Levels of gemcitabine transport and metabolism proteins predict survival times of patients treated with gemcitabine for pancreatic adenocarcinoma

Gastroenterology. 2012 Sep;143(3):664-674.e6. doi: 10.1053/j.gastro.2012.06.006. Epub 2012 Jun 13.

Abstract

Background & aims: Patients who undergo surgery for pancreatic ductal adenocarcinoma (PDAC) frequently receive adjuvant gemcitabine chemotherapy. Key determinants of gemcitabine cytotoxicity include the activities of the human equilibrative nucleoside transporter 1 (hENT1), deoxycytidine kinase (dCK), and ribonucleotide reductase subunit 1 (RRM1). We investigated whether tumor levels of these proteins were associated with efficacy of gemcitabine therapy following surgery.

Methods: Sequential samples of resected PDACs were retrospectively collected from 434 patients at 5 centers; 142 patients did not receive adjuvant treatment (33%), 243 received adjuvant gemcitabine-based regimens (56%), and 49 received nongemcitabine regimens (11%). We measured protein levels of hENT1, dCK, and RRM1 by semiquantitative immunohistochemistry with tissue microarrays and investigated their relationship with patients' overall survival time.

Results: The median overall survival time of patients was 32.0 months. Among patients who did not receive adjuvant treatment, levels of hENT1, RRM1, and dCK were not associated with survival time. Among patients who received gemcitabine, high levels of hENT1 and dCK were significantly associated with longer survival time (hazard ratios of 0.34 [P < .0001] and 0.57 [P = .012], respectively). Interaction tests for gemcitabine administration and hENT1 and dCK status were statistically significant (P = .0007 and P = .016, respectively). On multivariate analysis of this population, hENT1 and dCK retained independent predictive values, and those patients with high levels of each protein had the longest survival times following adjuvant therapy with gemcitabine.

Conclusions: High levels of hENT1 and dCK in PDAC predict longer survival times in patients treated with adjuvant gemcitabine.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimetabolites, Antineoplastic / metabolism
  • Antimetabolites, Antineoplastic / therapeutic use*
  • Biological Transport
  • Biotransformation
  • Carcinoma, Pancreatic Ductal / chemistry
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / mortality
  • Carcinoma, Pancreatic Ductal / pathology
  • Carcinoma, Pancreatic Ductal / surgery
  • Chemotherapy, Adjuvant
  • Chi-Square Distribution
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / metabolism
  • Deoxycytidine / therapeutic use
  • Deoxycytidine Kinase / analysis*
  • Equilibrative Nucleoside Transporter 1 / analysis*
  • Female
  • France
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Male
  • Multivariate Analysis
  • Pancreatectomy
  • Pancreatic Neoplasms / chemistry
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / mortality
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / surgery
  • Proportional Hazards Models
  • Retrospective Studies
  • Risk Assessment
  • Risk Factors
  • Time Factors
  • Tissue Array Analysis / methods
  • Treatment Outcome
  • Tumor Suppressor Proteins / analysis*

Substances

  • Antimetabolites, Antineoplastic
  • Equilibrative Nucleoside Transporter 1
  • SLC29A1 protein, human
  • Tumor Suppressor Proteins
  • Deoxycytidine
  • gemcitabine
  • RRM1 protein, human
  • Deoxycytidine Kinase