Abstract
ABSTRACTBackgroundDihydropyrimidine 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.MethodsDPD 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).ResultsDPD 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).ConclusionDPD 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.
Highlights
Immunohistochemical staining and scoring We stained tissue cores from 303 patients: 272 patients randomised and treated in the chemotherapy arms of the European Study Group for Pancreatic Cancer (ESPAC)-3(2) trial,[7] and 31 patients randomised to observation in the combined ESPAC-1/ESPAC-3(v1) trials.[4,5,6,7]
This difference was significant in the 5-fluorouracil/folinic acid (5FU/FA) arm (HR: 2.07, 95% confidence intervals (CI): 1.22–3.53, p = 0.007), but not in the gemcitabine arm (HR: 1.47, 95% CI: 0.91–2.37, p = 0.119)
Tumour expression of human equilibrative nucleoside transporter 1 (hENT1) was not prognostic for the whole chemotherapy cohort (HR: 0.84, 95% CI: 0.63–1.12, p = 0.230), but was predictive for improved survival with gemcitabine (HR: 0.56, 95% CI: 0.38–0.82, p = 0.003) but not for 5FU/FA (HR: 1.19, 95% CI: 0.80–1.78, p = 0.390)
Summary
Pancreatic ductal adenocarcinoma is one of the leading causes of cancer-related death worldwide and will shortly overtake breast cancer as the second leading cause of cancer death in the USA, with limited survival following primary treatment.[1,2,3] Following multicentre studies by the European Study Group for Pancreatic Cancer (ESPAC) and others, it is clear that adjuvant chemotherapy with either 5-fluorouracil with folinic acid (5FU/ FA), gemcitabine monotherapy, or gemcitabine plus capecitabine (a 5FU prodrug) for 6 months following pancreatic resection increases long-term survival.[4,5,6,7,8,9,10] Adjuvant S-1, an orally active drug containing tegafur (another 5FU prodrug), has improved survival in patients from Japan.[11] Both 5FU/FA and gemcitabine are efficient at the cohort level, specific individuals may benefit more from either gemcitabine or 5FU/FA. Together with tumour expression of hENT1, DPD tumour expression defined patient subgroups that might benefit from either postoperative 5FU/FA or gemcitabine
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