A Validation Study for Recurrence Risk Stratification of Stage II Colon Cancer Using the 55-Gene Classifier

4000 Background: New clinical tools are needed to improve risk assessment and treatment decisions in stage II colon cancer. Four development studies [Surgery (Sx) alone: NSABP C-01/C-02 (n=270) and CCF study (n=765); Sx+5FU/LV: NSABP C-04 (n=308) and C-06 (n=508)] were performed to select the genes for prediction of recurrence and 5FU/LV benefit. To determine clinical utility of the prespecified assay, we performed a large, independent, prospectively designed, clinical validation study in stage II colon cancer pts from the QUASAR trial. Methods: Gene expression was quantitated by RT-PCR from 30 μm manually microdissected fixed paraffin-embedded primary colon cancer tissue. Recurrence-free interval (RFI), disease-free survival (DFS), and overall survival (OS) were analyzed using Cox regression. Results: Combined analysis of the four development studies (total n=1,851; 761 candidate genes) identified 48 genes significantly associated with recurrence risk and 66 genes predictive of 5FU/LV benefit. Multivariate analysis, in the context of stage, grade, nodes examined, and MSI status, yielded 18 genes (7 prognostic genes, 6 predictive genes, 5 reference genes) and separate prognostic recurrence score (RS) and predictive treatment score (TS) algorithms. In the QUASAR validation study, tumor blocks were collected for 68% of pts; 1,490 pts with blocks had stage II colon cancer and RT-PCR was successful in 1,436 eligible pts (711 Sx, 725 Sx+5FU/LV). Median FU=6.6 yrs. In the primary analysis of RFI in pts following Sx, the RS predicted recurrence risk (HR/25 units=1.58, 95% CI 1.15–2.15; p=0.004). The RS also predicted DFS (p=0.01) and OS (p=0.04). Recurrence risk increased monotonically with increasing RS. In multivariate analyses, RS retained prognostic significance (p=0.008) independent of mismatch repair (MMR), T stage, nodes examined, grade, and lymphovascular invasion. MMR deficiency (HR=0.31, 95% CI 0.15–0.63; p<0.001) and T4 stage (HR=1.94, 95% CI 1.35–2.79; p=0.005), together ∼25% of pts, also were independently prognostic. 5FU/LV benefit was significant (p<0.001). However, TS was not validated as a predictor of 5FU/LV benefit (interaction p=0.19). Conclusions: The colon cancer recurrence score is a validated, independent predictor of individualized recurrence risk for stage II colon cancer patients following surgery. [Table: see text]

Download Full-text

Tumour budding is a reproducible index for risk stratification of patients with Stage II colon cancer

Colorectal Disease ◽

10.1111/codi.12454 ◽

2014 ◽

Vol 16 (4) ◽

pp. 259-264 ◽

Cited By ~ 32

Author(s):

Y.-H. Lai ◽

L.-C. Wu ◽

P.-S. Li ◽

W.-H. Wu ◽

S.-B. Yang ◽

...

Keyword(s):

Colon Cancer ◽

Risk Stratification ◽

Stage Ii ◽

Stage Ii Colon Cancer ◽

Tumour Budding

Download Full-text

The PARSC trial, a prospective study for the assessment of recurrence risk in stage II colon cancer (CC) patients using ColoPrint.

Journal of Clinical Oncology ◽

10.1200/jco.2010.28.15_suppl.tps199 ◽

2010 ◽

Vol 28 (15_suppl) ◽

pp. TPS199-TPS199 ◽

Cited By ~ 2

Author(s):

R. Salazar ◽

J. Marshall ◽

L. Stork-Sloots ◽

I. Simon ◽

M. Lutke Holzik ◽

...

Keyword(s):

Colon Cancer ◽

Prospective Study ◽

Recurrence Risk ◽

Stage Ii ◽

Stage Ii Colon Cancer ◽

A Prospective Study

Download Full-text

Specific activity of cyclin dependent kinase 1 as a novel predictor of recurrence risk in stage II colon cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.4_suppl.402 ◽

2011 ◽

Vol 29 (4_suppl) ◽

pp. 402-402

Author(s):

M. Maak ◽

E. Zeestraten ◽

M. Shibayama ◽

T. Schuster ◽

H. Friess ◽

...

