Levels of gemcitabine transport and metabolism proteins predict survival times of patients treated with gemcitabine for pancreatic adenocarcinoma.
OBJECTIVE
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.
Department of Gastroenterology and Gastrointestinal Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium. Electronic address: raphael.marechal@erasme.ulb.ac.be.
Raphaël
R
Maréchal
Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France; EA4340 "Epidémiologie et oncogènes des tumeurs digestives," Versailles Saint-Quentin-en-Yvelines University, Saint-Quentin-en-Yvelines, France; Department of Hepato-Gastroenterology, Pitié Salpêtrière Hospital, APHP, Paris, France.
Jean-Baptiste
JB
Bachet
Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada.
John R
JR
Mackey
Department of Biostatistics and Epidemiology (EA4184), Georges François Leclerc Center, Dijon, France.
Cécile
C
Dalban
Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, and DIAPATH, Brussels, Belgium.
Pieter
P
Demetter
Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada.
Kathryn
K
Graham
Department of Pathology, Beaujon Hospital, APHP, Clichy, France.
Anne
A
Couvelard
Department of Pathology, Saint Antoine Hospital, APHP, Paris, France.
Magali
M
Svrcek
Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France; Department of Pathology, Pitié Salpêtrière Hospital, APHP, Paris, France.
Armelle
A
Bardier-Dupas
Department of Gastroenterology, Beaujon Hospital, APHP, Clichy, France.
Pascal
P
Hammel
Department of Surgery, Beaujon Hospital, APHP, Clichy, France.
Alain
A
Sauvanet
Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France; Department of Oncology, Saint Antoine Hospital, APHP, Paris, France.
Christophe
C
Louvet
Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France; Department of Surgery, Saint Antoine Hospital, APHP, Paris, France.
François
F
Paye
EA4340 "Epidémiologie et oncogènes des tumeurs digestives," Versailles Saint-Quentin-en-Yvelines University, Saint-Quentin-en-Yvelines, France; Department of Digestive Oncology, Hôpital Européen Georges Pompidou, APHP, Paris, France.
Philippe
P
Rougier
EA4340 "Epidémiologie et oncogènes des tumeurs digestives," Versailles Saint-Quentin-en-Yvelines University, Saint-Quentin-en-Yvelines, France; Department of Surgery, Ambroise Paré Hospital, APHP, Boulogne Billancourt, France.
Christophe
C
Penna
Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France; Department of Hepato-Gastroenterology, Pitié Salpêtrière Hospital, APHP, Paris, France.
Thierry
T
André
Centre de Cancer de Lyon, Lyon, France; Hospices Civils de Lyon, Lyon, France.
Charles
C
Dumontet
Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada.
Carol E
CE
Cass
Centre de Cancer de Lyon, Lyon, France.
Lars Petter
LP
Jordheim
Centre de Cancer de Lyon, Lyon, France.
Eva-Laure
EL
Matera
Department of Surgery, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.
Jean
J
Closset
Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, and DIAPATH, Brussels, Belgium.
Isabelle
I
Salmon
Department of Gastroenterology and Gastrointestinal Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.
Jacques
J
Devière
EA4340 "Epidémiologie et oncogènes des tumeurs digestives," Versailles Saint-Quentin-en-Yvelines University, Saint-Quentin-en-Yvelines, France; Department of Pathology, Ambroise Paré Hospital, APHP, Boulogne Billancourt, France.
Jean-François
JF
Emile
Department of Gastroenterology and Gastrointestinal Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.
Jean-Luc
JL
Van Laethem
D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000627:therapeutic use*; D001692:Biological Transport; D001711:Biotransformation; D021441:Carcinoma, Pancreatic Ductal / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D016009:Chi-Square Distribution; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D003842:Deoxycytidine Kinase / Q000032:analysis*; D033721:Equilibrative Nucleoside Transporter 1 / Q000032:analysis*; D005260:Female; D005602:France; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D015999:Multivariate Analysis; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012262:Ribonucleoside Diphosphate Reductase; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D046888:Tissue Array Analysis / Q000379:methods; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000032:analysis*; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D033721:Equilibrative Nucleoside Transporter 1; C438649:SLC29A1 protein, human; D025521:Tumor Suppressor Proteins; D003841:Deoxycytidine; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; D003842:Deoxycytidine Kinase; D000093542:Gemcitabine