Transcript HIGH risk

Le point sur Oncotype et les
équivalents
SFCP 19 septembre 2008
Dominique Spaëth
Centre d’Oncologie de Gentilly - NANCY
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Prescrivons nous un traitement adapté ?
Adjuvant on line
Prognosis Classifier for Breast
Cancer based on Genomic Profiling
Rows: 70 significant
prognosis genes
Columns: tumor samples
Threshold set with 10% false negatives
91% sensitivity; 73% specificity
Good signature
threshold
Poor signature
Metastases: white = +
Van ‘t Veer et al Nature 415, p530-536, 2002
Comparison between genomic and multivariable
clinical predictive models
M Buyse et al, J Natl Cancer Inst 98:1183, 2006
(These results are only applicable to node negative patients)
70-gene signature
(Age<55, T<5cm, N0, DMS 5yrs)
Discordance rates clinical vs gene signature
High clinical risk
67%
33%
Low gene sign. risk
High gene signature
risk
Low clinical risk
64%
36%
Low gene signature. High gene sign. risk
risk
SABS 2004, Dr Martine Piccart-Gephart JBI, Brussels
Multi-Gene Predictors in Breast Cancer
GeneSearch
(Veridex)
OncotypeDx
Genomic
Health
MammaPrint
Agendia
Number of
Genes
76
21
70
Indication
Prognosis
Prognosis
Tamox/CMF
Prognosis
Guide to
Specific
Therapy
No
Yes
CMF
ERl/HER2
No
Platform
Affymetrix
RT-PCR
GE/Agilent
Formalin
Paraffin
No
Yes
No
FDA Approval
No
? Pending
Yes
Commercial
Status
To be Released
On the Market
On the Market
C’est déjà du concret !
Genomic Health
Oncotype Dx 21-Gene
Recurrence Score
Assay
Agendia Mammaprint 70-Gene
Prognostic Signature Assay
Time’s Best Invention of the Year, 2007
Development and Validation of a 21-Gene Assay
for N–, ER+, Tam+ Patients
YEAR
Develop real-time RT-PCR method for paraffin block
2001
Select candidate genes (250 genes)
2002
Model building studies
(N = 447, including 233 from NSABP B-20)
2002
Commit to a single 21-gene assay
2003
Validation studies in NSABP B-14 and
Kaiser Permanente
2003
Paik et al. N Engl J Med. 2004;351:2817-2826.
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Oncotype DX® 21-Gene
Recurrence Score (RS) Assay
16 Cancer and 5 Reference Genes From 3 Studies
PROLIFERATION
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
ESTROGEN RS =
ER
PR
Bcl2
SCUBE2
GSTM1
INVASION
Stromelysin 3
Cathepsin L2
HER2
GRB7
HER2
BAG1
CD68
REFERENCE
Beta-actin
GAPDH
RPLPO
GUS
TFRC
+ 0.47 x HER2 Group Score
- 0.34 x ER Group Score
+ 1.04 x Proliferation Group Score
+ 0.10 x Invasion Group Score
+ 0.05 x CD68
- 0.08 x GSTM1
- 0.07 x BAG1
Category
RS (0-100)
Low risk
RS <18
Int risk
RS ≥18 and <31
High risk
RS ≥31
Paik et al. N Engl J Med. 2004;351:2817-2826.
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A Multigene Assay to Predict Recurrence of TamoxifenTreated, Node-Negative Breast Cancer
Results: Population distribution by Oncotype DX risk group
Low risk
51.0%
Intermed. risk
27.0%
High risk
22.0%
Paik .S. et al. N Engl J Med 2004;351:2817-26
Distant Recurrence-Free
Survival (%)
93%
100
P < 0.00001
DRFS (%)
80
69%
60
40
All patients
Low Risk (RS < 18)
Intermediate Risk (RS 18 - 30)
High Risk (RS  31)
20
0
0
2
4
6
8
10
12
14
16
Years
Paik .S. et al. N Engl J Med 2004;351:2817-26
Oncotype DX® Clinical Validation:
RS as Continuous Predictor
40%
IntermediateRisk Group
Distant Recurrence at 10 Years
Low-Risk Group
35%
High-Risk Group
My RS is 30. What is the chance
of recurrence within 10 years?