Keyword(s):

Colon Cancer ◽

High Risk ◽

Cancer Patients ◽

Specific Activity ◽

Risk Group ◽

Tumor Resection ◽

Recurrence Risk ◽

High Risk Group ◽

Stage Ii ◽

Stage Ii Colon Cancer

402 Background: Altered cell cycle dynamics and check points are typical features of solid tumors, and cyclin dependent kinases (CDKs) play pivotal roles in these processes. Previously we have demonstrated that CDK-based analysis, composed of CDK1 and CDK2, is useful in the prediction of outcomes in early breast cancer patients (Ann Oncol. 19(1):68-72, 2008, Br J Cancer. 100(3):494-500, 2009). Clinically, there is a need for risk stratification in patients with stage II colon cancer who have a recurrence risk of 20 to 30%. Therefore we investigated the use of CDK-based analysis for recurrence prediction of stage II colon cancer patients. Methods: Fresh frozen tissue samples of 254 patients with histologically confirmed adenocarcinoma of the colon, UICC stage II, who received primary tumor resection in Munich (217 cases), and Leiden (37 cases) were used. Protein expression and activity of CDK1 and CDK2 were determined by in vitro assays as previously described. Specific activity (SA) of CDKs was calculated as kinase activity in relation to its corresponding mass concentration. Results: Development of distant metastasis was observed in 27 patients (10.6%) after a median follow up of 86 months. We found that predictive performance of CDK1SA, but not CDK2SA, for the metastasis was substantial and almost constant for long-term event prediction (average area under the curve (AUC) = 0.69). Tumor recurrence risk analysis in association with CDK1SA identified a low- (41% of population) and high- risk group (59%). Cox proportional hazard model analysis retained the CDK-based patient classification as an independent prognostic factor for distant metastases-free survival (low vs. high-risk group: Hazard ratio = 6.2, 95% CI: 1.45 to 26.9, p=0.0049). Clinical parameters such as grading, T-categories, age, and sex were excluded as confounding factors for CDK1SA-risk. Conclusions: CDK1SA allows stratification of different risk subgroups of stage II colon cancer patients. CDK1SA-based analysis is useful for predicting patients with high risk of distant recurrence, who should be treated with chemotherapy. No significant financial relationships to disclose.

Download Full-text

The PARSC trial, a prospective study for the assessment of recurrence risk in stage II colon cancer (CC) patients using ColoPrint.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.678 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 678-678 ◽

Cited By ~ 2

Author(s):

Ramon Salazar ◽

Jan Willem de Waard ◽

Bengt Glimelius ◽

John Marshall ◽

Joost Klaase ◽

...

Keyword(s):

