title: Phospho-ERK and AKT status, but not KRAS mutation status, are associated with outcomes in rectal cancer treated with chemoradiotherapy.
abstract: BACKGROUND
  KRAS mutations may predict poor response to radiotherapy. Downstream events from KRAS, such as activation of BRAF, AKT and ERK, may also confer prognostic information but have not been tested in rectal cancer (RC). Our objective was to explore the relationships of KRAS and BRAF mutation status with p-AKT and p-ERK and outcomes in RC.
  
  
  METHODS
  Pre-radiotherapy RC tumor biopsies were evaluated. KRAS and BRAF mutations were assessed by pyrosequencing; p-AKT and p-ERK expression by immunohistochemistry.
  
  
  RESULTS
  Of 70 patients, mean age was 58; 36% stage II, 56% stage III, and 9% stage IV. Responses to neoadjuvant chemoradiotherapy: 64% limited, 19% major, and 17% pathologic complete response. 64% were KRAS WT, 95% were BRAF WT. High p-ERK levels were associated with improved OS but not for p-AKT. High levels of p-AKT and p-ERK expression were associated with better responses. KRAS WT correlated with lower p-AKT expression but not p-ERK expression. No differences in OS, residual disease, or tumor downstaging were detected by KRAS status.
  
  
  CONCLUSIONS
  KRAS mutation was not associated with lesser response to chemoradiotherapy or worse OS. High p-ERK expression was associated with better OS and response. Higher p-AKT expression was correlated with better response but not OS.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7305, USA. janine.davies@bccancer.bc.ca
authors.forename: Janine M
authors.initials: JM
authors.lastname: Davies
authors.forename: Dimitri
authors.initials: D
authors.lastname: Trembath
authors.forename: Allison M
authors.initials: AM
authors.lastname: Deal
authors.forename: William K
authors.initials: WK
authors.lastname: Funkhouser
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Calvo
authors.forename: Timothy
authors.initials: T
authors.lastname: Finnegan
authors.forename: Karen E
authors.initials: KE
authors.lastname: Weck
authors.forename: Joel E
authors.initials: JE
authors.lastname: Tepper
authors.forename: Bert H
authors.initials: BH
authors.lastname: O'Neil
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy / Q000379:methods; D059248:Chemoradiotherapy / Q000379:methods*; D004252:DNA Mutational Analysis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012004:Rectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D012042:Registries; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins