Development and Independent Validation of a Prognostic Assay for Stage II Colon Cancer Using Formalin-Fixed Paraffin-Embedded Tissue

2011 ◽  
Vol 29 (35) ◽  
pp. 4620-4626 ◽  
Author(s):  
Richard D. Kennedy ◽  
Max Bylesjo ◽  
Peter Kerr ◽  
Timothy Davison ◽  
Julie M. Black ◽  
...  
Keyword(s):  
Colon Cancer ◽  
High Risk ◽  
Gene Signature ◽  
Stage Ii ◽  
Independent Validation ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded ◽  
Risk Patients ◽  
Stage Ii Colon Cancer ◽  
Formalin Fixed

PurposeCurrent prognostic factors are poor at identifying patients at risk of disease recurrence after surgery for stage II colon cancer. Here we describe a DNA microarray–based prognostic assay using clinically relevant formalin-fixed paraffin-embedded (FFPE) samples.Patients and MethodsA gene signature was developed from a balanced set of 73 patients with recurrent disease (high risk) and 142 patients with no recurrence (low risk) within 5 years of surgery.ResultsThe 634–probe set signature identified high-risk patients with a hazard ratio (HR) of 2.62 (P < .001) during cross validation of the training set. In an independent validation set of 144 samples, the signature identified high-risk patients with an HR of 2.53 (P < .001) for recurrence and an HR of 2.21 (P = .0084) for cancer-related death. Additionally, the signature was shown to perform independently from known prognostic factors (P < .001).ConclusionThis gene signature represents a novel prognostic biomarker for patients with stage II colon cancer that can be applied to FFPE tumor samples.

scholarly journals Independent Validation of EarlyR Gene Signature in BIG 1-98: A Randomized, Double-Blind, Phase III Trial Comparing Letrozole and Tamoxifen as Adjuvant Endocrine Therapy for Postmenopausal Women With Hormone Receptor–Positive, Early Breast Cancer

2019 ◽  
Vol 3 (4) ◽  
Author(s):  
Steven A Buechler ◽  
Kathryn P Gray ◽  
Yesim Gökmen-Polar ◽  
Scooter Willis ◽  
Beat Thürlimann ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Confidence Interval ◽  
Gene Signature ◽  
Distant Recurrence ◽  
Free Interval ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded ◽  
Risk Patients ◽  
Formalin Fixed

Abstract Background EarlyR gene signature in estrogen receptor–positive (ER+) breast cancer is computed from the expression values of ESPL1, SPAG5, MKI67, PLK1, and PGR. EarlyR has been validated in multiple cohorts profiled using microarrays. This study sought to verify the prognostic features of EarlyR in a case-cohort sample from BIG 1–98, a randomized clinical trial of ER+ postmenopausal breast cancer patients treated with adjuvant endocrine therapy (letrozole or tamoxifen). Methods Expression of EarlyR gene signature was estimated by Illumina cDNA-mediated Annealing, Selection, and Ligation assay of RNA from formalin-fixed, paraffin-embedded primary breast cancer tissues in a case-cohort subset of ER+ women (N = 1174; 216 cases of recurrence within 8 years) from BIG 1–98. EarlyR score and prespecified risk strata (≤25 = low, 26–75 = intermediate, &gt;75 = high) were “blindly” computed. Analysis endpoints included distant recurrence–free interval and breast cancer–free interval at 8 years after randomization. Hazard ratios (HRs) and test statistics were estimated with weighted analysis methods. Results The distribution of the EarlyR risk groups was 67% low, 19% intermediate, and 14% high risk in this ER+ cohort. EarlyR was prognostic for distant recurrence–free interval; EarlyR high-risk patients had statistically increased risk of distant recurrence within 8 years (HR = 1.73, 95% confidence interval = 1.14 to 2.64) compared with EarlyR low-risk patients. EarlyR was also prognostic of breast cancer–free interval (HR = 1.74, 95% confidence interval = 1.21 to 2.62). Conclusions This study confirmed the prognostic significance of EarlyR using RNA from formalin-fixed, paraffin-embedded tissues from a case-cohort sample of BIG 1–98. EarlyR identifies a set of high-risk patients with relatively poor prognosis who may be considered for additional treatment. Further studies will focus on analyzing the predictive value of EarlyR signature.

