title: Glycogen Synthase Kinase 3 Beta Predicts Survival in Resected Adenocarcinoma of the Pancreas.
abstract: OBJECTIVE
  GSK3β is a protein kinase that can suppress a number of key oncoproteins. We have previously shown in preclinical models of pancreatic ductal adenocarcinoma (PDAC) that inhibition of GSK3β causes stabilization and nuclear translocation of β-catenin, poor differentiation, proliferation, and resistance to radiation. The objective of this study was to determine its utility as a biomarker of clinical outcomes.
  
  
  METHODS
  Automated Quantitative Immunofluorescence Analysis (AQUA) of GSK3β was performed on a tissue microarray with samples from 163 patients treated on RTOG 9704. On the basis of findings in an exploratory cohort, GSK3β was analyzed as a categorical variable using its upper quartile (>Q3) as a cut point. Overall survival (OS) and disease-free survival (DFS) were estimated with the Kaplan-Meier method, and GSK3β groupings were compared using the log-rank test. Univariable and multivariable Cox proportional hazards models were used to determine associations between GSK3β and OS/DFS.
  
  
  RESULTS
  The 3-year OS rates for GSK3β≤Q3 versus GSK3β >Q3 were 16% (95% confidence intervals; CI, 10%-23%) and 30% (95% CI, 17%-44%), respectively, P = 0.0082. The 3-year DFS rates were 9% (95% CI, 5%-15%) and 20% (95% CI, 9%-33%) respectively, P value = 0.0081. On multivariable analysis, GSK3β was a significant predictor of OS. Patients with GSK3β >Q3 had a 46% reduced risk of dying of pancreatic cancer (HR, 0.54; 95% CI, 0.31-0.96, P value = 0.034). The HR for DFS was 0.65 (95% CI, 0.39-1.07; P value = 0.092).
  
  
  CONCLUSIONS
  GSK3β expression is a strong prognosticator in PDAC, independent of other known factors such as tumor (T) stage, nodal status, surgical margins and CA19-9. Clin Cancer Res; 21(24); 5612-8. ©2015 AACR.
authors.affiliation: University of Pennsylvania, Philadelphia, Pennsylvania. edgar.ben-josef@uphs.upenn.edu.
authors.forename: Edgar
authors.initials: E
authors.lastname: Ben-Josef
authors.affiliation: Radiation Therapy Oncology Group-Statistical Center, Philadelphia, Pennsylvania.
authors.forename: Asha
authors.initials: A
authors.lastname: George
authors.affiliation: University of Maryland Medical Systems, Baltimore, Maryland.
authors.forename: William F
authors.initials: WF
authors.lastname: Regine
authors.affiliation: Rush University Medical Center, Chicago, Illinois.
authors.forename: Ross
authors.initials: R
authors.lastname: Abrams
authors.affiliation: University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Meredith
authors.initials: M
authors.lastname: Morgan
authors.affiliation: University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Dafydd
authors.initials: D
authors.lastname: Thomas
authors.affiliation: Toledo Community Hospital Oncology Program CCOP, Toledo, Ohio.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Schaefer
authors.affiliation: Providence, Rhode Island.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: DiPetrillo
authors.affiliation: Akron General Medical Center, Akron, Ohio.
authors.forename: Mitchel
authors.initials: M
authors.lastname: Fromm
authors.affiliation: Northwestern Memorial Hospital, Chicago, Illinois.
authors.forename: William
authors.initials: W
authors.lastname: Small
authors.affiliation: Michigan Cancer Research Consortium CCOP, Ann Arbor, Michigan.
authors.forename: Samir
authors.initials: S
authors.lastname: Narayan
authors.affiliation: Radiation Therapy Oncology Group-Statistical Center, Philadelphia, Pennsylvania.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Winter
authors.affiliation: University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Kent A
authors.initials: KA
authors.lastname: Griffith
authors.affiliation: Montefiore Medical Center, Moses Campus, Bronx, New York.
authors.forename: Chandan
authors.initials: C
authors.lastname: Guha
authors.affiliation: Ohio State University Medical Center, Columbus, Ohio.
authors.forename: Terence M
authors.initials: TM
authors.lastname: Williams
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D015331:Cohort Studies; D003131:Combined Modality Therapy; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D011379:Prognosis; D016016:Proportional Hazards Models; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3