title: Pancreatic cancer hENT1 expression and survival from gemcitabine in patients from the ESPAC-3 trial.
abstract: BACKGROUND
  Human equilibrative nucleoside transporter 1 (hENT1) levels in pancreatic adenocarcinoma may predict survival in patients who receive adjuvant gemcitabine after resection.
  
  
  METHODS
  Microarrays from 434 patients randomized to chemotherapy in the ESPAC-3 trial (plus controls from ESPAC-1/3) were stained with the 10D7G2 anti-hENT1 antibody. Patients were classified as having high hENT1 expression if the mean H score for their cores was above the overall median H score (48). High and low hENT1-expressing groups were compared using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. All statistical tests were two-sided.
  
  
  RESULTS
  Three hundred eighty patients (87.6%) and 1808 cores were suitable and included in the final analysis. Median overall survival for gemcitabine-treated patients (n = 176) was 23.4 (95% confidence interval [CI] = 18.3 to 26.0) months vs 23.5 (95% CI = 19.8 to 27.3) months for 176 patients treated with 5-fluorouracil/folinic acid (χ(2) 1=0.24; P = .62). Median survival for patients treated with gemcitabine was 17.1 (95% CI = 14.3 to 23.8) months for those with low hENT1 expression vs 26.2 (95% CI = 21.2 to 31.4) months for those with high hENT1 expression (χ(2)₁= 9.87; P = .002). For the 5-fluorouracil group, median survival was 25.6 (95% CI = 20.1 to 27.9) and 21.9 (95% CI = 16.0 to 28.3) months for those with low and high hENT1 expression, respectively (χ(2)₁ = 0.83; P = .36). hENT1 levels were not predictive of survival for the 28 patients of the observation group (χ(2)₁ = 0.37; P = .54). Multivariable analysis confirmed hENT1 expression as a predictive marker in gemcitabine-treated (Wald χ(2) = 9.16; P = .003) but not 5-fluorouracil-treated (Wald χ(2) = 1.22; P = .27) patients.
  
  
  CONCLUSIONS
  Subject to prospective validation, gemcitabine should not be used for patients with low tumor hENT1 expression.
authors.affiliation: Affiliations of authors: Liverpool Cancer Research UK Cancer Trials Unit, Liverpool Cancer Research UK Centre, University of Liverpool, Liverpool, UK (WG, JPN, EG, TFC, PG, EC, CMH, CLR, FC, RJ); the Princess Margaret Hospital, Toronto, Canada (MJM); Manchester Academic Health Sciences Centre, Christie NHS Foundation Trust, School of Cancer and Enabling Sciences, University of Manchester, UK (JWV); Queen Elizabeth Hospital, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK (DHP); Beatson West of Scotland Cancer Centre, Glasgow, UK (ACM); Glasgow Royal Infirmary, Glasgow, UK (RC); Hôpital Tenon, Université, Pierre et Marie Curie, Paris, France (FL); Austin Health, Melbourne, Australia (NCT); Prince of Wales Hospital and Clinical School University of New South Wales, New South Wales, Australia (DG); Nepean Cancer Centre and University of Sydney, Sydney, Australia (JS); Agia Olga Hospital, Athens, Greece (CD); Medical Oncology, Clatterbridge Centre for Oncology, Bebington, Merseyside, UK (DS); Department of Oncology, Akademiska Sjukhuset, Uppsala University, Uppsala, Sweden (BG); University Hospital, North Staffordshire, UK (MD); Freeman Hospital, Newcastle upon Tyne, UK (RMC); Service de Chirurgie Digestive et Viscérale, Hôpital Tenon, Paris, France (FL); Cross Cancer Institute and University of Alberta, Alberta, Canada (JRM, AGS); Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, UK (MRM); St James's University Hospital, Leeds, UK (AA); Department of Medicine A, University Medicine Greifswald, Greifswald, Germany (JM); Petz Aladar Hospital, Gyor, Hungary (AO); Departments of Surgery and Pathology and ARC-NET Research Center, University of Verona, Italy (AS, CB); Department of Surgery, University of Heidelberg, Heidelberg, Germany (MWB).
authors.forename: William
authors.initials: W
authors.lastname: Greenhalf
authors.forename: Paula
authors.initials: P
authors.lastname: Ghaneh
authors.forename: John P
authors.initials: JP
authors.lastname: Neoptolemos
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Palmer
authors.forename: Trevor F
authors.initials: TF
authors.lastname: Cox
authors.forename: Richard F
authors.initials: RF
authors.lastname: Lamb
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Garner
authors.forename: Fiona
authors.initials: F
authors.lastname: Campbell
authors.forename: John R
authors.initials: JR
authors.lastname: Mackey
authors.forename: Eithne
authors.initials: E
authors.lastname: Costello
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: Moore
authors.forename: Juan W
authors.initials: JW
authors.lastname: Valle
authors.forename: Alexander C
authors.initials: AC
authors.lastname: McDonald
authors.forename: Ross
authors.initials: R
authors.lastname: Carter
authors.forename: Niall C
authors.initials: NC
authors.lastname: Tebbutt
authors.forename: David
authors.initials: D
authors.lastname: Goldstein
authors.forename: Jennifer
authors.initials: J
authors.lastname: Shannon
authors.forename: Christos
authors.initials: C
authors.lastname: Dervenis
authors.forename: Bengt
authors.initials: B
authors.lastname: Glimelius
authors.forename: Mark
authors.initials: M
authors.lastname: Deakin
authors.forename: Richard M
authors.initials: RM
authors.lastname: Charnley
authors.forename: François
authors.initials: F
authors.lastname: Lacaine
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Scarfe
authors.forename: Mark R
authors.initials: MR
authors.lastname: Middleton
authors.forename: Alan
authors.initials: A
authors.lastname: Anthoney
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Halloran
authors.forename: Julia
authors.initials: J
authors.lastname: Mayerle
authors.forename: Attila
authors.initials: A
authors.lastname: Oláh
authors.forename: Richard
authors.initials: R
authors.lastname: Jackson
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Rawcliffe
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.forename: Claudio
authors.initials: C
authors.lastname: Bassi
authors.forename: Markus W
authors.initials: MW
authors.lastname: Büchler
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality*; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018572:Disease-Free Survival; D033721:Equilibrative Nucleoside Transporter 1 / Q000378:metabolism*; D005060:Europe / Q000453:epidemiology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality*; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D033721:Equilibrative Nucleoside Transporter 1; C438649:SLC29A1 protein, human; D003841:Deoxycytidine; D002955:Leucovorin; D005472:Fluorouracil; D000093542:Gemcitabine