Risk Assessment ◽

Colon Cancer ◽

High Risk ◽

Prospective Study ◽

Relapse Rate ◽

Recurrence Risk ◽

Low Risk ◽

Stage Ii ◽

Risk Patients ◽

Stage Ii Colon Cancer

678 Background: An 18-gene expression profile, ColoPrint, has been developed for identifying CC patients more likely to develop recurrent disease and who would be candidates for adjuvant chemotherapy. The gene signature was validated in in-silico datasets and independent patient cohorts of stage II and III patients. Uni-and multivariate analysis was performed on the pooled stage II patient set (n=320) who had a median follow-up of 70 months. ColoPrint identified two-third of the stage II patients (209/320) as low risk. The 3-year relapse-free survival was 94% for Low Risk patients and 79% for High Risk patients with a HR of 2.74 (95% CI 1.54 - 4.88; p=0.006). Moreover, the profile stratified patients independent of ASCO clinical risk factors. Methods: A prospective trial, PARSC (Prospective study for the Assessment of Recurrence risk in Stage II CC patients) using ColoPrint has been initiated. Objectives are: (1) to validate the performance of ColoPrint in estimating the 3-year relapse rate in patients with stage II colon cancer; (2) to compare the risk assessment in stage II patients using the ColoPrint profile vs. a clinical risk assessment based on Investigator’s assessment of risk and ASCO high-risk recommendations; (3) to investigate therapy as a potential confounding factor for ColoPrint results; and (4) to assess the performance of ColoPrint in estimating the 3-year relapse rate in patients with stage III colon cancer. Inclusion criteria: age ≥ 18 years, adenocarcinoma of the colon, stage II and III, no prior neo-adjuvant therapy, no synchronous tumors, fresh tumor sample, and written informed consent. The treatment of the patient is at the discretion of the physician adhering to National Comprehensive Cancer Network (NCCN)-approved regimens or a recognized alternative. Results: The trial started in Sept. 2008 with currently 30 participating sites in 11 countries. Thus far, 288 eligible stage 2 and 251 stage 3 patients have been enrolled. Conclusions: The aim is to enroll 575 stage II patients to differentiate between 3 year RFS predicted by ColoPrint and clinical factors.

Download Full-text

2160 GIV as a novel marker of recurrence risk in MMR proficient stage II colon cancer

European Journal of Cancer ◽

10.1016/s0959-8049(16)31081-4 ◽

2015 ◽

Vol 51 ◽

pp. S387

Author(s):

P Gibbs ◽

J. Tie ◽

P Ghosh ◽

A. Muranyi ◽

P Brunhoeber ◽

...

Keyword(s):

Colon Cancer ◽

Recurrence Risk ◽

Stage Ii ◽

Stage Ii Colon Cancer

Download Full-text

Validation of the 12-Gene Colon Cancer Recurrence Score in NSABP C-07 As a Predictor of Recurrence in Patients With Stage II and III Colon Cancer Treated With Fluorouracil and Leucovorin (FU/LV) and FU/LV Plus Oxaliplatin

Journal of Clinical Oncology ◽

10.1200/jco.2012.47.3116 ◽

2013 ◽

Vol 31 (36) ◽

pp. 4512-4519 ◽

Cited By ~ 99

Author(s):

Greg Yothers ◽

Michael J. O'Connell ◽

Mark Lee ◽

Margarita Lopatin ◽

Kim M. Clark-Langone ◽

...

Keyword(s):

Colon Cancer ◽

Adjuvant Therapy ◽

Cox Regression ◽

Cancer Recurrence ◽

Recurrence Score ◽

Recurrence Risk ◽

Stage Ii ◽

Stage Iii ◽

Treatment Benefit ◽

Stage Ii Colon Cancer

Purpose Accurate assessments of recurrence risk and absolute treatment benefit are needed to inform colon cancer adjuvant therapy. The 12-gene Recurrence Score assay has been validated in patients with stage II colon cancer from the Cancer and Leukemia Group B 9581 and Quick and Simple and Reliable (QUASAR) trials. We conducted an independent, prospectively designed clinical validation study of Recurrence Score, with prespecified end points and analysis plan, in archival specimens from patients with stage II and III colon cancer randomly assigned to fluorouracil (FU) or FU plus oxaliplatin in National Surgical Adjuvant Breast and Bowel Project C-07. Methods Recurrence Score was assessed in 892 fixed, paraffin-embedded tumor specimens (randomly selected 50% of patients with tissue). Data were analyzed by Cox regression adjusting for stage and treatment. Results Continuous Recurrence Score predicted recurrence (hazard ratio for a 25-unit increase in score, 1.96; 95% CI, 1.50 to 2.55; P < .001), as well as disease-free and overall survival (both P < .001). Recurrence Score predicted recurrence risk (P = .001) after adjustment for stage, mismatch repair, nodes examined, grade, and treatment. Recurrence Score did not have significant interaction with stage (P = .90) or age (P = .76). Relative benefit of oxaliplatin was similar across the range of Recurrence Score (interaction P = .48); accordingly, absolute benefit of oxaliplatin increased with higher scores, most notably in patients with stage II and IIIA/B disease. Conclusion The 12-gene Recurrence Score predicts recurrence risk in stage II and stage III colon cancer and provides additional information beyond conventional clinical and pathologic factors. Incorporating Recurrence Score into the clinical context may better inform adjuvant therapy decisions in stage III as well as stage II colon cancer.

