Download ColoPrint / MSI-Print

Title of the
Poster Presentation
Here to Predict Outcome and Chemotherapy
Genomic
Classifiers
(ColoPrint Goes
/ MSI-Print)
Authors of the Poster Presentation Goes Here
Benefit
in Stage II and III Colon Cancer Patients
Institutional and/or Graduate School of Biomedical Sciences Affiliation Goes Here
Scott Kopetz1*, Zhi-Qin Jiang1, Michael J Overman1, Christa Dreezen2, Sun Tian2, Ying Li2, Iris Simon2, George J Chang3, Dipen M Maru4
36X60
Department of 1Gastrointestinal Medical Oncology, 3Surgical Oncology, 4Pathology, University of Texas, MD Anderson Cancer Center. 2Agendia NV, Amsterdam, Netherlands and Agendia Inc., Irvine CA
Abstract #378
Background: Although the benefit of chemotherapy in
stage II and III colon cancer patients is significant, many
patients might not need adjuvant chemotherapy because
they have a good prognosis even without additional
treatment. ColoPrint is a gene expression classifier that
distinguish patients with low or high risk of disease
recurrence. It was developed using whole genome
expression data and has been validated in public datasets,
independent European patient cohorts and technical
studies.
Results
ColoPrint:
•
•
Gene expression signature
Developed on tumor tissue from 188 patients with known
outcome, using whole genome arrays.
From the comprehensive pool of 33,834 gene probes, an
optimal set of 18 nonredundant probes showed robust
clinical outcome association.
These 18 genes were used to construct a nearest centroidbased prognostic classifier (ColoPrint).
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MSI-Print:
Methods: In this study, the commercial ColoPrint test was
validated in stage II (n=96) and III patients (n=94) treated at
the MD Anderson Cancer Center from 2001 to 2009. Frozen
tissue specimen, clinical parameters and follow-up data
(median follow-up 64 months) were available. The 64-gene
MSI-signature developed to identify patients with deficient
mismatch repair (dMMR) system was evaluated for its
accuracy to identify MSI patients and also for prognosis.
Results: In this cohort, ColoPrint classified 56% of stage II
and III patients as being at low risk. The 3-year recurrenceFree-Survival (RFS) was 90.6% for Low Risk and 78.4% for
High Risk patients with a HR of 2.33 (P=0.012). In uni-and
multivariate analysis ColoPrint and stage were the only
significant factors to predict outcome. The MSI-signature
classified 47 patients (24.6%) as MSI-H and most MSI-H
patients were ColoPrint low risk (81%). Patients who were
ColoPrint low risk and MSI-H by signature had the best
outcome with a 3-year RFS of 95%, while patients with
ColoPrint high risk had a worse outcome independently of
the MSI-status. Low Risk ColoPrint patients had a good
outcome independent of stage or chemotherapy treatment
(90.1% 3-year RFS for treated patients, 91.4% for untreated
patients) while ColoPrint high risk patients treated with
adjuvant chemotherapy had 3-year RFS of 84%, compared
to 70.1% 3-year RFS in untreated patients (P=0.037).
Conclusions: The combination of ColoPrint and MSI-Print
improves the prognostic accuracy in stage II and stage III
patients and may help the identification of patients at higher
risk who are more likely to benefit from additional treatment.
Background
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•
•
•
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A genomic signature for the
detection of colorectal cancer
patients with microsatellite
instability phenotype and
high mutation frequency.
MSI-Print identifies not only
patients with MSI-H as
measured by traditional
methods but all patients with
hypermutation phenotype.
The 64-gene MSI signature
could be linked to a deficient
mismatch repair (dMMR)
phenotype, as both MSI and
MSI-like patients showed a
high mutation frequency.
Methods
•
•
•
•
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Stage II and III colon cancer patients from MD Anderson
Cancer Center
Staging pTNM by AJCC 6th edition
Validation cohort: N=190
Frozen tumor and normal tissue available
Surgery time: 2001-2009
Median follow-up time: 64 months
RNA extracted and microarray performed by Agilent
platform as previously described
MSI by IHC or PCR has not been performed
Results
Table 1. 190 stage II and III colon cancer patients characteristics
Variables
56% of patients were considered low-risk
ColoPrint is prognostic for recurrence (Fig.1)
-- 3-year RFS of 90.6% and 5-year RFS of 87.1% for low
risk group, 78.4% and 71.5% for high risk group.
ColoPrint
Low risk
N=107
ColoPrint
High risk
N=83
n (%)
97 (51)
62
96 (51)
n (%)
54 (50)
62
59 (55)
n (%)
43 (52)
59
37 (45)
53 (50)
54 (50)
43 (52)
40 (48)
Male gender
Median age
Right-sided tumor
TNM Stage
II
96 (51)
III
94 (49)
pT stage
T1
0 (0)
T2
8 (4)
T3
152 (80)
T4
30 (16)
pN stage
N0
96 (51)
N1
60 (32)
N2
34 (18)
Differentiation
Well to Moderate
156 (82)
Poor
34 (18)
Obstruction & Perforation
Yes
9 (5)
No
158 (83)
Unknown
23 (12)
P-value
0 (0)
4 (4)
82 (77)
21 (20)
0.855
0.487
0.053
0.756
Fig. 3. Probability of recurrence or death between ColoPrint
high-risk and low-risk group with or without adjuvant
chemotherapy.