Independent validation of a prognostic genomic profile (ColoPrint) for stage II colon cancer (CC) patients.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 358-358 ◽  
Author(s):  
R. Rosenberg ◽  
M. Maak ◽  
I. Simon ◽  
U. Nitsche ◽  
T. Schuster ◽  
...  
Keyword(s):  
Colon Cancer ◽  
High Risk ◽  
Distant Metastasis ◽  
Stage Ii ◽  
Genomic Profile ◽  
High Risk Patients ◽  
Independent Validation ◽  
Risk Patients ◽  
Stage Ii Colon Cancer

358 Background: Adjuvant therapy is not routinely recommended for stage II CC patients but may be considered for high-risk patients. In this study we aim to independently validate a genomic profile that was developed to identify high-risk patients and can assist in treatment decisions. Methods: An 18-gene profile had been developed using gene expression data from whole genome Agilent 44K oligonucleotide arrays and was validated in samples from an independent cohort of 206 CC patients and in in-silico datasets (Salazar et al. JCO 2010 in press). The profile was translated into a robust diagnostic test (ColoPrint) using customized 8-pack arrays. For this study, 233 patients who underwent curative resection (R0) for colon cancer stages II or III at the Klinikum rechts der Isar from 1987 to 2003 were selected. Fresh frozen tissues, clinical parameters and follow-up data for all patients were available. The samples were hybridized and the ColoPrint index was determined for all samples blinded from the clinical data. Results: Patients in this study had a median age of 64 years and median follow-up of 97 months. The median number of resected lymph nodes was 21, giving an indirect measure of the quality of surgery. In the 135 stage II patients, ColoPrint identified most patients (73%) as low risk. The 5-year distant-metastasis free survival was 95% for low-risk patients and 80% for high-risk patients. In the univariate analysis, ColoPrint was the only significant parameter to predict the development of distant metastasis with a HR of 4.1 (95% CI 1.31-13.01, p=0.009). Using clinical parameters from the ASCO recommendation (T4, perforation, less than 12 LN assessed and/ or high grade) for the identification of high-risk patients was not significant (HR 2.3; 95% CI 0.68-7.53, p=0.18) and did not add power to the ColoPrint classification. These results are in good agreement with results from the first independent validation. Conclusions: ColoPrint is able to predict the development of distant metastasis of stage II colon cancer patients and facilitates the identification of patients who may be safely managed without chemotherapy. [Table: see text]

scholarly journals Use of a Combination of CEA and Tumor Budding to Identify High-risk Patients with Stage II Colon Cancer

2017 ◽  
Vol 32 (3) ◽  
pp. 267-273 ◽  
Author(s):  
Changzheng Du ◽  
Weicheng Xue ◽  
Fangyuan Dou ◽  
Yifan Peng ◽  
Yunfeng Yao ◽  
...  
Keyword(s):  
Colon Cancer ◽  
High Risk ◽  
Disease Progression ◽  
Disease Free Survival ◽  
Stage Ii ◽  
Tumor Budding ◽  
High Risk Patients ◽  
Prognostic Accuracy ◽  
Risk Patients ◽  
Stage Ii Colon Cancer

Background High-risk patients with stage II colon cancer may benefit from adjuvant chemotherapy, but identifying this patient population can be difficult. We assessed the prognosis value for predicting tumor progression in patients with stage II colon cancer, of a panel of 2 biomarkers for colon cancer: tumor budding and preoperative carcinoembryonic antigen (CEA). Methods Consecutive patients (N = 134) with stage II colon cancer who underwent curative surgery from 2000 to 2007 were included. Multivariate analysis was used to evaluate the association of CEA and tumor budding grade with 5-year disease-free survival (DFS). The prognostic accuracy of CEA, tumor budding grade and the combination of both (CEA-budding panel) was determined. Results The study found that both CEA and tumor budding grade were associated with 5-year DFS. The prognostic accuracy for disease progression was higher for the CEA-budding panel (82.1%) than either CEA (70.9%) or tumor budding grade (72.4%) alone. Conclusions The findings indicate that the combination of CEA levels and tumor budding grade has greater prognostic value for identifying patients with stage II colon cancer who are at high-risk for disease progression, than either marker alone.

