title: Test of four colon cancer risk-scores in formalin fixed paraffin embedded microarray gene expression data.
abstract: BACKGROUND
  Prognosis prediction for resected primary colon cancer is based on the T-stage Node Metastasis (TNM) staging system. We investigated if four well-documented gene expression risk scores can improve patient stratification.
  
  
  METHODS
  Microarray-based versions of risk-scores were applied to a large independent cohort of 688 stage II/III tumors from the PETACC-3 trial. Prognostic value for relapse-free survival (RFS), survival after relapse (SAR), and overall survival (OS) was assessed by regression analysis. To assess improvement over a reference, prognostic model was assessed with the area under curve (AUC) of receiver operating characteristic (ROC) curves. All statistical tests were two-sided, except the AUC increase.
  
  
  RESULTS
  All four risk scores (RSs) showed a statistically significant association (single-test, P < .0167) with OS or RFS in univariate models, but with HRs below 1.38 per interquartile range. Three scores were predictors of shorter RFS, one of shorter SAR. Each RS could only marginally improve an RFS or OS model with the known factors T-stage, N-stage, and microsatellite instability (MSI) status (AUC gains < 0.025 units). The pairwise interscore discordance was never high (maximal Spearman correlation = 0.563) A combined score showed a trend to higher prognostic value and higher AUC increase for OS (HR = 1.74, 95% confidence interval [CI] = 1.44 to 2.10, P < .001, AUC from 0.6918 to 0.7321) and RFS (HR = 1.56, 95% CI = 1.33 to 1.84, P < .001, AUC from 0.6723 to 0.6945) than any single score.
  
  
  CONCLUSIONS
  The four tested gene expression-based risk scores provide prognostic information but contribute only marginally to improving models based on established risk factors. A combination of the risk scores might provide more robust information. Predictors of RFS and SAR might need to be different.
authors.affiliation: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland (AFDN, SR, VP, PW, EB, MD); Digestive Oncology Unit and Center for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium (ST); Department of Pathology, Lausanne University, Lausanne, Switzerland (PY, FB); Oncology Research Unit, Worldwide Research and Development, Pfizer Inc., La Jolla, CA (TX, HE, AP, MM, EM, WS); Oncosurgery, Geneva University Hospital Geneva, Switzerland (AR); SAKK Coordination Center, Bern, Switzerland (AR); Ludwig Center for Cancer Research (MD) and Oncology Department, University of Lausanne, Lausanne, Switzerland (MD).
authors.forename: Antonio F
authors.initials: AF
authors.lastname: Di Narzo
authors.affiliation: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland (AFDN, SR, VP, PW, EB, MD); Digestive Oncology Unit and Center for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium (ST); Department of Pathology, Lausanne University, Lausanne, Switzerland (PY, FB); Oncology Research Unit, Worldwide Research and Development, Pfizer Inc., La Jolla, CA (TX, HE, AP, MM, EM, WS); Oncosurgery, Geneva University Hospital Geneva, Switzerland (AR); SAKK Coordination Center, Bern, Switzerland (AR); Ludwig Center for Cancer Research (MD) and Oncology Department, University of Lausanne, Lausanne, Switzerland (MD).
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
authors.affiliation: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland (AFDN, SR, VP, PW, EB, MD); Digestive Oncology Unit and Center for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium (ST); Department of Pathology, Lausanne University, Lausanne, Switzerland (PY, FB); Oncology Research Unit, Worldwide Research and Development, Pfizer Inc., La Jolla, CA (TX, HE, AP, MM, EM, WS); Oncosurgery, Geneva University Hospital Geneva, Switzerland (AR); SAKK Coordination Center, Bern, Switzerland (AR); Ludwig Center for Cancer Research (MD) and Oncology Department, University of Lausanne, Lausanne, Switzerland (MD).
authors.forename: Simona
authors.initials: S
authors.lastname: Rossi
authors.affiliation: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland (AFDN, SR, VP, PW, EB, MD); Digestive Oncology Unit and Center for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium (ST); Department of Pathology, Lausanne University, Lausanne, Switzerland (PY, FB); Oncology Research Unit, Worldwide Research and Development, Pfizer Inc., La Jolla, CA (TX, HE, AP, MM, EM, WS); Oncosurgery, Geneva University Hospital Geneva, Switzerland (AR); SAKK Coordination Center, Bern, Switzerland (AR); Ludwig Center for Cancer Research (MD) and Oncology Department, University of Lausanne, Lausanne, Switzerland (MD).
