References

1. 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.

2. 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.

3. 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.

Title of the Poster Presentation Goes HereAuthors of the Poster Presentation Goes Here

Institutional and/or Graduate School of Biomedical Sciences Affiliation Goes Here 36X60

Genomic Classifiers (ColoPrint / MSI-Print) to Predict Outcome and Chemotherapy Benefit in Stage II and III Colon Cancer Patients

Scott Kopetz1*, Zhi-Qin Jiang1, Michael J Overman1, Christa Dreezen2, Sun Tian2, Ying Li2, Iris Simon2, George J Chang3, Dipen M Maru4

Department of 1Gastrointestinal Medical Oncology, 3Surgical Oncology, 4Pathology, University of Texas, MD Anderson Cancer Center. 2Agendia NV, Amsterdam, Netherlands and Agendia Inc., Irvine CA

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. 

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 recurrence-Free-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.

• 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 centroid-based prognostic classifier (ColoPrint).

• 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.

MSI-Print:

Table 1. 190 stage II and III colon cancer patients characteristics

ColoPrint:

Fig. 1. Probability of recurrence or death between ColoPrint high-risk and low-risk group.

Fig. 3. Probability of recurrence or death between ColoPrint high-risk and low-risk group with or without adjuvant chemotherapy.

Fig. 2. Probability of recurrence or death between ColoPrint high-risk and low-risk group in stage II or stage III patients.

Fig. 5 Probability of recurrence or death between ColoPrint high-risk and low-risk group combined with MSI-print.

Table 2. Multivariate cox regression analysis for stage II and III colon cancer.

Abstract #378

• 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.

Fig. 4. Probability of recurrence or death between MSI-Print high and MSI-Print low group.

Table 3. ColoPrint risk groups vs. ASCO clinical risk groups

Background

• Benefit of chemotherapy in stage II and III colon cancer patients is significant

• However, many low-risk patients might not need adjuvant chemotherapy

• How to identify low-risk and high-risk patients still remains unclear

• 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

P<0.001

Methods

*Corresponding author : Scott Kopetz, M.D., Ph.D: skopetz@mdanderson.org

Results

• 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.

• 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

Results

• 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.)

• 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.)

Conclusions

• 25% of patients were characterized as MSI-Print high which was previously defined to incorporate both MSI-high 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)

--Most MSI-Print high patients were ColoPrint low risk. These patients had the best outcome with RFS of 95% at 3 years.

  ColoPrint high risk ColoPrint low risk

ASCO high riskclinical features

34% 41%

ASCO low riskclinical features

9% 16%

     

VariablesTotal

N=190

ColoPrint Low risk

N=107

ColoPrint High risk

N=83P-value

    n (%) n (%) n (%)  Male gender 97(51) 54(50) 43(52) 0.855Median age 62 62 59 0.487Right-sided tumor 96(51) 59(55) 37(45) 0.053TNM Stage 0.756

II 96(51) 53(50) 43(52)III 94(49) 54(50) 40(48)

pT stage 0.252T1 0(0) 0(0) 0(0)T2 8(4) 4(4) 4(5)T3 152(80) 82(77) 70(84)T4 30(16) 21(20) 9(11)

pN stage 0.540N0 96(51) 53(50) 43(52)N1 60(32) 33(31) 27(33)N2 34(18) 21(20) 13(16)

Differentiation 0.009Well to Moderate 156(82) 81(76) 75(90)Poor 34(18) 26(24) 8(10)

Obstruction & Perforation 0.695Yes 9(5) 4(4) 5(6)No 158(83) 90(84) 68(82)Unknown 23(12) 13(12) 10(12)

Lymphvascular/Perineural invasion

0.245

Yes 106(56) 54(50) 52(63)No 68(36) 43(40) 25(30)Both 16(8) 10(9) 6(7)

Median LN assessed 21(11) 22(21) 20(24) 0.493Adjuvant chemotherapy 120(63) 71(66) 49(59) 0.300Median OS months 70(37) 75(70) 64(77) 0.445Months to recurrence 61(32) 69(64) 52(62) 0.037MSI-Print high 47(25) 38(36) 9(11) <0.001

Covariates HR 95% CI P-valueColoPrint

(high-risk vs. low-risk)2.55 1.17-5.52 0.018

TNM Stage (stage III vs. stage II)

3.48 1.48-8.19 0.004

       

Time (months) Time (months)

Time (months)

MSI-Print lowMSI-Print high

Time (months)

CP low risk, MSI-Print lowCP low risk, MSI-Print highCP high risk, MSI-Print lowCP high risk, MSI-Print high

Time (months)

P=0.037 P=0.309

P=0.059

P=0.012