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

N O Elander, K Aughton, P Ghaneh, J P Neoptolemos, D H Palmer, T F Cox, F Campbell, E Costello, C M Halloran, J R Mackey, A G Scarfe, J W Valle, A C McDonald, R Carter, N C Tebbutt, D Goldstein, J Shannon, C Dervenis, B Glimelius, M Deakin, R M Charnley, Alan Anthoney, M M Lerch, J Mayerle, A Oláh, M W Büchler, W Greenhalf

Journal: British journal of cancer 2019;118(7):947-954

PMID: 29515256

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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.

Address: From the Cancer Research U.K. Liverpool Cancer Trials Unit, University of Liverpool, Liverpool, UK.; The Department of Surgery, University of Heidelberg, Heidelberg, Germany.; Cross Cancer Institute and University of Alberta, Alberta, Canada.; University of Manchester/The Christie NHS Foundation Trust, Manchester, UK.; The Beatson West of Scotland Cancer Centre, Glasgow, Scotland, UK.; Glasgow Royal Infirmary, Glasgow, Scotland, UK.; Austin Health, Melbourne, Australia.; Prince of Wales hospital and Clinical School University of New South Wales, New South Wales, Australia.; Nepean Cancer Centre and University of Sydney, Sydney, Australia.; The Agia Olga Hospital, Athens, Greece.; Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.; University Hospital, North Staffordshire, UK.; Freeman Hospital, Newcastle upon Tyne, UK.; St James's University Hospital, Leeds, UK.; Department of Medicine A, University Medicine Greifswald, Greifswald, Germany.; Department of Medicine II, University Hospital of the Ludwig-Maximilians-University, Munich, Germany.; The Petz Aladar Hospital, Gyor, Hungary.; From the Cancer Research U.K. Liverpool Cancer Trials Unit, University of Liverpool, Liverpool, UK. [email protected].

DOI: 10.1038/s41416-018-0004-2