Download Recurrence Risk - Research To Practice

A Quantitative Multi-Gene
RT-PCR Assay for Prediction of
Recurrence in Stage II Colon
Cancer (CC): Selection of the
Genes in 4 Large Studies and
Results of the Independent,
Prospectively-Designed QUASAR
Validation Study
Kerr D et al.
ASCO 2009; Abstract 4000. (Oral Presentation)
Study Goals
Develop and validate a multi-gene expression assay
that improves treatment decisions for patients with
stage II colon cancer, and…
– provides individualized assessment of recurrence risk
following surgery
– identifies patients with differential 5FU/LV benefit
– provides clinical value in the context of other
measures such as T-stage and MMR/MSI
– is optimized for fixed, paraffin-embedded colon
tumor tissue
Assay Development and Validation
Colon Cancer Technical Feasibility
Development Studies
Surgery Alone
Development Studies
Surgery + 5FU/LV
NSABP C-01/C-02 (n=270)
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
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
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 (711 surgery alone,
725 surgery + chemo)
54 excluded (3.6%):
29 synchronous tumors
8 insufficient tissue
7 identifier queries
6 RNA quality/quantity
4 ineligible histology
QUASAR: Pre-Specified Primary
Endpoint — Recurrence Risk
RECURRENCE SCORE
Calculated from Tumor
Gene Expression
Is there a significant relationship
between the risk of recurrence
and the pre-specified continuous
Recurrence Score in patients with
stage II colon cancer randomly
assigned to surgery alone?
STROMAL
FAP
INHBA
BGN
CELL CYCLE
Ki-67
C-MYC
MYBL2
GADD45B
REFERENCE
ATP5E
GPX1
PGK1
UBB
VDAC2
QUASAR Results: Continuous RS
Predicts Recurrence in Stage II
CC (N = 711) Following Surgery
35%
30%
25%
3-year
recurrence
rate
20%
15%
10%
5%
p = 0.004
0%
0
10
20
30
40
50
60
70
Recurrence Score
Source: With permission from Kerr D et al. ASCO 2009; Abstract 4000.
QUASAR Results: Recurrence Risk
in Pre-Specified Recurrence Risk
Groups (n = 711)
1.0
0.8
Proportion
Event Free
0.6
0.4
Recurrence
Risk Group
Low
Intermediate
High
Range
of RS
Proportion
of patients
<30
43.7%
30-40
30.7%
≥41
25.6%
Kaplan-Meier Estimates (95% CI)
of Recurrence Risk at 3 years
Recurrence Risk Group
Low
12%
Intermediate 18%
High
22%
0.2
0.0
0
1
2
(9% -16%)
(13%-24%)
(16%-29%)
3
Years
Source: With permission from Kerr D et al. ASCO 2009; Abstract 4000.
4
5
Results: Clinical/Pathologic
Covariates and Recurrence
Prespecified Multivariate Analysis: Patients Who Underwent Surgery
Alone (n=605)
Variable
Categories
HR
P value
13% deficient vs 87% proficient
0.32
<0.001
15% T4 vs 85% T3
1.83
0.005
Tumor grade
29% High vs 71% Low
0.62
0.026
No. nodes examined
62% <12 vs 38% >12
1.47
0.040
13% Present vs 87% Absent
1.40
0.175
Continuous
1.61
0.008
MMR
T stage
LVI
RS per 25 units
Source: Kerr D et al. ASCO 2009; Abstract 4000.
RS, T Stage and MMR Deficiency:
Key Independent Predictors of
Recurrence in Stage II CC
T4 stage
(13% of Stage II patients)
45%
40%
35%
30%
3-year
25%
recurrence
rate 20%
T3 and MMR proficient
(76% of Stage II patients)
15%
10%
MMR deficient
(11% of Stage II patients)
5%
0%
0
10
20
30
40
50
60
70
Recurrence Score
Source: With permission from Kerr D et al. ASCO 2009; Abstract 4000.
Treatment Score
Prediction of 5FU/LV Benefit

Treatment Score by treatment interaction was not
significant for RFS (p = 0.19), DFS (p = 0.12) or
OS (p = 0.15)

"The proportional benefits of chemotherapy were
maintained across the recurrence score prognostic
categories. Therefore if you had a high chance of the
tumor recurring as predicted by the Recurrence Score,
the absolute benefits of chemotherapy would be
somewhat higher.”
Editor: Overall, QUASAR demonstrated that chemo resulted
in fewer recurrences — HR = 0.78 (0.67-0.91; p = 0.001)*
*Lancet 2007; 370: 2020-29
Source: Kerr D et al. ASCO 2009; Abstract 4000.
Key Conclusions



First demonstration that a prospectively-defined gene
expression assay can independently predict recurrence in
stage II CC following surgery
– Recurrence Score (RS) provides independent value
beyond available prognostic factors
RS provides individualized assessment of recurrence risk
– 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 patients)
The continuous Treatment Score (TS) did not predict a
differential benefit from 5FU/LV
Source: Kerr D et al. ASCO 2009; Abstract 4000.