Relevance of dihydropyrimidine-dehydrogenase and thymidylate-synthase in patients with pancreatic neuroendocrine neoplasms treated with 5-FU-based chemotherapy

Abstract

Background: Chemotherapy with 5-FU and Streptozotocin (STZ) is recommended as first-line treatment in patients with metastatic pancreatic neuroendocrine neoplasms (PNEN). However, data about biomarkers involved in the 5-FU metabolism to predict response are still limited.

Objectives: Evaluation of clinicopathological features and potential predictive and prognostic markers of patients with PNEN treated with 5-FU based regimens.

Patients and methods: We retrospectively analyzed 41 patients with PNEN who were treated at the University Hospital Marburg between 2000 and 2013. Dihydropyrimidine-Dehydrogenase (DPD) and Thymidylate-Synthase (TS) expression was correlated with treatment response in 19 patients who had available tumour tissue and response data. The median overall survival (OS) and progression free survival (PFS) were calculated using Kaplan-Meier and Cox regression methods, respectively.

Results: The median PFS in patients receiving 5-FU/STZ was 17 months with a median OS of 50 months. Objective response rate (ORR) and disease control rate (DCR) were 32% and 73%, respectively. Biochemical response (p = 0.005) and high DPD expression (p = 0.018) were predictive markers of response to 5-FU-based chemotherapy. Univariate analysis identified Ki-67 > 10%, no biochemical response, positive 5-HIAA levels and TS deficiency as independent risk factors for shorter PFS. Moreover, performance status (PS) ≥1 was an independent risk factors for impaired OS.

Conclusions: DPD expression and biochemical response represent promising predictive biomarkers for response to 5-FU based chemotherapy. Moreover, Ki-67, PS and TS are independent prognostic markers of OS and PFS in patients with PNEN.

Keywords: 5-FU; Chemotherapy; DPD; PNEN; TS.