title: MRE11-deficiency associated with improved long-term disease free survival and overall survival in a subset of stage III colon cancer patients in randomized CALGB 89803 trial.
abstract: OBJECTIVE
  Colon cancers deficient in mismatch repair (MMR) may exhibit diminished expression of the DNA repair gene, MRE11, as a consequence of contraction of a T11 mononucleotide tract. This study investigated MRE11 status and its association with prognosis, survival and drug response in patients with stage III colon cancer.
  
  
  METHODS
  Cancer and Leukemia Group B 89803 (Alliance) randomly assigned 1,264 patients with stage III colon cancer to postoperative weekly adjuvant bolus 5-fluorouracil/leucovorin (FU/LV) or irinotecan+FU/LV (IFL), with 8 year follow-up. Tumors from these patients were analyzed to determine stability of a T11 tract in the MRE11 gene. The primary endpoint was overall survival (OS), and a secondary endpoint was disease-free survival (DFS). Non-proportional hazards were addressed using time-dependent covariates in Cox analyses.
  
  
  RESULTS
  Of 625 tumor cases examined, 70 (11.2%) exhibited contraction at the T11 tract in one or both MRE11 alleles and were thus predicted to be deficient in MRE11 (dMRE11). In pooled treatment analyses, dMRE11 patients showed initially reduced DFS and OS but improved long-term DFS and OS compared with patients with an intact MRE11 T11 tract. In the subgroup of dMRE11 patients treated with IFL, an unexplained early increase in mortality but better long-term DFS than IFL-treated pMRE11 patients was observed.
  
  
  CONCLUSIONS
  Analysis of this relatively small number of patients and events showed that the dMRE11 marker predicts better prognosis independent of treatment in the long-term. In subgroup analyses, dMRE11 patients treated with irinotecan exhibited unexplained short-term mortality. MRE11 status is readily assayed and may therefore prove to be a useful prognostic marker, provided that the results reported here for a relatively small number of patients can be generalized in independent analyses of larger numbers of samples.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00003835.
authors.affiliation: Department of Immunology, University of Washington, Seattle, Washington, United States of America; Department of Chemistry, University of Washington, Seattle, Washington, United States of America.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pavelitz
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, United States of America; Department of Chemistry, University of Washington, Seattle, Washington, United States of America.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Renfro
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Foster
authors.affiliation: Department of Immunology, University of Washington, Seattle, Washington, United States of America; Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, Washington, United States of America.
authors.forename: Amber
authors.initials: A
authors.lastname: Caracol
authors.affiliation: Department of Genome Sciences, University of Washington Medical School, Seattle, Washington, United States of America.
authors.forename: Piri
authors.initials: P
authors.lastname: Welsch
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; Department of Surgery, University of Washington Medical School, Seattle, Washington, United States of America.
authors.forename: Victoria Valinluck
authors.initials: VV
authors.lastname: Lao
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; Department of Medicine, University of Washington Medical School, Seattle, Washington, United States of America.
authors.forename: William B
authors.initials: WB
authors.lastname: Grady
authors.affiliation: Cancer and Leukemia Group B Statistical Center, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Donna
authors.initials: D
authors.lastname: Niedzwiecki
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Leonard B
authors.initials: LB
authors.lastname: Saltz
authors.affiliation: Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Monica M
authors.initials: MM
authors.lastname: Bertagnolli
authors.affiliation: The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Goldberg
authors.affiliation: Department of Pathology, University of Washington Medical School, Seattle, Washington, United States of America.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Rabinovitch
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
authors.forename: Mary
authors.initials: M
authors.lastname: Emond
authors.affiliation: Department of Genome Sciences, University of Washington Medical School, Seattle, Washington, United States of America; Department of Pathology, University of Washington Medical School, Seattle, Washington, United States of America.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Monnat
authors.affiliation: Department of Immunology, University of Washington, Seattle, Washington, United States of America; Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, Washington, United States of America; Department of Pathology, University of Washington Medical School, Seattle, Washington, United States of America; Department of Biochemistry, University of Washington, Seattle, Washington, United States of America.
authors.forename: Nancy
authors.initials: N
authors.lastname: Maizels
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000627:therapeutic use; D005500:Follow-Up Studies; D056726:Genetic Association Studies; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage / Q000627:therapeutic use; D000076228:MRE11 Homologue Protein; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; D000077146:Irinotecan; D000076228:MRE11 Homologue Protein; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin