title: Mismatch Repair Deficiency, Microsatellite Instability, and Survival: An Exploratory Analysis of the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) Trial.
abstract: OBJECTIVE
  Mismatch repair (MMR) deficiency (MMRD) and microsatellite instability (MSI) are prognostic for survival in many cancers and for resistance to fluoropyrimidines in early colon cancer. However, the effect of MMRD and MSI in curatively resected gastric cancer treated with perioperative chemotherapy is unknown.
  
  
  OBJECTIVE
  To examine the association among MMRD, MSI, and survival in patients with resectable gastroesophageal cancer randomized to surgery alone or perioperative epirubicin, cisplatin, and fluorouracil chemotherapy in the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial.
  
  
  METHODS
  This secondary post hoc analysis of the MAGIC trial included participants who were treated with surgery alone or perioperative chemotherapy plus surgery for operable gastroesophageal cancer from July 1, 1994, through April 30, 2002. Tumor sections were assessed for expression of the MMR proteins mutL homologue 1, mutS homologue 2, mutS homologue 6, and PMS1 homologue 2. The association among MSI, MMRD, and survival was assessed.
  
  
  METHODS
  Interaction between MMRD and MSI status and overall survival (OS).
  
  
  RESULTS
  Of the 503 study participants, MSI results were available for 303 patients (283 with microsatellite stability or low MSI [median age, 62 years; 219 males (77.4%)] and 20 with high MSI [median age, 66 years; 14 males (70.0%)]). A total of 254 patients had MSI and MMR results available. Patients treated with surgery alone who had high MSI or MMRD had a median OS that was not reached (95% CI, 11.5 months to not reached) compared with a median OS among those who had neither high MSI nor MMRD of 20.5 months (95% CI, 16.7-27.8 months; hazard ratio, 0.42; 95% CI, 0.15-1.15; P = .09). In contrast, patients treated with chemotherapy plus surgery who had either high MSI or MMRD had a median OS of 9.6 months (95% CI, 0.1-22.5 months) compared with a median OS among those who were neither high MSI nor MMRD of 19.5 months (95% CI, 15.4-35.2 months; hazard ratio, 2.18; 95% CI, 1.08-4.42; P = .03).
  
  
  CONCLUSIONS
  In the MAGIC trial, MMRD and high MSI were associated with a positive prognostic effect in patients treated with surgery alone and a differentially negative prognostic effect in patients treated with chemotherapy. If independently validated, MSI or MMRD determined by preoperative biopsies could be used to select patients for perioperative chemotherapy.
authors.affiliation: Department of Gastrointestinal Oncology and Lymphoma, Royal Marsden Hospital, London and Sutton, United Kingdom.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Smyth
authors.affiliation: Department of Pathology, Royal Marsden Hospital, London and Sutton, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wotherspoon
authors.affiliation: Department of Clinical Research and Development, Royal Marsden Hospital, London and Sutton, United Kingdom.
authors.forename: Clare
authors.initials: C
authors.lastname: Peckitt
authors.affiliation: Department of Molecular Pathology, The Institute of Cancer Research, London and Sutton, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Gonzalez
authors.affiliation: Department of Molecular Pathology, The Institute of Cancer Research, London and Sutton, United Kingdom.
authors.forename: Sanna
authors.initials: S
authors.lastname: Hulkki-Wilson
authors.affiliation: Department of Pathology, Royal Marsden Hospital, London and Sutton, United Kingdom.
authors.forename: Zakaria
authors.initials: Z
authors.lastname: Eltahir
authors.affiliation: Department of Medicine, Surgical Pathology Unit, University of Padua, Padua, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Fassan
authors.affiliation: Department of Medicine, Surgical Pathology Unit, University of Padua, Padua, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Rugge
authors.affiliation: Department of Gastrointestinal Oncology and Lymphoma, Royal Marsden Hospital, London and Sutton, United Kingdom.|Department of Molecular Pathology, The Institute of Cancer Research, London and Sutton, United Kingdom.
authors.forename: Nicola
authors.initials: N
authors.lastname: Valeri
authors.affiliation: Department of Gastrointestinal Oncology and Lymphoma, Royal Marsden Hospital, London and Sutton, United Kingdom.
authors.forename: Alicia
authors.initials: A
authors.lastname: Okines
authors.affiliation: St Luke's Cancer Centre, Royal Surrey County Hospital, Surrey, United Kingdom.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Hewish
authors.affiliation: Department of Surgery, Royal Marsden Hospital, London and Sutton, United Kingdom.
authors.forename: William
authors.initials: W
authors.lastname: Allum
authors.affiliation: Medical Research Council Clinical Trials Unit, University College London, Institute of Clinical Trials and Methodology, London, United Kingdom.
authors.forename: Sally
authors.initials: S
authors.lastname: Stenning
authors.affiliation: Medical Research Council Clinical Trials Unit, University College London, Institute of Clinical Trials and Methodology, London, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Nankivell
authors.affiliation: Medical Research Council Clinical Trials Unit, University College London, Institute of Clinical Trials and Methodology, London, United Kingdom.
authors.forename: Ruth
authors.initials: R
authors.lastname: Langley
authors.affiliation: Department of Gastrointestinal Oncology and Lymphoma, Royal Marsden Hospital, London and Sutton, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Cunningham
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000008:administration & dosage; D053843:DNA Mismatch Repair; D004268:DNA-Binding Proteins / Q000032:analysis; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005743:Gastrectomy; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2 / Q000032:analysis; D000070957:MutL Protein Homolog 1 / Q000032:analysis; D051718:MutS Homolog 2 Protein / Q000032:analysis; D011379:Prognosis; D013274:Stomach Neoplasms / Q000737:chemistry* / Q000235:genetics* / Q000628:therapy; D015996:Survival Rate
chemical_list: D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D015251:Epirubicin; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D002945:Cisplatin; D005472:Fluorouracil