Download ASCO_2009_files/Kerr Oncotype Colon QUASAR ASCO 2009

A quantitative multi-gene RT-PCR assay for
prediction of recurrence in stage II colon cancer:
Selection of the genes in 4 large studies and results
of the independent, prospectively-designed
QUASAR validation study
David Kerr1, Richard Gray2, Philip Quirke3, Drew Watson4,
Greg Yothers5, Ian Lavery6, Mark Lee4, Michael O'Connell5,
Steven Shak4, Norman Wolmark5 and the Genomic Health
& QUASAR Colon Teams
1. University of Oxford, Oxford, UK & SIDRA, Qatar; 2. Birmingham
Clinical Trials Unit, Birmingham, UK; 3. Leeds Institute of Molecular
Medicine, Leeds, UK; 4. Genomic Health, Inc., Redwood City, CA;
5. National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA;
6. Cleveland Clinic, Cleveland, OH
1
Disclosures
D. Kerr, consultant, educational grant, Genomic Health, Inc.
R. Gray, educational grant, Genomic Health, Inc.
P. Quirke, consultant, educational grant, Genomic Health, Inc.
D. Watson, employee, Genomic Health, Inc.
G. Yothers, consultant, educational grant, Genomic Health, Inc.
I.C. Lavery, consultant, educational grant, Genomic Health, Inc.
M. Lee, employee, Genomic Health, Inc.
M. J. O'Connell, consultant, educational grant, Genomic Health, Inc.
S. Shak, employee, Genomic Health, Inc.
N. Wolmark, consultant, educational grant, Genomic Health, Inc.
2
The Need for Individualized Therapy in
Stage II Colon Cancer
• The challenge: Which stage II colon cancer patients should
be treated with adjuvant chemotherapy?
– 75-80% cured with surgery alone, but no method to
identify them
– Benefit of chemotherapy is small* and no consensus in
guidelines on who to treat
– Chemotherapy has significant toxicity
• Today, decision to give chemotherapy subjectively based on:
– Clinical/pathologic markers of risk which are inadequate
• Not informative for majority of patients
– Patient age, co-morbidities, preferences
* Lancet 2007 370:2020-9
3
Stage II Colon Cancer: Overall Goal
To develop and validate a multi-gene expression
assay which improves treatment decisions for
patients with stage II colon cancer, providing:
• Individualized assessment of recurrence risk following
surgery
• Identification of patients with differential 5FU/LV benefit
• Independent clinical value in the context of other
measures such as T-stage and MMR/MSI
• Optimized for fixed, paraffin-embedded colon tumor tissue
4
Real-time RT-PCR for RNA Quantification from
Fixed Paraffin-Embedded Tumor Tissue
Reporter
Forward
Primer
R
Probe
Quencher
Q
Polymerization
Reverse
Primer
R
Q
Strand Displacement
and Cleavage of Probe
Q
R
Polymerization
Completed
Cronin et al. Am J Pathol. 2004;164:35-42.
5
Development and Validation of a Multi-Gene
RT-PCR Colon Cancer Assay
Colon Cancer Technical Feasibility
Development Studies
Surgery Alone
NSABP C-01/C-02 (n=270)
Development Studies
Surgery + 5FU/LV
NSABP C-04 (n=308)
Cleveland Clinic (n = 765)
NSABP C-06 (n=508)
Selection of Final Gene List & Algorithm
Standardization and Validation of Analytical Methods
Clinical Validation Study – Stage II Colon Cancer
QUASAR (n=1,436)
Test Prognosis and Treatment Benefit
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Assessment of 761 Candidate Genes in 1,851 Patients in
the Development Studies to Yield Final Pre-specified
Assay for Validation in QUASAR
48 Recurrence and 66 Treatment Benefit Genes
Significant Across Development Studies
Modeling and Analytical Performance
FINAL ASSAY
7 Recurrence Genes 6 Treatment Benefit Genes
RECURRENCE
SCORE
TREATMENT
SCORE
(0-100)
(0-100)
5 Reference Genes
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QUASAR: Evaluable Stage II Colon Cancer
Patients
Parent QUASAR study
n=3,239
Patients with collected blocks
n=2,197 (68%)
707 cases stage III and
rectal cancer
Confirmed stage II colon cancer
n=1,490 (69%)
Final evaluable population
n=1,436
54 excluded (3.6%):
29 synchronous tumors
8 insufficient tissue
7 identifier queries
6 RNA quality/quantity
4 ineligible histology
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QUASAR: Demographics of 1,436 Evaluable
Patients
Characteristic
Age
Gender
T Stage
# Nodes
Examined
LVI
Tumor Grade
Tumor Type
MMR
Location
Values
<60
60 to <70
70+
Female
T4
<12
≥12
Present
High
Mucinous
Deficient
Right
Surgery Alone
(total = 711)
N (%)
251 (35.3)
308 (43.3)
152 (21.4)
302 (42.5)
108 (15.3)
413 (62.9)
244 (37.1)
90 (12.7)
222 (31.2)
144 (20.3)
89 (13.6)
273 (46.9)
Surgery + 5FU/LV
(total = 725)
N (%)
269 (37.1)
317 (43.7)
139 (19.2)
295 (40.7)
113 (15.7)
409 (61.0)
262 (39.0)
110 (15.2)
219 (30.2)
169 (23.3)
92 (14.1)
278 (46.2)
Two Arms are Balanced
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QUASAR: 5FU/LV Chemotherapy Benefit in the
1,436 Evaluable Stage II Colon Cancer Patients
DFS
1.0
Proportion Event Free
1.0
0.8
0.6
0.4
0.2
0.0 Treatment
0
1
Surgery
2
Chemo
3
4
0.8
0.6
0.4
0.2
0.0 Treatment
5
0
Surgery
1
Years
2
Chemo
3
4
5
Years
OS
Proportion Event Free
Proportion Event Free
RFI
1.0
0.8
0.6
0.4
0.2
0.0 Treatment
0
1
Surgery
2
Chemo
3
Years
4
5
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QUASAR: Pre-Specified Primary Endpoint:
Recurrence Risk
Is there a significant relationship
between the risk of recurrence
and the pre-specified
continuous Recurrence Score in
stage II colon cancer patients
randomized to surgery alone?