Download Full-text

Faculty Opinions recommendation of Biologic determinants of tumor recurrence in stage II colon cancer: validation study of the 12-gene recurrence score in cancer and leukemia group B (CALGB) 9581.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718013262.793479522 ◽

2013 ◽

Author(s):

Daniel Vorobiof ◽

Keo Tabane

Keyword(s):

Colon Cancer ◽

Validation Study ◽

Tumor Recurrence ◽

Recurrence Score ◽

Stage Ii ◽

Stage Ii Colon Cancer ◽

Group B ◽

Leukemia Group

Download Full-text

Validation of the 12-gene colon cancer recurrence score (RS) in NSABP C07 as a predictor of recurrence in stage II and III colon cancer patients treated with 5FU/LV (FU) and 5FU/LV+oxaliplatin (FU+Ox).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.3512 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 3512-3512 ◽

Cited By ~ 10

Author(s):

Michael O'Connell ◽

Mark Lee ◽

Margarita Lopatin ◽

Greg Yothers ◽

Kim Clark-Langone ◽

...

Keyword(s):

Colon Cancer ◽

Cox Regression ◽

Cox Model ◽

Disease Free Survival ◽

Recurrence Score ◽

Recurrence Risk ◽

Stage Ii ◽

Rt Pcr ◽

Relative Benefit ◽

Stage Ii Colon Cancer

3512 Background: Standardized clinical tools which accurately quantify recurrence risk are needed for optimal adjuvant treatment of colon cancer. The 12-gene RS has been validated in stage II colon cancer pts from QUASAR and CALGB 9581. We conducted a large prospectively-designed clinical validation study of RS, w/ pre-specified endpoints, methods, and analysis plan, in stage II and III colon cancer pts randomized to FU or FU+Ox in NSABP C-07. Methods: 50% of C-07 pts w/ tissue were randomly selected, stratified on stage (AJCC 6th) and recurrence. Gene expression was quantitated by RT-PCR on 25 µm manually microdissected fixed colon tumor tissue. Data were analyzed by Cox regression controlling for stage and treatment (TRT). Results: RT-PCR was successful in 892/921 pts (97%): 449 FU, 443 FU + Ox; 264 st II, 409 st IIIA/B, 219 st IIIC. The primary endpoint was met: RS predicted recurrence (HR/25 units=1.96, 95% CI 1.50-2.55 p<.001). RS also predicted disease-free survival (p<.001) and overall survival (p<.001). RS predicted recurrence (p=.001) independent of T and N stage, MMR, nodes examined, grade, and TRT. Predefined high RS group (26% of pts) had higher recurrence risk than low RS group (39% of pts): HR=2.11, p<.001. Cox model 5 yr recurrence risk (95%CI) in FU treated pts by RS group (low, int, high): st II 9% (6-13%), 13% (8-17%), 18% (12-25%); st IIIA/B 21% (16-26%), 29% (24-34%), 38% (30-46%); st IIIC 40% (32-48%), 51% (43-59%), 64% (55-74%). RS did not have significant interaction w/ stage (p=0.90) or age (p=0.76). Relative benefit of Ox was similar across range of RS (interaction p=0.48); accordingly, in Cox model and Kaplan-Meier analyses, absolute benefit of Ox increased w/ higher RS. Conclusions: RS predicts recurrence risk in stage II and III colon cancer, capturing underlying biology and providing risk information beyond conventional factors. RS is not predictive of relative benefit of Ox added to adjuvant FU but enables better discrimination of absolute Ox benefit as a function of risk. Incorporating RS into the clinical context may better inform adjuvant therapy decisions for pts w/ stage III as well as stage II colon cancer.

Download Full-text