Glycogen Synthase Kinase 3beta predicts survival in adenocarcinoma of the pancreas Journal Article

Authors: Ben-Josef, E.; George, A.; Regine, W.; Abrams, R. A.; Morgan, M. A.; Thomas, D. G.; Schaefer, P.; DiPetrillo, T.; Fromm, M.; Small, W., Jr; Narayan, S; Winter, K; Griffith, K. A.; Guha, C.; Williams, T. M.
Article Title: Glycogen Synthase Kinase 3beta predicts survival in adenocarcinoma of the pancreas
Abstract: Purpose GSK3beta 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 GSK3beta causes stabilization, nuclear translocation of beta-catenin, poor differentiation, proliferation and resistance to radiation. The objective of this study was to determine its utility as a biomarker of clinical outcomes. Experimental Design Automated Quantitative Immunofluorescence Analysis (AQUA) of GSK3beta was performed on a tissue microarray with samples from 163 patients treated on RTOG 9704. Based on findings in an exploratory cohort, GSK3beta 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 GSK3beta groupings were compared using the log-rank test. Univariable and multivariable Cox proportional hazards models were used to determine associations between GSK3beta and OS/DFS. Results The 3-yr. OS rates for GSK3betaQ3 were 16% (95% CI: 10%-23%) and 30% (95% CI: 17%-44%), respectively, p=0.0082. The 3-yr. DFS rates were 9% (95% CI: 5%-15%) and 20% (95% CI: 9%-33%) respectively, p-value =0.0081. On multivariable analysis, GSK3beta was a significant predictor of OS. Patients with GSK3beta >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 GSK3beta expression is a strong prognosticator in PDAC, independent of other known factors such as tumor (T) stage, nodal status, surgical margins and CA-19-9.
Journal Title: Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1078-0432; 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2015
Language: ENG
Notes: LR: 20150918; CI: Copyright (c) 2015; GR: U10 CA021661/CA/NCI NIH HHS/United States; GR: U10 CA037422/CA/NCI NIH HHS/United States; GR: U10 CA180868/CA/NCI NIH HHS/United States; JID: 9502500; aheadofprint