title: Prognostic factors in gemcitabine-cisplatin polychemotherapy regimens in pancreatic cancer: XPD-Lys751Gln polymorphism strikes back.
abstract: The use of platinated agents in combination chemotherapy regimens for advanced pancreatic cancer is controversial owing to the lack of an outstanding impact on the outcome and a substantial increase in hematologic and extra-hematologic toxicities. Pharmacogenetic studies to identify patients who could benefit most from such therapies are urgently needed. The Xeroderma-Pigmentosum group-D polymorphism at codon-751 (XPD-Lys751Gln) emerged as the most significant independent predictor for death- and progression-risk in our previous study on functional polymorphisms in 122 advanced pancreatic cancer patients treated with cisplatin-docetaxel-capecitabine-gemcitabine and cisplatin-epirubicin-capecitabine-gemcitabine (or EC-GemCap). To confirm the prognostic role of this variable, we further evaluated the correlation of XPD-Lys751Gln with outcome in another 125 patients treated with the same regimens, and 90 treated with gemcitabine monotherapy. Genotyping was successfully carried out in the vast majority of DNA samples. Genotype frequencies followed Hardy-Weinberg equilibrium, and XPD-Lys751Gln was associated with differential progression-free and overall-survival. Multivariate analysis confirmed its prognostic significance in platinum-based regimens. In particular, XPD-Gln751Gln was significantly associated with risk of death (hazard ratio, HR = 1.7, 95% confidence interval [CI], 1.1-2.6, p = 0.011) and risk of progression (HR = 1.7, 95% CI, 1.1-2.5, p = 0.013). No correlation was observed in gemcitabine monotherapy-treated patients. The analysis of DNA damage using extra-long-PCR in lymphocytes supported the association of XPD-Gln751Gln with greater resistance to cisplatin-induced damage. The increasing evidence of XPD-Lys751Gln impact on the outcome of gemcitabine-cisplatin-based polychemotherapy leads to plan prospective studies to validate the role of this polymorphism as a new tool for optimization of the currently available treatments in pancreatic cancer.
authors: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Amir
authors: A
authors: Avan
authors: Paola
authors: P
authors: Pacetti
authors: Michele
authors: M
authors: Reni
authors: Michele
authors: M
authors: Milella
authors: Enrico
authors: E
authors: Vasile
authors: Andrea
authors: A
authors: Mambrini
authors: Vanja
authors: V
authors: Vaccaro
authors: Sara
authors: S
authors: Caponi
authors: Stefano
authors: S
authors: Cereda
authors: Godefridus J
authors: GJ
authors: Peters
authors: Maurizio
authors: M
authors: Cantore
authors: Elisa
authors: E
authors: Giovannetti
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005998:Glycine / Q000235:genetics*; D006801:Humans; D008239:Lysine / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011379:Prognosis; D051759:Xeroderma Pigmentosum Group D Protein / Q000737:chemistry / Q000235:genetics*; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human; D008239:Lysine; D002945:Cisplatin; D005998:Glycine; D000093542:Gemcitabine