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

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

Author information

1
Department of Gastroenterology and Gastrointestinal Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium. Electronic address: raphael.marechal@erasme.ulb.ac.be.
2
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.
3
Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada.
4
Department of Biostatistics and Epidemiology (EA4184), Georges François Leclerc Center, Dijon, France.
5
Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, and DIAPATH, Brussels, Belgium.
6
Department of Pathology, Beaujon Hospital, APHP, Clichy, France.
7
Department of Pathology, Saint Antoine Hospital, APHP, Paris, France.
8
Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France; Department of Pathology, Pitié Salpêtrière Hospital, APHP, Paris, France.
9
Department of Gastroenterology, Beaujon Hospital, APHP, Clichy, France.
10
Department of Surgery, Beaujon Hospital, APHP, Clichy, France.
11
Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France; Department of Oncology, Saint Antoine Hospital, APHP, Paris, France.
12
Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France; Department of Surgery, Saint Antoine Hospital, APHP, Paris, France.
13
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.
14
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.
15
Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France; Department of Hepato-Gastroenterology, Pitié Salpêtrière Hospital, APHP, Paris, France.
16
Centre de Cancer de Lyon, Lyon, France; Hospices Civils de Lyon, Lyon, France.
17
Centre de Cancer de Lyon, Lyon, France.
18
Department of Surgery, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.
19
Department of Gastroenterology and Gastrointestinal Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.
20
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.

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.

PMID:
22705007
DOI:
10.1053/j.gastro.2012.06.006
[Indexed for MEDLINE]

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