authors.forename: Pu
authors.initials: P
authors.lastname: Yan
authors.affiliation: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland (AFDN, SR, VP, PW, EB, MD); Digestive Oncology Unit and Center for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium (ST); Department of Pathology, Lausanne University, Lausanne, Switzerland (PY, FB); Oncology Research Unit, Worldwide Research and Development, Pfizer Inc., La Jolla, CA (TX, HE, AP, MM, EM, WS); Oncosurgery, Geneva University Hospital Geneva, Switzerland (AR); SAKK Coordination Center, Bern, Switzerland (AR); Ludwig Center for Cancer Research (MD) and Oncology Department, University of Lausanne, Lausanne, Switzerland (MD).
authors.forename: Vlad
authors.initials: V
authors.lastname: Popovici
authors.affiliation: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland (AFDN, SR, VP, PW, EB, MD); Digestive Oncology Unit and Center for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium (ST); Department of Pathology, Lausanne University, Lausanne, Switzerland (PY, FB); Oncology Research Unit, Worldwide Research and Development, Pfizer Inc., La Jolla, CA (TX, HE, AP, MM, EM, WS); Oncosurgery, Geneva University Hospital Geneva, Switzerland (AR); SAKK Coordination Center, Bern, Switzerland (AR); Ludwig Center for Cancer Research (MD) and Oncology Department, University of Lausanne, Lausanne, Switzerland (MD).
authors.forename: Pratyaksha
authors.initials: P
authors.lastname: Wirapati
authors.affiliation: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland (AFDN, SR, VP, PW, EB, MD); Digestive Oncology Unit and Center for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium (ST); Department of Pathology, Lausanne University, Lausanne, Switzerland (PY, FB); Oncology Research Unit, Worldwide Research and Development, Pfizer Inc., La Jolla, CA (TX, HE, AP, MM, EM, WS); Oncosurgery, Geneva University Hospital Geneva, Switzerland (AR); SAKK Coordination Center, Bern, Switzerland (AR); Ludwig Center for Cancer Research (MD) and Oncology Department, University of Lausanne, Lausanne, Switzerland (MD).
authors.forename: Eva
authors.initials: E
authors.lastname: Budinska
authors.affiliation: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland (AFDN, SR, VP, PW, EB, MD); Digestive Oncology Unit and Center for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium (ST); Department of Pathology, Lausanne University, Lausanne, Switzerland (PY, FB); Oncology Research Unit, Worldwide Research and Development, Pfizer Inc., La Jolla, CA (TX, HE, AP, MM, EM, WS); Oncosurgery, Geneva University Hospital Geneva, Switzerland (AR); SAKK Coordination Center, Bern, Switzerland (AR); Ludwig Center for Cancer Research (MD) and Oncology Department, University of Lausanne, Lausanne, Switzerland (MD).
authors.forename: Tao
authors.initials: T
authors.lastname: Xie
authors.affiliation: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland (AFDN, SR, VP, PW, EB, MD); Digestive Oncology Unit and Center for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium (ST); Department of Pathology, Lausanne University, Lausanne, Switzerland (PY, FB); Oncology Research Unit, Worldwide Research and Development, Pfizer Inc., La Jolla, CA (TX, HE, AP, MM, EM, WS); Oncosurgery, Geneva University Hospital Geneva, Switzerland (AR); SAKK Coordination Center, Bern, Switzerland (AR); Ludwig Center for Cancer Research (MD) and Oncology Department, University of Lausanne, Lausanne, Switzerland (MD).
authors.forename: Heather
authors.initials: H
authors.lastname: Estrella
authors.affiliation: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland (AFDN, SR, VP, PW, EB, MD); Digestive Oncology Unit and Center for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium (ST); Department of Pathology, Lausanne University, Lausanne, Switzerland (PY, FB); Oncology Research Unit, Worldwide Research and Development, Pfizer Inc., La Jolla, CA (TX, HE, AP, MM, EM, WS); Oncosurgery, Geneva University Hospital Geneva, Switzerland (AR); SAKK Coordination Center, Bern, Switzerland (AR); Ludwig Center for Cancer Research (MD) and Oncology Department, University of Lausanne, Lausanne, Switzerland (MD).
