Predictive role of human equilibrative nucleoside transporter 1 in patients with pancreatic cancer treated by curative resection and gemcitabine-only adjuvant chemotherapy

Aoyama,Toru; Kazama,Keisuke; Miyagi,Yohei; Murakawa,Masaaki; Yamaoku,Koichiro; Atsumi,Yosuke; Shiozawa,Manabu; Ueno,Makoto; Morimoto,Manabu; Oshima,Takashi; Yukawa,Norio; Yoshikawa,Takaki; Rino,Yasushi; Masuda,Munetaka; Morinaga,Soichiro

doi:10.3892/ol.2017.6220

July-2017 Volume 14 Issue 1

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July-2017 Volume 14 Issue 1

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Article Open Access

Predictive role of human equilibrative nucleoside transporter 1 in patients with pancreatic cancer treated by curative resection and gemcitabine-only adjuvant chemotherapy

Authors:
- Toru Aoyama
- Keisuke Kazama
- Yohei Miyagi
- Masaaki Murakawa
- Koichiro Yamaoku
- Yosuke Atsumi
- Manabu Shiozawa
- Makoto Ueno
- Manabu Morimoto
- Takashi Oshima
- Norio Yukawa
- Takaki Yoshikawa
- Yasushi Rino
- Munetaka Masuda
- Soichiro Morinaga
View Affiliations / Copyright

Affiliations: Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Kanagawa 241‑8515, Japan, Molecular Pathology and Genetics Division, Kanagawa Cancer Center, Yokohama, Kanagawa 241‑8515, Japan, Department of Hepatobiliary Pancreatic Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa 241‑8515, Japan, Department of Surgery, Yokohama City University, Yokohama, Kanagawa 236‑0027, Japan

Copyright: © Aoyama et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Pages: 599-606
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Published online on: May 19, 2017

https://doi.org/10.3892/ol.2017.6220
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Abstract

The predictive roles of human equilibrative nucleoside transporter 1 (hENT‑1) in patients who undergo curative resection and adjuvant chemotherapy with gemcitabine alone have not been established. The present study retrospectively analyzed the clinical data from 101 consecutive patients who underwent curative resection and who received gemcitabine adjuvant chemotherapy for the treatment of pancreatic cancer at Kanagawa Cancer Center (Yokohama, Japan) between 2005 and 2014. The associations between the hENT‑1 status and the survival and clinicopathological features of the patients were investigated. Of the 101 patients, 60 patients (59.4%) had high levels of hENT‑1 expression. A significant association was observed between hENT‑1 status and sex; however, for all the other clinicopathological parameters, including tumor and node stages, no differences were observed between the high and low hENT‑1 expression groups. The median follow‑up period of the present study was 67.3 months. Between the high and low hENT‑1 expression groups, there was a statistically significant difference in the 5‑year overall survival (OS) rates following surgery (20.6 and 8.9%, respectively; P=0.019). In addition, a significant difference was observed in the recurrence‑free survival (RFS) rates at 5 years following surgery (P=0.049). hENT‑1 status was one of the important predictive factors for OS and RFS in patients with pancreatic cancer who underwent curative resection followed by adjuvant chemotherapy with gemcitabine. Adjuvant chemotherapy with gemcitabine alone may be insufficient, particularly in patients with certain relevant risk factors.

