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

N. O. Elander; K Augthton; P. Ghaneh; J. P. Neoptolemos; DH Palmer; T. F. Cox; F Campbell; E Costello; CM Halloran; JR. Mackey; A.G. Scarfe; Juan Valle; AC McDonald; R Carter; NC Tebbutt; D Goldstein; J Shannon; C Dervenis; B Glimelius; M Deakin; RM Charnley; Alan Anthoney; MM Lerch; Julia Mayerle; A Olah; MW Buchler; W Greenhalf

doi:10.1038/s41416-018-0004-2

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

N. O. Elander, K Augthton, P. Ghaneh, J. P. Neoptolemos, DH Palmer, T. F. Cox, F Campbell, E Costello, CM Halloran, JR. Mackey, A.G. Scarfe, Juan Valle, AC McDonald, R Carter, NC Tebbutt, D Goldstein, J Shannon, C Dervenis, B Glimelius, M DeakinRM Charnley, Alan Anthoney, MM Lerch, Julia Mayerle, A Olah, MW Buchler, W Greenhalf

Division of Cancer Sciences (L5)

Research output: Contribution to journal › Article › peer-review

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Abstract

Background: Tumour dihydropyrimidine dehydrogenase (DPD) may provide added value to human equilibrative nucleoside transporter-1 (hENT1) in predicting survival following pyrimidine based adjuvant chemotherapy.
Methods: DPD and hENT1 immunohistochemistry scoring was undertaken on tumour cores from 238 patients with pancreatic cancer in the ESPAC-3(v2) trial, randomised to 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 (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). Patients with low hENT1 and high DPD expression had a reduced median [95% CI] survival with 5FU/FA (9.7 [5.3-30.4] versus 29.2 [19.5-41.9] months, p=0.002) but not with gemcitabine (14.0 [9.1-15.7] versus 18.0 [7.6-15.3] months, p=1.000). Interaction of treatment and DPD expression was not significant (p=0.303), but interaction of treatment 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.

Original language	English
Pages (from-to)	947-954
Number of pages	7
Journal	British Journal of Cancer
Volume	118
Early online date	8 Mar 2018
DOIs	https://doi.org/10.1038/s41416-018-0004-2
Publication status	Published - 2018

Keywords

Dihydropyrimidine dehydrogenase (DPD)
human equilibrative nucleoside transporter 1 (hENT1)
pancreatic cancer
5-fluorouracil
gemcitabine
randomized trial
adjuvant
predictive
prognostic

Research Beacons, Institutes and Platforms

Manchester Cancer Research Centre

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41416-018-0004-2

2018 Elander et al BJC - DPD and hENT1 in PDAC Resubmission ms DPD 26-11-2017 NEAccepted author manuscript, 8.3 MB

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Elander, N. O., Augthton, K., Ghaneh, P., Neoptolemos, J. P., Palmer, DH., Cox, T. F., Campbell, F., Costello, E., Halloran, CM., Mackey, JR., Scarfe, A. G., Valle, J., McDonald, AC., Carter, R., Tebbutt, NC., Goldstein, D., Shannon, J., Dervenis, C., Glimelius, B., ... Greenhalf, W. (2018). Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer. British Journal of Cancer, 118, 947-954. https://doi.org/10.1038/s41416-018-0004-2

@article{1c8e6ce448d0487ba9540937a0c0f3d2,

title = "Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer.",

abstract = "Background: Tumour dihydropyrimidine dehydrogenase (DPD) may provide added value to human equilibrative nucleoside transporter-1 (hENT1) in predicting survival following pyrimidine based adjuvant chemotherapy.Methods: DPD and hENT1 immunohistochemistry scoring was undertaken on tumour cores from 238 patients with pancreatic cancer in the ESPAC-3(v2) trial, randomised to 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 (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). Patients with low hENT1 and high DPD expression had a reduced median [95% CI] survival with 5FU/FA (9.7 [5.3-30.4] versus 29.2 [19.5-41.9] months, p=0.002) but not with gemcitabine (14.0 [9.1-15.7] versus 18.0 [7.6-15.3] months, p=1.000). Interaction of treatment and DPD expression was not significant (p=0.303), but interaction of treatment 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.",

keywords = "Dihydropyrimidine dehydrogenase (DPD), human equilibrative nucleoside transporter 1 (hENT1), pancreatic cancer, 5-fluorouracil, gemcitabine, randomized trial, adjuvant, predictive , prognostic",

author = "Elander, {N. O.} and K Augthton and P. Ghaneh and Neoptolemos, {J. P.} and DH Palmer and Cox, {T. F.} and F Campbell and E Costello and CM Halloran and JR. Mackey and A.G. Scarfe and Juan Valle and AC McDonald and R Carter and NC Tebbutt and D Goldstein and J Shannon and C Dervenis and B Glimelius and M Deakin and RM Charnley and Alan Anthoney and MM Lerch and Julia Mayerle and A Olah and MW Buchler and W Greenhalf",

year = "2018",

doi = "10.1038/s41416-018-0004-2",

language = "English",

volume = "118",

pages = "947--954",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Springer Nature",

