title: Rapid deaminator status is associated with poor clinical outcome in pancreatic cancer patients treated with a gemcitabine-based regimen.
abstract: BACKGROUND
  Gemcitabine is a mainstay in the treatment of biliary and pancreatic cancers, with limited efficacy in most settings. The gemcitabine elimination pattern is primarily driven by deamination in the liver by CDA. CDA is affected by genetic polymorphisms, leading to marked variations in activity and, subsequently, to erratic drug plasma exposures in patients administered with standard dosage. CDA deficiency has been a rising concern with gemcitabine since several studies have proven that poor metabolizer patients experience life-threatening toxicities upon drug intake. In theory, ultrarapid metabolizer (UM) patients should be conversely at risk of treatment failure, although thus far few studies have addressed this issue in digestive oncology.
  
  
  METHODS
  A pilot study was conducted on 40 pancreatic cancer patients, all treated with gemcitabine-based therapy. CDA status was primarily established on a phenotypic basis determined by measurement of residual CDA enzymatic activity in serum. Additionally, a search for c208G>A and c79A>C polymorphisms was carried out.
  
  
  RESULTS
  No patients carrying c208G>A polymorphisms were found, and only heterozygous c79A>C patients were observed. Eight out of the 40 patients (i.e., 20%) were identified as UM, with CDA activities over 6 U/mg. CDA activity was significantly different between progressive disease patients and patients with controlled disease (8.4 vs 3 U/mg; p < 0.001). Conversely, fewer gemcitabine-related severe toxicities were observed in UM patients.
  
  
  CONCLUSIONS
  This pilot study strongly suggests that UM patients are nearly five-times more likely to have progressive disease than patients with normal or low CDA activities, and that beside molecular events at the tumor level, upstream deregulations affecting drug disposition should be taken into account.
authors.affiliation: Transfer Oncology Laboratory, Nord University Hospital of Marseille, Inserm S_911 CRO2, Aix-Marseille University, Marseille, France.
authors.forename: Cindy
authors.initials: C
authors.lastname: Serdjebi
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Seitz
authors.forename: Joseph
authors.initials: J
authors.lastname: Ciccolini
authors.forename: Muriel
authors.initials: M
authors.lastname: Duluc
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Norguet
authors.forename: Frédéric
authors.initials: F
authors.lastname: Fina
authors.forename: Bruno
authors.initials: B
authors.lastname: Lacarelle
authors.forename: L'houcine
authors.initials: L
authors.lastname: Ouafik
authors.forename: Laetitia
authors.initials: L
authors.lastname: Dahan
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D003564:Cytidine Deaminase / Q000235:genetics* / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D018450:Disease Progression; D005838:Genotype; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D003564:Cytidine Deaminase; D000093542:Gemcitabine