOW RISK



Use genomic riskUse clinical riskHigh risk Low risk


N=84080%



Low riskHigh riskN=84080%

N=21020%

N=21020%

N=42020%

N=168080%

N=330055%

N=60010%


Genomic Risks



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

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