title: Multicenter retrospective analysis of metastatic colorectal cancer (CRC) with high-level microsatellite instability (MSI-H).
abstract: BACKGROUND
  The microsatellite instability-high (MSI-H) phenotype, present in 15% of early colorectal cancer (CRC), confers good prognosis. MSI-H metastatic CRC is rare and its impact on outcomes is unknown. We describe survival outcomes and the impact of chemotherapy, metastatectomy, and BRAF V600E mutation status in the largest reported cohort of MSI-H metastatic colorectal cancer (CRC).
  
  
  METHODS
  A retrospective review of 55 MSI-H metastatic CRC patients from two institutions, Royal Melbourne Hospital (Australia) and The University of Texas MD Anderson Cancer Center (United States), was conducted. Statistical analyses utilized Kaplan-Meier method, Log-rank test, and Cox proportional hazards models.
  
  
  RESULTS
  Median age was 67 years (20-90), 58% had poor differentiation, and 45% had stage IV disease at presentation. Median overall survival (OS) from metastatic disease was 15.4 months. Thirteen patients underwent R0/R1 metastatectomies, with median OS from metastatectomy 33.8 months. Thirty-one patients received first-line systemic chemotherapy for metastatic disease with median OS from the start of chemotherapy 11.5 months. No statistically significant difference in progression-free survival or OS was seen between fluoropyrimidine, oxaliplatin, or irinotecan based chemotherapy. BRAF V600E mutation was present in 14 of 47 patients (30%). BRAF V600E patients demonstrated significantly worse median OS; 10.1 versus 17.3 months, P = 0.03. In multivariate analyses, BRAF V600E mutants had worse OS (HR 4.04; P = 0.005), while patients undergoing metastatectomy (HR 0.11; P = <0.001) and patients who initially presented as stage IV disease had improved OS (HR 0.27; P = 0.003).
  
  
  CONCLUSIONS
  Patients with MSI-H metastatic CRC do not appear to have improved outcomes. BRAF V600E mutation is a poor prognostic factor in MSI-H metastatic CRC.
authors.affiliation: Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, USA.
authors.forename: J
authors.initials: J
authors.lastname: Goldstein
authors.forename: B
authors.initials: B
authors.lastname: Tran
authors.forename: J
authors.initials: J
authors.lastname: Ensor
authors.forename: P
authors.initials: P
authors.lastname: Gibbs
authors.forename: H L
authors.initials: HL
authors.lastname: Wong
authors.forename: S F
authors.initials: SF
authors.lastname: Wong
authors.forename: E
authors.initials: E
authors.lastname: Vilar
authors.forename: J
authors.initials: J
authors.lastname: Tie
authors.forename: R
authors.initials: R
authors.lastname: Broaddus
authors.forename: S
authors.initials: S
authors.lastname: Kopetz
authors.forename: J
authors.initials: J
authors.lastname: Desai
authors.forename: M J
authors.initials: MJ
authors.lastname: Overman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000235:genetics / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics / Q000401:mortality* / Q000556:secondary / Q000628:therapy; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D015999:Multivariate Analysis; D020125:Mutation, Missense; D011379:Prognosis; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF V600E mutation; chemotherapy; colorectal cancer; metastatectomy; microsatellite instability-high; survival