• In univariate analysis, significant prognostic factors
were ColoPrint and stage.
• In multivariate analysis, both ColoPrint (HR 2.55
for high risk) and stage (HR 3.48 for stage III)
remained significant (Table 2.)
0 (0)
4 (5)
70 (84)
9 (11)
43 (52)
27 (33)
13 (16)
106 (56)
68 (36)
16 (8)
21 (11)
120 (63)
70 (37)
61 (32)
47 (25)
Fig. 4. Probability of recurrence or death between
MSI-Print high and MSI-Print low group.
CP low risk, MSI-Print low
CP low risk, MSI-Print high
CP high risk, MSI-Print low
CP high risk, MSI-Print high
P=0.059
0.009
81 (76)
26 (24)
75 (90)
8 (10)
Table 2. Multivariate cox regression analysis for stage II
and III colon cancer.
0.695
4 (4)
90 (84)
13 (12)
5 (6)
68 (82)
10 (12)
Covariates
ColoPrint
(high-risk vs. low-risk)
TNM Stage
(stage III vs. stage II)
0.245
Yes
No
Both
Median LN assessed
Adjuvant chemotherapy
Median OS months
Months to recurrence
MSI-Print high
Time (months)
Time (months)
0.540
53 (50)
33 (31)
21 (20)
P=0.309
P=0.037
0.252
Lymphvascular/
Perineural invasion
54 (50)
43 (40)
10 (9)
22 (21)
71 (66)
75 (70)
69 (64)
38 (36)
52 (63)
25 (30)
6 (7)
20 (24)
49 (59)
64 (77)
52 (62)
9 (11)
HR
95% CI
P-value
2.55
1.17-5.52
0.018
3.48
1.48-8.19
0.004
Time (months)
Fig. 5 Probability of recurrence or death between
ColoPrint high-risk and low-risk group combined
with MSI-print.
Conclusions
0.493
0.300
0.445
0.037
<0.001
•
ColoPrint is independent of traditional ASCO high risk
features, with 50% of cases discordant based on
presence/absence of high risk features and ColoPrint
results (Table 3.)
•
Coloprint and MSI-Print can identify
high-risk patients group among stage II
and III colon cancer patients after
surgery.
•
This may help to select high risk patients
who would derive the most benefit from
additional treatment.
Table 3. ColoPrint risk groups vs. ASCO clinical risk groups
•
•
•
Total
N=190
MSI-Print low
MSI-Print high
When separated by stage, ColoPrint remained prognostic
(Fig. 2.)
-- 3-year RFS of 95.5% in low risk and 88.4% in high risk
group for stage II
-- 3-year RFS of 84.3% in low risk and 64.2% in high risk
group for stage III
ColoPrint high risk ColoPrint low risk
ASCO high risk
clinical features
ASCO low risk
clinical features
34%
41%
References
1.
9%
16%
Benefit of chemotherapy in stage II and III colon
cancer patients is significant
However, many low-risk patients might not need
adjuvant chemotherapy
P=0.012
Time (months)
Fig. 1. Probability of recurrence or death between ColoPrint
high-risk and low-risk group.
25% of patients were characterized as MSI-Print high
which was previously defined to incorporate both MSIhigh tumors and additional tumors which share similar
gene expression features
•
In this population, MSI-Print did not provide independent
prognostic ability, but provided additional information
when combined with ColoPrint. (Fig. 4 and Fig. 5)
P<0.001
How to identify low-risk and high-risk patients still
remains unclear
*Corresponding author : Scott Kopetz, M.D., Ph.D:
[email protected]
•
Time (months)
Fig. 2. Probability of recurrence or death between ColoPrint
high-risk and low-risk group in stage II or stage III patients.
--Most MSI-Print high patients were ColoPrint low risk.
These patients had the best outcome with RFS of 95% at
3 years.
2.
3.
Salazar R, Roepman P, Capella G et al.
Gene expression signature to improve
prognosis prediction of stage II and III
colorectal cancer. J Clin Oncol 2011; 29:
17-24.
Maak M, Simon I, Nitsche U et al.
Independent Validation of a Prognostic
Genomic Signature (ColoPrint) for
Patients With Stage II Colon Cancer. Ann
Surg 2013.
Tian S, Roepman P, Popovici V et al. A
robust genomic signature for the detection
of colorectal cancer patients with
microsatellite instability phenotype and
high mutation frequency. J Pathol 2012;
228: 586-595.