title: Prognosis of stage II and III colon cancer treated with adjuvant 5-fluorouracil or FOLFIRI in relation to microsatellite status: results of the PETACC-3 trial.
abstract: BACKGROUND
  Although colon cancer (CC) with microsatellite instability (MSI) has a more favorable prognosis than microsatellite stable (MSS) CC, the impact varies according to clinicopathological parameters. We studied how MSI status affects prognosis in a trial-based cohort of stage II and III CC patients treated with 5-fluorouracil (5-FU)/leucovorin or FOLFIRI.
  
  
  METHODS
  Tissue specimens of 1254 patients were tested for 10 different loci and were classified as MSI-high (MSI-H) when three or more loci were unstable and MSS otherwise. Study end points were overall survival (OS) and relapse-free survival (RFS).
  
  
  RESULTS
  In stage II, RFS and OS were better for patients with MSI-H than with MSS CC [hazard ratio (HR) 0.26, 95% CI 0.10-0.65, P = 0.004 and 0.16, 95% CI 0.04-0.64, P = 0.01). In stage III, RFS was slightly better for patients with MSI-H CC (HR 0.67, 95% CI 0.46-0.99, P = 0.04), but the difference was not statistically significant for OS (HR 0.70, 95% CI 0.44-1.09, P = 0.11). Outcomes for patients with MSI-H CC were not different between the two treatment arms. RFS was better for patients with MSI-H than with MSS CC in the right and left colon, whereas for OS this was significant only in the right colon. For patients with KRAS- and BRAF-mutated CC, but not for double wild-type patients, RFS and OS were significantly better when the tumors were also MSI-H. An interaction test was statistically significant for KRAS and MSI status (P = 0.005), but not for BRAF status (P = 0.14).
  
  
  CONCLUSIONS
  Our results confirm that for patients with stage II CC but less so for those with stage III MSI-H is strongly prognostic for RFS and OS. In the presence of 5-FU treatment, stage II patients with MSI-H tumors maintain their survival advantage in comparison with MSS patients and adding irinotecan has no added benefit. CLINICALTRIALS.GOV IDENTIFIER: NCT00026273.
authors.affiliation: SAKK Swiss Group for Clinical Cancer Research, Coordinating Center, Bern; SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Klingbiel
authors.affiliation: Laboratory of Tumor Cell Biology School of Medicine, University of Crete, Heraklion, Greece; Center for Human Genetics O&N1, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Z
authors.initials: Z
authors.lastname: Saridaki
authors.affiliation: Oncosurgery Unit, Geneva University Hospital, Geneva.
authors.forename: A D
authors.initials: AD
authors.lastname: Roth
authors.affiliation: Department of Pathology, Lausanne University, Lausanne.
authors.forename: F T
authors.initials: FT
authors.lastname: Bosman
authors.affiliation: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland; Ludwig Center for Cancer Research; Department of Oncology, University of Lausanne, Lausanne, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Delorenzi
authors.affiliation: Center for Human Genetics O&N1, Katholieke Universiteit Leuven, Leuven, Belgium; Laboratory of Molecular Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium. Electronic address: sabine.tejpar@uz.kuleuven.ac.be.
authors.forename: S
authors.initials: S
authors.lastname: Tejpar
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use; D053842:Microsatellite Instability; D018895:Microsatellite Repeats / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000517:prevention & control
chemical_list: D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin
keywords: adjuvant treatment; colon cancer; microsatellite instability; survival; translational research