title: Integrated analysis of molecular and clinical prognostic factors in stage II/III colon cancer.
abstract: BACKGROUND
  The prognostic potential of individual clinical and molecular parameters in stage II/III colon cancer has been investigated, but a thorough multivariable assessment of their relative impact is missing.
  
  
  METHODS
  Tumors from patients (N = 1404) in the PETACC3 adjuvant chemotherapy trial were examined for BRAF and KRAS mutations, microsatellite instability (MSI), chromosome 18q loss of heterozygosity (18qLOH), and SMAD4 expression. Their importance in predicting relapse-free survival (RFS) and overall survival (OS) was assessed by Kaplan-Meier analyses, Cox regression models, and recursive partitioning trees. All statistical tests were two-sided.
  
  
  RESULTS
  MSI-high status and SMAD4 focal loss of expression were identified as independent prognostic factors with better RFS (hazard ratio [HR] of recurrence = 0.54, 95% CI = 0.37 to 0.81, P = .003) and OS (HR of death = 0.43, 95% CI = 0.27 to 0.70, P = .001) for MSI-high status and worse RFS (HR = 1.47, 95% CI = 1.19 to 1.81, P < .001) and OS (HR = 1.58, 95% CI = 1.23 to 2.01, P < .001) for SMAD4 loss. 18qLOH did not have any prognostic value in RFS or OS. Recursive partitioning identified refinements of TNM into new clinically interesting prognostic subgroups. Notably, T3N1 tumors with MSI-high status and retained SMAD4 expression had outcomes similar to stage II disease.
  
  
  CONCLUSIONS
  Concomitant assessment of molecular and clinical markers in multivariable analysis is essential to confirm or refute their independent prognostic value. Including molecular markers with independent prognostic value might allow more accurate prediction of prognosis than TNM staging alone.
authors.affiliation: Oncosurgery Unit, Geneva University Hospital, Geneva, Switzerland. arnaud.roth@hcuge.ch
authors.forename: Arnaud D
authors.initials: AD
authors.lastname: Roth
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
authors.forename: Pu
authors.initials: P
authors.lastname: Yan
authors.forename: Dirk
authors.initials: D
authors.lastname: Klingbiel
authors.forename: Roberto
authors.initials: R
authors.lastname: Fiocca
authors.forename: Giovanni
authors.initials: G
authors.lastname: d'Ario
authors.forename: Laura
authors.initials: L
authors.lastname: Cisar
authors.forename: Roberto
authors.initials: R
authors.lastname: Labianca
authors.forename: David
authors.initials: D
authors.lastname: Cunningham
authors.forename: Bernard
authors.initials: B
authors.lastname: Nordlinger
authors.forename: Fred
authors.initials: F
authors.lastname: Bosman
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D017024:Chemotherapy, Adjuvant; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007150:Immunohistochemistry; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage; D019656:Loss of Heterozygosity; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012107:Research Design; D051901:Smad4 Protein / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D000077146:Irinotecan; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin