title: 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.
  
  
  OBJECTIVE
  Evaluation of clinicopathological features and potential predictive and prognostic markers of patients with PNEN treated with 5-FU based regimens.
  
  
  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.
authors.affiliation: Department of Internal Medicine I, Martin Luther University, Halle (Saale), Germany; Department of Gastroenterology and Endocrinology, Philipps-University, Marburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Krug
authors.affiliation: Institute of Pathology, Philipps-University, Marburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Boch
authors.affiliation: Institute of Pathology, Philipps-University, Marburg, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Nimphius
authors.affiliation: Department of Gastroenterology and Endocrinology, Philipps-University, Marburg, Germany.
authors.forename: T M
authors.initials: TM
authors.lastname: Gress
authors.affiliation: Department of Internal Medicine I, Martin Luther University, Halle (Saale), Germany. Electronic address: patrick.michl@uk-halle.de.
authors.forename: P
authors.initials: P
authors.lastname: Michl
authors.affiliation: Department of Gastroenterology and Endocrinology, Philipps-University, Marburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Rinke
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism*; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis; D013940:Thymidylate Synthase / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D005472:Fluorouracil
keywords: 5-FU; Chemotherapy; DPD; PNEN; TS