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1	Jemal A, Siegel R, Xu J and Ward E: Cancer statistics, ٢٠١٠. CA Cancer J Clin.
2	Nakao A, Fujii T, Sugimoto H, Kanazumi N, Nomoto S, Kodera Y, Inoue S and Takeda S: Oncological problems in pancreatic cancer surgery. World J Gastroenterol. 12:4466–4472. 2006. View Article : Google Scholar : PubMed/NCBI
3	Matsuno S, Egawa S, Fukuyama S, Motoi F, Sunamura M, Isaji S, Imaizumi T, Okada S, Kato H, Suda K, et al: Pancreatic cancer registry in Japan: 20 years of experience. Pancreas. 28:219–230. 2004. View Article : Google Scholar : PubMed/NCBI
4	Carpelan-Holmström M, Nordling S, Pukkala E, Sankila R, Lüttges J, Klöppel G and Haglund C: Does anyone survive pancreatic ductal adenocarcinoma? A nationwide study re-evaluating the data of the Finnish Cancer Registry. Gut. 54:385–387. 2005. View Article : Google Scholar : PubMed/NCBI
5	Wagner M, Redaelli C, Lietz M, Seiler CA, Friess H and Büchler MW: Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma. Br J Surg.
6	Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, et al: A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 350:1200–1210. 2004. View Article : Google Scholar : PubMed/NCBI
7	Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, et al: Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: A randomized controlled trial. JAMA. 304:1073–1081. 2010. View Article : Google Scholar : PubMed/NCBI
8	Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, et al: Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: A randomized controlled trial. JAMA. 297:267–277. 2007. View Article : Google Scholar : PubMed/NCBI
9	Zhang J, Visser F, King KM, Baldwin SA, Young JD and Cass CE: The role of nucleoside transporters in cancer chemotherapy with nucleoside drugs. Cancer Metastasis Rev.
10	Mackey JR, Mani RS, Selner M, Mowles D, Young JD, Belt JA, Crawford CR and Cass CE: Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. Cancer Res. 58:4349–4357. 1998.PubMed/NCBI
11	Pérez-Torras S, García-Manteiga J, Mercadé E, Casado FJ, Carbó N, Pastor-Anglada M and Mazo A: Adenoviral-mediated overexpression of human equilibrative nucleoside transporter 1 (hENT-1) enhances gemcitabine response in human pancreatic cancer. Biochem Pharmacol. 76:322–329. 2008. View Article : Google Scholar : PubMed/NCBI
12	Mori R, Ishikawa T, Ichikawa Y, Taniguchi K, Matsuyama R, Ueda M, Fujii Y, Endo I, Togo S, Danenberg PV and Shimada H: Human equilibrative nucleoside transporter 1 is associated with the chemosensitivity of gemcitabine in human pancreatic adenocarcinoma and biliary tract carcinoma cells. Oncol Rep. 17:1201–1205. 2007.PubMed/NCBI
13	Giovannetti E, Del Tacca M, Mey V, Funel N, Nannizzi S, Ricci S, Orlandini C, Boggi U, Campani D, Del Chiaro M, et al: Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine. Cancer Res. 66:3928–3935. 2006. View Article : Google Scholar : PubMed/NCBI
14	Spratlin J, Sangha R, Glubrecht D, Dabbagh L, Young JD, Dumontet C, Cass C, Lai R and Mackey JR: The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabine-treated pancreas adenocarcinoma. Clin Cancer Res. 10:6956–6961. 2004. View Article : Google Scholar : PubMed/NCBI
15	Farrell JJ, Elsaleh H, Garcia M, Lai R, Ammar A, Regine WF, Abrams R, Benson AB, Macdonald J, Cass CE, et al: Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. Gastroenterology. 136:187–195. 2009. View Article : Google Scholar : PubMed/NCBI
16	Marechal R, Mackey JR, Lai R, Demetter P, Peeters M, Polus M, Cass CE, Young J, Salmon I, Devière J and Van Laethem JL: Human equilibrative nucleoside transporter 1 and human concentrative nucleoside transporter 3 predict survival after adjuvant gemcitabine therapy in resected pancreatic adenocarcinoma. Clin Cancer Res. 15:2913–2919. 2009. View Article : Google Scholar : PubMed/NCBI
17	Sobin LH and Wittekind CH: TNM Classification of Malignant Tumors. ٧th. John Wiley & Sons; New York:
18	Büchler MW, Friess H, Wagner M, Kulli C, Wagener V and Z'Graggen K: Pancreatic fistula after pancreatic head resection. Br J Surg. ٨٧: ٨٨٣-٨٨٩, ٢٠٠٠.
19	Wagner M, Z'graggen K, Vagianos CE, Redaelli CA, Holzinger F, Sadowski C, Kulli C, Zimmermann H, Baer HU and Büchler MW: Pylorus-preserving total pancreatectomy. Early and late results. Dig Surg. 18:188–195. 2001. View Article : Google Scholar : PubMed/NCBI
20	Andrén-Sandberg A, Wagner M, Tihanyi T, Löfgren P and Friess H: Technical aspects of left-sided pancreatic surgery for cancer. Dig Surg.
21	Morinaga S, Nakamura Y, Watanabe T, Mikayama H, Tamagawa H, Yamamoto N, Shiozawa M, Akaike M, Ohkawa S, Kameda Y and Miyagi Y: Immunohistochemical analysis of human equilibrative nucleoside transporter-1 (hENT-1) predicts survival in resected pancreatic cancer patients treated with adjuvant gemcitabine monotherapy. Ann Surg Oncol. 19 Suppl 3:S558–S564. 2012. View Article : Google Scholar : PubMed/NCBI
22	Kim R, Tan A, Lai KK, Jiang J, Wang Y, Rybicki LA and Liu X: Prognostic roles of human equilibrative transporter ١ (hENT-١) and ribonucleoside reductase subunit M١ (RRM١) in resected pancreatic cancer. Cancer.
23	Povoski SP, Karpeh MS Jr, Conlon KC, Blumgart LH and Brennan MF: Association of preoperative biliary drainage with postoperative outcome following pancreaticoduodenectomy. Ann Surg. PubMed/NCBI
24	Yeo CJ, Cameron JL, Lillemoe KD, Sohn TA, Campbell KA, Sauter PK, Coleman J, Abrams RA and Hruban RH: Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma, part 2: Randomized controlled trial evaluating survival, morbidity, and mortality. Ann Surg. 236:355–368. 2002. View Article : Google Scholar : PubMed/NCBI
25	Kawai M, Tani M, Terasawa H, Ina S, Hirono S, Nishioka R, Miyazawa M, Uchiyama K and Yamaue H: Early removal of prophylactic drains reduces the risk of intra-abdominal infections in patients with pancreatic head resection: Prospective study for 104 consecutive patients. Ann Surg. 244:1–7. 2006. View Article : Google Scholar : PubMed/NCBI
26	Munoz-Bongrand N, Sauvanet A, Denys A, Sibert A, Vilgrain V and Belghiti J: Conservative management of pancreatic fistula after pancreaticoduodenectomy with pancreaticogastrostomy. J Am Coll Surg.