[en] BACKGROUND: Gemcitabine (2',2'-difluorodeoxycytidine) administration after resection of pancreatic cancer improves both disease-free survival (DFS) and overall survival (OS). Deoxycytidine kinase (dCK) mediates the rate-limiting catabolic step in the activation of gemcitabine. The authors of this report studied patient outcomes according to the expression of dCK after a postoperative gemcitabine-based chemoradiation regimen. METHODS: Forty-five patients with resected pancreatic adenocarcinoma received adjuvant gemcitabine based-therapy in the context of multicenter phase 2 studies. Their tumors were evaluated retrospectively for dCK protein expression by immunohistochemistry. A composite score based on the percentage of dCK-positive cancer cells and the intensity of staining was generated, and the results were dichotomized at the median values. RESULTS: The median follow-up was 19.95 months (95% confident interval [CI], 3.3-107.4 months). The lymph node (LN) ratio and dCK protein expression were significant predictors of DFS and OS in univariate analysis. On multivariate analysis, dCK protein expression was the only independent prognostic variable (DFS: hazard ratio [HR], 3.48; 95% CI, 1.66-7.31; P = .001; OS: HR, 3.2; 95% CI,1.44-7.13; P = .004). CONCLUSIONS: dCK protein expression was identified as an independent and strong prognostic factor in patients with resected pancreatic adenocarcinoma who received adjuvant gemcitabine therapy. The authors concluded that it deserves prospective evaluation as a predictive biomarker for patient selection.
Disciplines :
Gastroenterology & hepatology
Author, co-author :
Marechal, Raphael
Mackey, John R
Lai, Raymond
Demetter, Pieter
Peeters, Marc
Polus, Marc ; Centre Hospitalier Universitaire de Liège - CHU > Gastro-Entérologie-Hépatologie
Cass, Carol E
Salmon, Isabelle
Deviere, Jacques
Van Laethem, Jean*-Luc
Language :
English
Title :
Deoxycitidine kinase is associated with prolonged survival after adjuvant gemcitabine for resected pancreatic adenocarcinoma.
Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007; 297: 267-277.
Neuhaus P, Riess H, Post S, et al. CONKO-001: Final results of the randomized, prospective, multicenter phase III trial of adjuvant chemotherapy with gemcitabine versus observation in patients with resected pancreatic cancer (PC) [abstract]. J Clin Oncol. 2008; 26 (15S). Abstract 4504.
Huang P, Plunkett W,. Induction of apoptosis by gemcitabine. Semin Oncol. 1995; 15: 2403-2413.
Ruiz van Haperen VW, Veerman G, Vermorken JB, et al. 2′,2′- Difluoro-deoxycitidine (gemcitabine) incorporation into RNA and DNA of tumour cell lines. Biochem Pharmacol. 1993; 46: 762-766.
Plunkett W, Huang P, Searcy CE, et al. Gemcitabine: preclinical pharmacology and mechanisms of action. Semin Oncol. 1996; 23: 3-15.
Lawrence TS, Change EY, Hohn TM, et al. Radiosensitization of pancreatic cancer cells by 2′,2′-difluoro-2′-deoxycytidine. Int J Radiat Oncol Biol Phys. 1996; 34: 867-872.
Milas L, Fujii T, Hunter NR, et al. Enhancement of tumor radioresponse in vivo by gemcitabine, Cancer Res. 1999; 59: 107-114.
Mason KA, Milas L, Hunter NR, et al. Maximizing therapeutic gain with gemcitabine and fractionated radiation. Int J Radiat Oncol Biol Phys. 1999; 44: 1125-1135.
Blackstock AW, Bernard SA, Richards F, et al. Phase I trial of twice-weekly gemcitabine and concurrent radiation in patients with advanced pancreatic cancer. J Clin Oncol. 1999; 17: 2208-2212.
Murphy JD, Adusumilli S, Kent A, et al. Full-dose gemcitabine and concurrent radiotherapy for unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys. 2007; 68: 801-808.
Van Laethem JL, Demols A, Gay F, et al. Postoperative adjuvant gemcitabine and concurrent radiation after curative resection of pancreatic head carcinoma: a phase II study. Int J Radiat Oncol Biol Phys. 2003; 56: 974-980.
Demols A, Peeters M, Polus M, et al. Adjuvant gemcitabine and concurrent continuous radiation (45 Gy) for resected pancreatic head carcinoma: a multicenter Belgian phase II study. Int J Radiat Oncol Biol Phys. 2005; 62: 1351-1356.
Van Laethem JL, Van Cutsem E, Hammel P, et al. Adjuvant chemotherapy alone versus chemoradiation after curative resection for pancreatic cancer: feasibility results of a randomised EORTC/FFCD/GERCOR phase II/III study (40013/22012/0304) [abstract]. J Clin Oncol. 2008; 26 (15S). Abstract 4514.
Regine WF, Winter KA, Abrams RA, et al. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008; 299: 1019-1026.
Farrell JJ, Elsaleh H, Garcia M, et al. Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. Gastroenterology. 2009; 136: 187-195.
Marechal R, Mackey JR, Lai R, et al. Human equilibrative nucleoside transporter 1 and human concentrative nucleoside transporter 3 predict after adjuvant gemcitabine therapy in resected pancreatic adenocarcinoma. Clin Cancer Res. 2009; 15: 2913-2919.
Hatzis P, Al-Madhoon AS, Jullig M, Petrakis TG, Eriksson S, Talianidis I,. The intracellular localization of deoxycytidine kinase. J Biol Chem. 1998; 273: 30239-30243.
Nakahira S, Nakamori S, Tsujie M, et al. Involvement of ribonucleotide reductase M1 subunit overexpression in gemcitabine resistance of human pancreatic cancer. Int J Cancer. 2007; 120: 1355-1363.
Itoi T, Sofuni A, Fukushima N, et al. Ribonucleotide reductase subunit M2 mRNA expression in pretreatment biopsies obtained from unresectable pancreatic carcinomas. J Gastroenterol. 2007; 42: 389-394.
Sebastiani V, Ricci F, Rubio-Viquiera B, et al. Immunohistochemical and genetic evaluation of deoxycytidine kinase in pancreatic cancer: relationship to molecular mechanisms of gemcitabine resistance and survival. Clin Cancer Res. 2006; 12: 2492-2497.
Hubeek I, Peters GJ, Broekhuizen AJ, et al. Immunocytochemical detection of deoxycytidine kinase in haematological malignancies and solid tumours. J Clin Pathol. 2005; 58: 695-699.
Keszler G, Spasokoukotskaja T, Csapo Z, et al. Activation of deoxycytidine kinase in lymphocytes is calcium dependent and involves a conformational change detectable by native immunostaining. Biochem Pharmacol. 2004; 67: 947-955.
Spyrou G, Reichard P,. Compartmentation of dCTP pools. Evidence from deoxyliponucleotide synthesis. J Biol Chem. 1987; 262: 16425-16432.
Spyrou G, Reichard P,. Intracellular compartmentation of deoxycytidine nucleotide pools in S phase mouse 3T3 fibroblasts. J Biol Chem. 1989; 264: 960-964.
Spasokukotskaja T, Spyrou G, Staub M,. Deoxycytidine is salvaged not only into DNA but also into phospholipid precursors. Biochem Biophys Res Commun. 1988; 155: 923-929.
Spasokukotskaja T, Taljanidisz J, Sasvari-Szekely M, Staub M,. Deoxycytidine is salvaged not only into DNA but also into phospholipid precursors. III. dCOP-diacylglycerol formation in tonsillar lymphocytes. Biochem Biophys Res Commun. 1991; 174: 680-687.