RECURRENCE SCORE
Calculated from Tumor Gene
Expression
STROMAL
FAP
INHBA
BGN
CELL CYCLE
Ki-67
C-MYC
MYBL2
GADD45B
REFERENCE
ATP5E
GPX1
PGK1
UBB
VDAC2
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QUASAR Results: Colon Cancer Recurrence Score
Predicts Recurrence Following Surgery
Prospectively-Defined Primary Analysis in Stage II Colon Cancer (n=711)
35%
Risk of Recurrence at 3 years
30%
25%
20%
15%
10%
p=0.004
5%
0%
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0
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10
20
30
40
50
60
|
70
Recurrence Score
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QUASAR Results: Recurrence Risk in
Pre-specified Recurrence Risk Groups (n=711)
1.0
Low
Intermediate
High
Range
of RS
Proportion of
patients
<30
43.7%
30-40
30.7%
≥41
25.6%
0.8
Proportion Event Free
Recurrence
Risk Group
0.6
0.4
Recurrence Risk Group
0.2
Low
Comparison of High vs. Low
Recurrence Risk Groups using
Cox Model: HR = 1.47 (p=0.046)
Intermediate
High
0.0
0
1
2
Kaplan-Meier Estimates (95% CI)
of Recurrence Risk at 3 years
12%
( 9% -16%)
18%
22%
(13%-24%)
(16%-29%)
3
4
5
Years
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QUASAR Results: Clinical/Pathological Covariates
and Recurrence
Pre-specified Multivariate Analysis, Surgery Alone Patients
(n=605)
Categories
HR
HR
95% CI
13% Deficient vs. 87% Proficient
0.32
(0.15,0.69)
<.001
15% T4 vs. 85% T3
1.83
(1.23,2.75)
0.005
Tumor Grade
29% High vs. 71% Low
0.62
(0.40,0.96)
0.026
Number of Nodes Examined
62% <12 vs. 38% ≥12
1.47
(1.01,2.14)
0.040
13% Present vs. 87% Absent
1.40
(0.88,2.23)
0.175
continuous per 25 units
1.61
(1.13,2.29)
0.008
Variable
Mismatch Repair (MMR)
T Stage
Lympho-Vascular Invasion
Recurrence Score
P value
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QUASAR Results: Recurrence Score and
Alternative Endpoints
Disease
Free
Survival
Overall
Survival
Variable
RS per 25 units
Variable
RS per 25 units
HR
HR
95% CI
P value
1.42
(1.09,1.84)
0.010
HR
HR
95% CI
P value
1.33
(1.01,1.76)
0.041
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QUASAR Results: Prediction of Differential
5FU/LV Benefit for Treatment Score
• Continuous Treatment Score and Treatment Benefit with
5FU/LV
– Treatment Score by Treatment Interaction for RFI:
interaction p = 0.19
• Selected Secondary Analyses
– Treatment Score by Treatment Interaction not
significant when adjusted for prognostic covariates
– Treatment Score by Treatment Interaction not
significant for DFS (interaction p=0.12) or OS
(interaction p=0.15)
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QUASAR Results: Prediction of Differential
5FU/LV Benefit for Recurrence Score
• Secondary Analysis: RS as a predictor of Chemotherapy
Benefit: interaction p=0.69
– No significant difference in PROPORTIONAL benefit of
chemotherapy was observed at low RS and at high RS
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Risk of recurrence at 3 years
QUASAR Results: Recurrence Score, T Stage, and
MMR Deficiency are Key Independent Predictors
of Recurrence in Stage II Colon Cancer
45%
T4 stage (13%)
40%
35%
30%
25%
T3 and MMR proficient (76%)
20%
15%
10%
MMR deficient (11%)
5%
0%
0
10
20
30
40
50
60
70
Recurrence Score
NB. 17 patients had both T4 and MMR Deficient tumors and had recurrence risks that
were similar to those for patients with T3 and MMR proficient tumors and were not
18
included in the plot
Summary and Conclusions
• The prospectively-defined continuous Recurrence Score has been
validated as a predictor of recurrence in stage II colon cancer patients
following surgery, and provides independent value beyond available
measures
• A separate score, based on a distinct set of 6 genes, was not
validated for prediction of differential 5FU/LV benefit
Implications for Clinical Practice
• The continuous RS provides individualized assessment of recurrence
risk and will have the greatest clinical utility when used in conjunction
with T stage and Mismatch Repair (MMR/MSI), particularly for the
majority of patients for whom those markers are uninformative (~70%
of pts)
• This is the first demonstration that a prospectively defined gene
expression assay can independently predict recurrence in colon
cancer
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Acknowledgements
• QUASAR Study Team
Laura Magill
Kelly Handley
Zoe Gray
Claire Beaumont
Rachel Midgley
• NSABP Study Team
Joe Costantino
Soon Paik
• Genomic Health Colon Team
Kim Langone
Rick Baehner
Joffre Baker
Margarita Lopatin
Carl Yoshizawa
Wayne Cowens
Lauren Intagliata
Claire Pomeroy
• Cleveland Clinic Study Team
• MRC, UK and CRUK for funding QUASAR trial
• Patients and investigators who participated in the NSABP, Cleveland
Clinic, and QUASAR studies
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