authors.forename: Adam
authors.initials: A
authors.lastname: Pavlicek
authors.affiliation: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland (AFDN, SR, VP, PW, EB, MD); Digestive Oncology Unit and Center for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium (ST); Department of Pathology, Lausanne University, Lausanne, Switzerland (PY, FB); Oncology Research Unit, Worldwide Research and Development, Pfizer Inc., La Jolla, CA (TX, HE, AP, MM, EM, WS); Oncosurgery, Geneva University Hospital Geneva, Switzerland (AR); SAKK Coordination Center, Bern, Switzerland (AR); Ludwig Center for Cancer Research (MD) and Oncology Department, University of Lausanne, Lausanne, Switzerland (MD).
authors.forename: Mao
authors.initials: M
authors.lastname: Mao
authors.affiliation: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland (AFDN, SR, VP, PW, EB, MD); Digestive Oncology Unit and Center for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium (ST); Department of Pathology, Lausanne University, Lausanne, Switzerland (PY, FB); Oncology Research Unit, Worldwide Research and Development, Pfizer Inc., La Jolla, CA (TX, HE, AP, MM, EM, WS); Oncosurgery, Geneva University Hospital Geneva, Switzerland (AR); SAKK Coordination Center, Bern, Switzerland (AR); Ludwig Center for Cancer Research (MD) and Oncology Department, University of Lausanne, Lausanne, Switzerland (MD).
authors.forename: Eric
authors.initials: E
authors.lastname: Martin
authors.affiliation: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland (AFDN, SR, VP, PW, EB, MD); Digestive Oncology Unit and Center for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium (ST); Department of Pathology, Lausanne University, Lausanne, Switzerland (PY, FB); Oncology Research Unit, Worldwide Research and Development, Pfizer Inc., La Jolla, CA (TX, HE, AP, MM, EM, WS); Oncosurgery, Geneva University Hospital Geneva, Switzerland (AR); SAKK Coordination Center, Bern, Switzerland (AR); Ludwig Center for Cancer Research (MD) and Oncology Department, University of Lausanne, Lausanne, Switzerland (MD).
authors.forename: Weinrich
authors.initials: W
authors.lastname: Scott
authors.affiliation: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland (AFDN, SR, VP, PW, EB, MD); Digestive Oncology Unit and Center for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium (ST); Department of Pathology, Lausanne University, Lausanne, Switzerland (PY, FB); Oncology Research Unit, Worldwide Research and Development, Pfizer Inc., La Jolla, CA (TX, HE, AP, MM, EM, WS); Oncosurgery, Geneva University Hospital Geneva, Switzerland (AR); SAKK Coordination Center, Bern, Switzerland (AR); Ludwig Center for Cancer Research (MD) and Oncology Department, University of Lausanne, Lausanne, Switzerland (MD).
authors.forename: Fred T
authors.initials: FT
authors.lastname: Bosman
authors.affiliation: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland (AFDN, SR, VP, PW, EB, MD); Digestive Oncology Unit and Center for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium (ST); Department of Pathology, Lausanne University, Lausanne, Switzerland (PY, FB); Oncology Research Unit, Worldwide Research and Development, Pfizer Inc., La Jolla, CA (TX, HE, AP, MM, EM, WS); Oncosurgery, Geneva University Hospital Geneva, Switzerland (AR); SAKK Coordination Center, Bern, Switzerland (AR); Ludwig Center for Cancer Research (MD) and Oncology Department, University of Lausanne, Lausanne, Switzerland (MD).
authors.forename: Arnaud
authors.initials: A
authors.lastname: Roth
authors.affiliation: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland (AFDN, SR, VP, PW, EB, MD); Digestive Oncology Unit and Center for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium (ST); Department of Pathology, Lausanne University, Lausanne, Switzerland (PY, FB); Oncology Research Unit, Worldwide Research and Development, Pfizer Inc., La Jolla, CA (TX, HE, AP, MM, EM, WS); Oncosurgery, Geneva University Hospital Geneva, Switzerland (AR); SAKK Coordination Center, Bern, Switzerland (AR); Ludwig Center for Cancer Research (MD) and Oncology Department, University of Lausanne, Lausanne, Switzerland (MD). mauro.delorenzi@unil.ch.
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry / Q000401:mortality* / Q000473:pathology*; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000032:analysis*; D003110:Colonic Neoplasms / Q000737:chemistry / Q000401:mortality* / Q000473:pathology*; D018572:Disease-Free Survival; D005260:Female; D005404:Fixatives; D005557:Formaldehyde; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D010232:Paraffin; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D012372:ROC Curve; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D012307:Risk Factors; D046888:Tissue Array Analysis; D059467:Transcriptome; D017211:Treatment Failure
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D005404:Fixatives; D005557:Formaldehyde; D010232:Paraffin