30%
25%
20%
15%
10%
5%
95% CI
0%
0
5
10
15
20
25
30
35
40
45
50
Recurrence Score
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Bénéfice du Tamoxifène et Oncotype DX®
NSABP B-14 Tam Benefit Study in N–, ER+ Patients
Design
Placebo-Eligible
Randomized
Tam-Eligible
Objective: Determine whether the 21-gene RS assay
provides information on:
1) Prognosis (likelihood of recurrence)
2) Response to tamoxifen (change in likelihood of
recurrence with tamoxifen)
3) Both
Paik et al. ASCO 2004. Abstract #510.
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NSABP B-14 Benefice du Tamoxifène
All Patients (N = 645)
1.0
0.9
0.8
DRFS
0.7
0.6
0.5
0.4
0.3
0.2
Placebo
Tamoxifen
0.1
0.0
0
2
4
6
8
10
12
14
16
Years
Paik et al. ASCO 2004. Abstract #510.
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1.0
0.8
0.8
DRFS
1.0
0.6
0.4
0.6
0.4
Low Risk (RS<18)
N
171
Placebo
Tamoxifen 142
0.2
Int Risk (RS 18-30)
N
85
Placebo
Tamoxifen 69
0.2
0.0
0.0
0
2
4
6
8
10
12
14
16
0
2
4
Years
6
8
10
12
14
16
Years
1.0
0.8
DRFS
DRFS
NSABP B-14 Benefice du Tamoxifène
0.6
0.4
High Risk (RS≥31)1
0.2
Placebo
Tamoxifen
N
99
79
0.0
0
2
4
6
8
Years
10
12
14
16
Paik et al. ASCO 2004. Abstract #510.
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Bénéfice de la chimiothérapie et Oncotype DX®
NSABP B-20 Chemo Benefit Study in N–, ER+ Pts
Design
Tam + MF
Randomized
Tam + CMF
Tam
Objective:
Determine the magnitude of the chemo
benefit as a function of the 21-gene RS assay
Paik et al. J Clin Oncol. 2006;24:3726-3734.
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NSABP B-20 Résultats
Tam vs Tam + Chemo – All 651 Patients
1.0
0.9
4.4% absolute
benefit from
tam + chemo
0.8
DRFS
0.7
0.6
0.5
0.4
0.3
0.2
All Patients
N
424
227
Tam + Chemo
Tam
0.1
Events
33
31
P = 0.02
0.0
0
2
4
6
Years
8
10
12
Paik et al. J Clin Oncol. 2006.
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NSABP B-20 Résultats
1.0
1.0
0.9
0.9
0.8
0.8
0.7
0.7
Low RS
DRFS
0.6
0.5
0.4
0.3
0.2
TAM +(RSChemo
Low Risk Patients
< 18)
Tam +
Chemo
TAM
Tam
0.1
218
135
Int RS
0.5
0.4
Low Risk Patients (RS<18)
N Events
Int Risk Patients (RS 18-31)
N Events
0.3
0.2
8
4
TAM + Chemo
TAM
89
45
Int Risk (RS 18 - 30)
Tam + Chemo
Tam
0.1
9
4
0.0
0.0
0
2
4
6
8
10
0
12
2
p = 0.61
Years
4
6
8
Years
10
12
p = 0.39
1.0
0.9
28% absolute
benefit from
tam + chemo
0.8
0.7
High RS
0.6
DRFS
DRFS
0.6
0.5
0.4
High Risk Patients (RS>31)
N Events
0.3
0.2
High Risk Patients (RS  31)
Tam + Chemo
Tam
TAM + Chemo
TAM
0.1
117
47
13
18
0.0
0
2
4
6
Years
8
10
12
p < 0.001
Paik et al. J Clin Oncol. 2006.
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B-20 Results:
Absolute % Increase in DRFS at 10 Years
n = 353
Low
RS <18
n = 134
Int
RS 18-30
n = 164
High
RS ≥31
0
10%
20%
30%
40%
% Increase in DRFS at 10 Yrs (mean ± SE)
Paik et al. J Clin Oncol. 2006. 20
Standardized Quantitative
Oncotype DX Assay
Recurrence Score in N-, ER+ patients
40%
Intermediate
Risk Group
Distant Recurrence at 10 Years
Low Risk Group
35%
High Risk Group
30%
25%
20%
15%
10%
5%
0%
0
5
10
15
20
25
30
35
40
45
50
Recurrence Score
Lower RS’s
•Lower likelihood of recurrence
•Greater magnitude of TAM benefit
•Minimal, if any, chemotherapy benefit
Higher RS’s
•Greater likelihood of recurrence
•Lower magnitude of TAM benefit
•Clear chemotherapy benefit
1) Paik et al NEJM 2004, 2) Habel et al Breast Cancer Research 2006
3) Paik et al JCO 2006, 4) Gianni et al JCO 2005
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Oncotype DX® en pratique
• Oncotype DX disponible depuis janvier 2004
– Genomic Health Californie
– Envoyer un bloc inclus en paraffine de tumeur ou 6
lames via FedEx avec le kit Oncotype DX™ Specimen
– réponse: +/- 10 jours
– USA : pris en charge
– Coût 3600 US $
– France
– CB obligatoire !