}

Elander, NO, Augthton, K, Ghaneh, P, Neoptolemos, JP, Palmer, DH, Cox, TF, Campbell, F, Costello, E, Halloran, CM, Mackey, JR, Scarfe, AG, Valle, J, McDonald, AC, Carter, R, Tebbutt, NC, Goldstein, D, Shannon, J, Dervenis, C, Glimelius, B, Deakin, M, Charnley, RM, Anthoney, A, Lerch, MM, Mayerle, J, Olah, A, Buchler, MW & Greenhalf, W 2018, 'Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer.', British Journal of Cancer, vol. 118, pp. 947-954. https://doi.org/10.1038/s41416-018-0004-2

TY - JOUR

T1 - Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer.

AU - Elander, N. O.

AU - Augthton, K

AU - Ghaneh, P.

AU - Neoptolemos, J. P.

AU - Palmer, DH

AU - Cox, T. F.

AU - Campbell, F

AU - Costello, E

AU - Halloran, CM

AU - Mackey, JR.

AU - Scarfe, A.G.

AU - Valle, Juan

AU - McDonald, AC

AU - Carter, R

AU - Tebbutt, NC

AU - Goldstein, D

AU - Shannon, J

AU - Dervenis, C

AU - Glimelius, B

AU - Deakin, M

AU - Charnley, RM

AU - Anthoney, Alan

AU - Lerch, MM

AU - Mayerle, Julia

AU - Olah, A

AU - Buchler, MW

AU - Greenhalf, W

PY - 2018

Y1 - 2018

N2 - Background: Tumour dihydropyrimidine dehydrogenase (DPD) may provide added value to human equilibrative nucleoside transporter-1 (hENT1) in predicting survival following pyrimidine based adjuvant chemotherapy.Methods: DPD and hENT1 immunohistochemistry scoring was undertaken on tumour cores from 238 patients with pancreatic cancer in the ESPAC-3(v2) trial, randomised to 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 (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). Patients with low hENT1 and high DPD expression had a reduced median [95% CI] survival with 5FU/FA (9.7 [5.3-30.4] versus 29.2 [19.5-41.9] months, p=0.002) but not with gemcitabine (14.0 [9.1-15.7] versus 18.0 [7.6-15.3] months, p=1.000). Interaction of treatment and DPD expression was not significant (p=0.303), but interaction of treatment 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.

AB - Background: Tumour dihydropyrimidine dehydrogenase (DPD) may provide added value to human equilibrative nucleoside transporter-1 (hENT1) in predicting survival following pyrimidine based adjuvant chemotherapy.Methods: DPD and hENT1 immunohistochemistry scoring was undertaken on tumour cores from 238 patients with pancreatic cancer in the ESPAC-3(v2) trial, randomised to 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 (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). Patients with low hENT1 and high DPD expression had a reduced median [95% CI] survival with 5FU/FA (9.7 [5.3-30.4] versus 29.2 [19.5-41.9] months, p=0.002) but not with gemcitabine (14.0 [9.1-15.7] versus 18.0 [7.6-15.3] months, p=1.000). Interaction of treatment and DPD expression was not significant (p=0.303), but interaction of treatment 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.

KW - Dihydropyrimidine dehydrogenase (DPD)

KW - human equilibrative nucleoside transporter 1 (hENT1)

KW - pancreatic cancer

KW - 5-fluorouracil

KW - gemcitabine

KW - randomized trial

KW - adjuvant

KW - predictive

KW - prognostic

U2 - 10.1038/s41416-018-0004-2

DO - 10.1038/s41416-018-0004-2

M3 - Article

SN - 0007-0920

VL - 118

SP - 947

EP - 954

JO - British Journal of Cancer

JF - British Journal of Cancer

ER -

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

Abstract

Keywords

Research Beacons, Institutes and Platforms

UN SDGs

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