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

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 678-678 ◽  
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.

scholarly journals Redefining high-risk patients with stage II colon cancer by risk index and microRNA-21: results from a population-based cohort

2014 ◽  
Vol 111 (7) ◽  
pp. 1285-1292 ◽  
Author(s):  
T F Hansen ◽  
S Kjær-Frifeldt ◽  
R D Christensen ◽  
S Morgenthaler ◽  
T Blondal ◽  
...  
Keyword(s):  
Colon Cancer ◽  
High Risk ◽  
Risk Index ◽  
Population Based ◽  
Stage Ii ◽  
High Risk Patients ◽  
Risk Patients ◽  
Stage Ii Colon Cancer

Clinical and technical validation of a genomic classifier (ColoPrint) for predicting outcome of patients with stage II colon cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 384-384 ◽  
Author(s):  
Josep Tabernero ◽  
Victor Moreno ◽  
Robert Rosenberg ◽  
Ulrich Nitsche ◽  
Thomas Bachleitner-Hofmann ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colon Cancer ◽  
Multivariate Analysis ◽  
High Risk ◽  
Low Risk ◽  
Stage Ii ◽  
Clinical Parameters ◽  
Risk Patients ◽  
Stage Ii Colon Cancer

384 Background: Between 25 and 35% of stage II colon cancer patients will experience a relapse of their disease and may benefit from adjuvant chemotherapy. ColoPrint is a gene expression classifier that can predict disease relapse in patients with early-stage colorectal cancer (Salazar et al. JCO 2011). Methods: ColoPrint was developed using gene expression data from whole genome microarrays and was validated in in-silico datasets and independent patient cohorts from 5 European hospitals. Fresh frozen tissues, clinical parameters, MSI-status and follow-up data for patients were available. Samples were hybridized to Agilent microarrays and the ColoPrint index was determined. Uni-and multivariate analysis was performed on the pooled stage II patient set (n=320) who had a median follow-up of 70 months. Reproducibility and precision studies were performed using clinical and control samples specific for each outcome level (high risk, low risk). Experiments were performed on 20 days with 2 runs per day by multiple technicians reflecting daily diagnostic conditions. Results: Performance of the prognostic classifier was confirmed in reproducibility and stability assays and stringent quality controls were established. In the clinical validation, ColoPrint classified two-third of 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). MSI-status and the number of assessed lymph nodes were the only significant clinical parameters in the univariate analysis. Using parameters from the ASCO recommendation (T4, perforation, less than 12 LN assessed and/ or high grade) for the identification of high risk patients was not significant (HR 1.43, 95% CI 0.81-2.55; p= 0.22) and no clinical parameter added power to the ColoPrint classification in multivariate analysis. Conclusions: ColoPrint is available as a routine diagnostic test with a high precision and reproducibility. ColoPrint significantly improves the prognostic accuracy of pathologic factors and MSI and facilitates the identification of low risk patients with stage II disease who may be safely managed without chemotherapy.

Tumor Budding as an Index to Identify High-Risk Patients with Stage II Colon Cancer

2008 ◽  
Vol 51 (5) ◽  
pp. 568-572 ◽  
Author(s):  
Takatoshi Nakamura ◽  
Hiroyuki Mitomi ◽  
Hideki Kanazawa ◽  
Yasuo Ohkura ◽  
Masahiko Watanabe
Keyword(s):  
Colon Cancer ◽  
High Risk ◽  
Stage Ii ◽  
Tumor Budding ◽  
High Risk Patients ◽  
Risk Patients ◽  
Stage Ii Colon Cancer
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