– Délicat +++
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Clinical development stages of genomic diagnostic tests
for breast cancer
Phase I
Discovery
Marker optimization
Phase II
Current evidence
ends here
Independent
validation of
accuracy
Phase III
Prove
clinical utility
95%
confidence interval
PROGNOSTIC TESTS
70-gene prognostic signature
21-gene recurrence score
76-gene prognostic signature
“molecular classification”
70-gene MammaPrint
21-gene Oncotype DX
76-gene VDX2 array
?
PREDICTIVE TESTS
44-gene Tamoxifen predictor
57-gene EC predictor
92-gene Docetaxel predictor
85-gene Docetaxel predictor
30-gene Taxol/FAC predictor
MDACC 2003-0321
MINDACT Trial
PACT Trial
TAILORx Trial Assigning IndividuaLized Options for Treatment (Rx)
ECOG, SWOG, NCCTG, CALGB, NCIC, ACOSOG, and NSABP
Promoteur NCI
Node-Neg, ER-Pos Breast Cancer
Register
Specimen
banking
Oncotype DX® Assay
RS 11-25
RS <10
Hormone
Therapy
Registry
Randomize
Hormone Rx
vs
Chemotherapy
+ Hormone Rx
RS >25
Chemotherapy
+
Hormone Rx
Primary study group
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MINDACT Design
(Microarray in Node-Negative Disease May Avoid
Chemotherapy Trial)
Evaluate clinico-pathological risk (Adjuvant!) AND 70-gene signature risk
32%
N=3300
55%
N=780
Discordant cases
Clinical pathological
AND
70-gene signature
HIGH risk
13%
Clinical pathological
AND
70-gene signature
Clin-Path HIGH risk
LOW risk 70-gene
LOW risk
Clin-Path LOW risk
70-gene HIGH risk
n=1920
Use Clin-Path risk to
decide on adjuvant
chemotherapy or not
chemotherapy
R
Use 70-gene risk to
decide on adjuvant
chemotherapy or not
No chemotherapy
All hormone responsive patients receive endocrine therapy
Buyse M et al, JNCI 2006
ASCO 2007 Updated Recommendations
for Breast Cancer Tumor Markers
• CA 15-3 and CA 27.29
• Carcinoembryonic Antigen (CEA)
• Estrogen receptors and Progesterone receptors (ER and PgR)
• DNA flow cytometry-based proliferation markers
• Immunohistochemically-based markers of proliferation NEW!
• HER2
• p53 as a marker for breast cancer
• Cathepsin D
• Urokinase plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1)
NEW!
• Cyclin E NEW!
• Proteomic Analysis NEW!
• Multiparameter
gene expression analysis NEW!
• Bone marrow micrometastases NEW!
• Circulating Tumor Cells NEW!
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Multiparameter Gene Expression
Analysis for Breast Cancer
• Oncotype DX™ can be used to determine prognosis in newly diagnosed patients
with node-negative, estrogen-receptor positive breast cancer who will receive
tamoxifen. Indications:
– To predict risk of recurrence in patients considering treatment with
tamoxifen
– To identify patients who are predicted to obtain the most therapeutic benefit
from adjuvant tamoxifen and may not require adjuvant chemotherapy
– Patients with high recurrence scores appear to achieve relatively more
benefit from adjuvant chemotherapy (specifically CMF) than from tamoxifen
• Conclusions may not be generalizable to hormonal therapies other than
tamoxifen, or to other chemotherapy regimens.
• Several other multi-parameter assays have been reported and a few are
commercially available, including Mammaprint and the Rotterdam Signature.
However, the Committee felt that the precise clinical utility and appropriate
application for these other assays were insufficiently defined to recommend
their use.
27
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Conclusions
• Les débuts d’une médecine prédictive
individualisée pour le cancer du sein
– Aussi tests prédictifs de sensibilité au Tt
• Oncotype pour N- RH+
• Moins de sur-traitement et plus
d’économies
• Si vous avez des doutes, ou pour faire
bénéficier gratis vos patientes …
participez à MINDACT !!!!
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