title: Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer.
abstract: OBJECTIVE
  Prior reports have indicated that patients with colon cancer who demonstrate high-level microsatellite instability (MSI-H) or defective DNA mismatch repair (dMMR) have improved survival and receive no benefit from fluorouracil (FU) -based adjuvant therapy compared with patients who have microsatellite-stable or proficient mismatch repair (pMMR) tumors. We examined MMR status as a predictor of adjuvant therapy benefit in patients with stages II and III colon cancer.
  
  
  METHODS
  MSI assay or immunohistochemistry for MMR proteins were performed on 457 patients who were previously randomly assigned to FU-based therapy (either FU + levamisole or FU + leucovorin; n = 229) versus no postsurgical treatment (n = 228). Data were subsequently pooled with data from a previous analysis. The primary end point was disease-free survival (DFS).
  
  
  RESULTS
  Overall, 70 (15%) of 457 patients exhibited dMMR. Adjuvant therapy significantly improved DFS (hazard ratio [HR], 0.67; 95% CI, 0.48 to 0.93; P = .02) in patients with pMMR tumors. Patients with dMMR tumors receiving FU had no improvement in DFS (HR, 1.10; 95% CI, 0.42 to 2.91; P = .85) compared with those randomly assigned to surgery alone. In the pooled data set of 1,027 patients (n = 165 with dMMR), these findings were maintained; in patients with stage II disease and with dMMR tumors, treatment was associated with reduced overall survival (HR, 2.95; 95% CI, 1.02 to 8.54; P = .04).
  
  
  CONCLUSIONS
  Patient stratification by MMR status may provide a more tailored approach to colon cancer adjuvant therapy. These data support MMR status assessment for patients being considered for FU therapy alone and consideration of MMR status in treatment decision making.
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Pathology, Mayo Clinic, Rochester, MN 55905, USA. sargent.daniel@mayo.edu
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sargent
authors.forename: Silvia
authors.initials: S
authors.lastname: Marsoni
authors.forename: Genevieve
authors.initials: G
authors.lastname: Monges
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: Roberto
authors.initials: R
authors.lastname: Labianca
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Hamilton
authors.forename: Amy J
authors.initials: AJ
authors.lastname: French
authors.forename: Brian
authors.initials: B
authors.lastname: Kabat
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Foster
authors.forename: Valter
authors.initials: V
authors.lastname: Torri
authors.forename: Christine
authors.initials: C
authors.lastname: Ribic
authors.forename: Axel
authors.initials: A
authors.lastname: Grothey
authors.forename: Malcolm
authors.initials: M
authors.lastname: Moore
authors.forename: Alberto
authors.initials: A
authors.lastname: Zaniboni
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Seitz
authors.forename: Frank
authors.initials: F
authors.lastname: Sinicrope
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D015415:Biomarkers; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D003131:Combined Modality Therapy; D053843:DNA Mismatch Repair; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic
chemical_list: D000964:Antimetabolites, Antineoplastic; D015415:Biomarkers; D005472:Fluorouracil