Intratumoural expression of deoxycytidylate deaminase or ribonuceotide reductase subunit M1 expression are not related to survival in patients with resected pancreatic cancer given adjuvant chemotherapy

Nils Elander ,R Carter,Daniel H Palmer ,Fiona Campbell ,John R Mackey ,Jenny Shannon ,Mark Deakin ,Trevor F Cox ,Karen Aughton ,Christopher Halloran ,Julia Mayerle ,Alan Anthoney ,Paula Ghaneh ,Eithne Costello ,Attila Oláh ,Richard Charnley ,Andrew Scarfe ,Niall C Tebbutt ,John P Neoptolemos ,Juan W Valle ,Christos Dervenis ,David Goldstein ,Bengt Glimelius ,Markus W Büchler ,Alexander Mcdonald ,Markus M Lerch ,William Greenhalf

doi:10.1038/s41416-018-0005-1

Abstract

BackgroundDeoxycytidylate deaminase (DCTD) and ribonucleotide reductase subunit M1 (RRM1) are potential prognostic and predictive biomarkers for pyrimidine-based chemotherapy in pancreatic adenocarcinoma.MethodsImmunohistochemical staining of DCTD and RRM1 was performed on tissue microarrays representing tumour samples from 303 patients in European Study Group for Pancreatic Cancer (ESPAC)-randomised adjuvant trials following pancreatic resection, 272 of whom had received gemcitabine or 5-fluorouracil with folinic acid in ESPAC-3(v2), and 31 patients from the combined ESPAC-3(v1) and ESPAC-1 post-operative pure observational groups.ResultsNeither log-rank testing on dichotomised strata or Cox proportional hazard regression showed any relationship of DCTD or RRM1 expression levels to survival overall or by treatment group.ConclusionsExpression of either DCTD or RRM1 was not prognostic or predictive in patients with pancreatic adenocarcinoma who had had post-operative chemotherapy with either gemcitabine or 5-fluorouracil with folinic acid.

Highlights

We have reported that high expression of human equilibrative nucleotide transporter-1 was associated with improved overall survival in patients randomised to gemcitabine in the European Study Group for Pancreatic Cancer (ESPAC)-3(v2) adjuvant trial, but not in those who had received 5-fluorouracil with folinic acid.[11]
Cox PH regression analysis did not reveal any significant association with overall survival of mean Deoxycytidylate deaminase (DCTD) expression level in the 5-fluorouracil with folinic acid group (HR 1.15, p = 0.33), gemcitabine group (HR 0.93, p = 0.65), or the observational group (HR 1.14, p = 0.64)
Analysis of mean ribonucleotide reductase subunit M1 (RRM1) expression levels did not reveal any significant association with overall survival in the 5-fluorouracil with folinic acid arm (HR 1.14, p = 0.42), the gemcitabine arm (HR 0.96, p = 0.79) or the observational subgroup (HR 1.97, p = 0.20)

Summary

Introduction

Ductal adenocarcinoma of the pancreas is among the five leading causes of cancer-related death worldwide.[1,2] Post-operative chemotherapy with pyrimidine monotherapy or combination regimens is the standard of care following resection.[3,4,5,6,7,8,9] Biomarkers that could select patients for specific types of chemotherapy to improve survival even further would be of significant clinical value in this disease.The biological response to 5-fluorouracil and gemcitabine is regulated by a series of proteins involved in the transmembrane uptake and intracellular metabolism of pyrimidines, and several of these are potential biomarkers for pyrimidine-based chemotherapy.[2,10] Recently, we have reported that high expression of human equilibrative nucleotide transporter (hENT)-1 was associated with improved overall survival in patients randomised to gemcitabine in the ESPAC-3(v2) adjuvant trial, but not in those who had received 5-fluorouracil with folinic acid.[11]Deoxycytidylate deaminase (DCTD) converts phosphorylated gemcitabine into its inactive metabolite[12] and ribonucleotide reductase subunit 1 (RRM1) is a key target of the bioactive gemcitabine metabolite.[13]. Deoxycytidylate deaminase (DCTD) and ribonucleotide reductase subunit M1 (RRM1) are potential prognostic and predictive biomarkers for pyrimidine-based chemotherapy in pancreatic adenocarcinoma. METHODS: Immunohistochemical staining of DCTD and RRM1 was performed on tissue microarrays representing tumour samples from 303 patients in European Study Group for Pancreatic Cancer (ESPAC)-randomised adjuvant trials following pancreatic resection, 272 of whom had received gemcitabine or 5-fluorouracil with folinic acid in ESPAC-3(v2), and 31 patients from the combined ESPAC-3(v1) and ESPAC-1 post-operative pure observational groups. CONCLUSIONS: Expression of either DCTD or RRM1 was not prognostic or predictive in patients with pancreatic adenocarcinoma who had had post-operative chemotherapy with either gemcitabine or 5-fluorouracil with folinic acid.

Methods

Results

Conclusion