1. Metodología y Objetivos
XIII Congreso Latinoamericano de Mastología
VIII Congreso Chileno de Mastología
Sheraton Santiago, Hotel & Convention Center
de Noviembre 2005
SIMPOSIO
GENETICA Y CANCER MAMA
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)

2. van’t Veer et al., Nature 2002; 155,530-36
positive
negative

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

4. Metástasis DFS N=34 N=44 St. Gallen 33 (97%) 31 (70%)
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 (94%) 40 (91%)
Perfil genético 31 (91%) 12 (27%)
van´t Veer et al.,
Nature 2002, 415:

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

8. 

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

14. TRANSLATING MOLECULAR KNOWLEDGE INTO EARLY BREAST CANCER MANAGEMENT

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

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
Assess clinical risk and genomic risk

21. Assess clinical risk and genomic risk
MINDACT – 6000 patients
Assess clinical risk and genomic risk
Clinical and Genomic
BOTH HIGH RISK
Clinical and Genomic
BOTH LOW RISK
N=3300
55%
N=600
10%

22. Assess clinical risk and genomic risk
MINDACT – 6000 patients
Assess clinical risk and genomic risk
Clinical and Genomic
BOTH HIGH RISK
Clinical and Genomic
BOTH LOW RISK
N=3300
55%
N=600
10%
Chemotherapy
± 4350 patients
No Chemotherapy
± 1650 patients

23. DISCORDANT Clinical and Genomic Risks Clinical and Genomic
MINDACT – 6000 patients
Assess clinical risk and genomic risk
Clinical and Genomic
BOTH HIGH RISK
DISCORDANT Clinical and Genomic Risks
Clinical and Genomic
BOTH LOW RISK
N=2100
35%
Chemotherapy
± 4350 patients
No Chemotherapy
± 1650 patients

24. DISCORDANT Clinical and Genomic Risks Clinical and Genomic
MINDACT – 6000 patients
Assess clinical risk and genomic risk
Clinical and Genomic
BOTH HIGH RISK
DISCORDANT Clinical and Genomic Risks
Clinical and Genomic
BOTH LOW RISK
Clinical HIGH RISK Genomic LOW RISK
N=1680
80%
Chemotherapy
± 4350 patients
No Chemotherapy
± 1650 patients

25. DISCORDANT Clinical and Genomic Risks Clinical and Genomic
MINDACT – 6000 patients
Assess clinical risk and genomic risk
Clinical and Genomic
BOTH HIGH RISK
DISCORDANT Clinical and Genomic Risks
Clinical and Genomic
BOTH LOW RISK
Clinical HIGH RISK Genomic LOW RISK
Genomic HIGH RISK Clinical LOW RISK
N=1680
80%
N=420
20%
Chemotherapy
± 4350 patients
No Chemotherapy
± 1650 patients

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

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

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

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

30. RANDOMIZE decision-making Use clinical risk Use genomic risk
MINDACT – 6000 patients
Assess clinical risk and genomic risk
Clinical and Genomic
BOTH HIGH RISK
DISCORDANT Clinical and Genomic Risks
Clinical and Genomic
BOTH LOW RISK
N=3300
55%
N=600
10%
Clinical HIGH RISK Genomic LOW RISK
Genomic HIGH RISK Clinical LOW RISK
N=1680
80%
RANDOMIZE
decision-making
N=420
20%
Use clinical risk
Use genomic risk
N=840
80%
High risk
Low risk
High risk
Low risk
Chemotherapy
± 4350 patients
N=210
20%
No Chemotherapy
± 1650 patients
N=840
80%
N=210
20%

31. PRIMARY TEST This test has 80% power
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: 840
Null hypothesis: 5-year DMFS = 92% will be tested.
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% power

32. TRANSBIG : STANDARDISATION/ VALIDATION PHASE
Jules Bordet Institute
Brussels
Karolinska Institute
Stockholm
Gustave Roussy Institute
Paris
NKI
Radcliffe Hospital
Oxford
Collection of frozen samples of BC patients with 5 year f-up
Node (-) = 400
KEY QUESTIONS TO BE ANSWERED
Validation
Transferability
Reproducibility
Are results reproducible across
laboratories
and platforms?
Part of the standardization and validation phase will also ensure that the signature is reproducible in other laboratories with the same technology. This phase will also refine the reproducibility and quality control of the technique developed by Netherlands Cancer Institute (NKI). Additionally, whilst MINDACT will be performed using the NKI Agilent platform on the dedicated “Breast Cancer prognosis” array, parallel studies will be conducted using the Affymetrix platform to find a signature that is applicable in as many laboratories as possible. These phases will be strictly, according to validation protocols outlining the procedures required and the definition of appropriate validation “a priori”.
Is the prognostic value of the 70 gene signature confirmed ?
Is the 70 gene signature transferable onto the Affymetrix platform?

33. on behalf of the TRANSBIG CONSORTIUM
SABCS, Dec. 8, 2004
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

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

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

36. ADJUVANT! ONLINE FOR BREAST CANCER
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%)

37. Levels of evidence for biomarkers studies
Independent
validation study on archive material
High powered clinical trial specifically addressing the gene signature’s utility
MINDACT
Amsterdam
gene-expression prognostic signature
N=78
Other populations
Internal + external quality assurance
Level 5 and 4
Level 3
Level 1
Levels of evidence for biomarkers studies
MINDACT is expected to begin recruitment in Currently several laboratories are involved in a “standardisation and validation” phase. This is a retrospective genomic analysis using over 300 archival samples from 4 other hospitals and countries. This step is crucial to ensure the Dutch 70-gene signature is reproducible and applicable across different populations in other countries. The “validation and standardization” phase will provide a “go/no go” decision step regarding MINDACT. The ultimate validation however is the prospective, multi-centre randomised clinical trial.
E.U. GRANT, 6th Framework Programme

38. @

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