Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Apr;118(7):947-954.
doi: 10.1038/s41416-018-0004-2. Epub 2018 Mar 8.

Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer

N O Elander  1 , K Aughton  1 , P Ghaneh  1 , J P Neoptolemos  2 , D H Palmer  1 , T F Cox  1 , F Campbell  1 , E Costello  1 , C M Halloran  1 , J R Mackey  3 , A G Scarfe  3 , J W Valle  4 , A C McDonald  5 , R Carter  6 , N C Tebbutt  7 , D Goldstein  8 , J Shannon  9 , C Dervenis  10 , B Glimelius  11 , M Deakin  12 , R M Charnley  13 , Alan Anthoney  14 , M M Lerch  15 , J Mayerle  16 , A Oláh  17 , M W Büchler  2 , W Greenhalf  18 ; European Study Group for Pancreatic Cancer
Affiliations

Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer

N O Elander et al. Br J Cancer. 2018 Apr.

Abstract

Background: Dihydropyrimidine dehydrogenase (DPD) tumour expression may provide added value to human equilibrative nucleoside transporter-1 (hENT1) tumour expression in predicting survival following pyrimidine-based adjuvant chemotherapy.

Methods: DPD and hENT1 immunohistochemistry and scoring was completed on tumour cores from 238 patients with pancreatic cancer in the ESPAC-3(v2) trial, randomised to either postoperative gemcitabine or 5-fluorouracil/folinic acid (5FU/FA).

Results: DPD tumour expression was associated with reduced overall survival (hazard ratio, HR = 1.73 [95% confidence interval, CI = 1.21-2.49], p = 0.003). This was significant in the 5FU/FA arm (HR = 2.07 [95% CI = 1.22-3.53], p = 0.007), but not in the gemcitabine arm (HR = 1.47 [0.91-3.37], p = 0.119). High hENT1 tumour expression was associated with increased survival in gemcitabine treated (HR = 0.56 [0.38-0.82], p = 0.003) but not in 5FU/FA treated patients (HR = 1.19 [0.80-1.78], p = 0.390). In patients with low hENT1 tumour expression, high DPD tumour expression was associated with a worse median [95% CI] survival in the 5FU/FA arm (9.7 [5.3-30.4] vs 29.2 [19.5-41.9] months, p = 0.002) but not in the gemcitabine arm (14.0 [9.1-15.7] vs. 18.0 [7.6-15.3] months, p = 1.000). The interaction of treatment arm and DPD expression was not significant (p = 0.303), but the interaction of treatment arm and hENT1 expression was (p = 0.009).

Conclusion: DPD tumour expression was a negative prognostic biomarker. Together with tumour expression of hENT1, DPD tumour expression defined patient subgroups that might benefit from either postoperative 5FU/FA or gemcitabine.

PubMed Disclaimer

Conflict of interest statement

J.P.N. reports a consulting or advisory role for Boehringer Ingelheim Pharma GmbH & Co. K.G. Novartis Pharma AG; KAEL GemVax and Astellas. Research Funding from Taiho Pharma (Japan), PI, paid to Institution; KAEL GemVax (Korea), PI, paid to Institution; AstraZeneca, PI, paid to Institution; Pharma Nord, PI, paid to Institution. Travel Expenses from NUCANA, Amgen and Mylan. B.G. reports a Consulting and Advisory role for Pledpharma AB and Isofol AB. M.D. reports a Consulting and Advisory role for socar research.com and travel expenses from Imotech. M.L. reports Consulting and Advisory role for Solvay, Axcan, Abbvie, Abbott, Mylan, Nordmark, AstraZeneca, Centogene, Roche, ISIS, Ionis and KMG Kliniken. Travel Expenses from Falk Foundation, Roche, Abbott and Abbvie, Falk Foundation, Roche, Menarini, Abbott, Abbvie, Mylan and Nordmark. Research Funding from Deutsche Forschungsgemeinschaft (DFG), Deutsche Krebshilfe/lvlildred Scheel Stiftung, Krupp Foundation, German Federal Ministry of Education and Research (BMBF), European Union (FP7, EFRE, ESF and Horizon 20120), the State Ministy of Education and Research Mecklenburg-Vorpommern, State Minisüry of Economics MV. Jo.M. reports Consulting and Advisory role for Pfizer, Stock or Other Ownership from Pacylex Pharmaceuticals Inc and Patent or intellectual Property from Pacylex Pharmaceutical Inc. Ju.M. reports Consulting or Advisory role for Metonomics Health. Research Funding from Astra Zeneca, Patent or Intellectual Property from Metanomics Health, Honoraria from Boehringer Ingelheim and Falk Foundation and Travel Expenses from Falk and Celgene. J.S. reports a Consulting or Advisory role for Amgen. W.G. reports Travel Expenses from Nucana Biomed. N.T. reports Travel Expenses from Roche and Honoraria from Amgen, Roche and Shire. N.E. reports Research Funding from NUCANA. D.G. reports Research Funding from Celgene. D.P. reports Research Funding from Nucana Biomed and Honoraria from Bayer, Nucana Biomed, Sictex, Celgene and Baxalta. A.S. reports Speakers’ Bureau from Amgen and Honoraria from Amgen, Sanofi, Roche, Lilly, Leo, and Celgene.

Figures

Fig. 1
Fig. 1
Kaplan–Meier survival curves and median overall survival for DPD-low vs. DPD-high tumour expression in the entire chemotherapy-treated population (5FU/FA plus gemcitabine), 5FU/FA treated patients, gemcitabine-treated patients, and the small observational (OBS) population
See this image and copyright information in PMC

References

    1. Rahib L, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74:2913–2921. doi: 10.1158/0008-5472.CAN-14-0155. - DOI - PubMed
    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. Cancer J. Clin. 2016;66:7–30. doi: 10.3322/caac.21332. - DOI - PubMed
    1. Kleeff J, et al. Pancreatic cancer. Nat. Rev. Dis. Prim. 2016;2:16022. doi: 10.1038/nrdp.2016.22. - DOI - PubMed
    1. Neoptolemos JP, et al. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: A randomised controlled trial. Lancet. 2001;358:1576–1585. doi: 10.1016/S0140-6736(01)06651-X. - DOI - PubMed
    1. Neoptolemos JP, et al. A randomised trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N. Engl. J. Med. 2004;350:1200–1210. doi: 10.1056/NEJMoa032295. - DOI - PubMed

Publication types

MeSH terms