title: Precision Medicine and Pancreatic Cancer: A Gemcitabine Pathway Approach.
abstract: There is a need for validated predictive markers of gemcitabine response to guide precision medicine treatment in pancreatic cancer. We previously validated human equilibrative nucleoside transporter 1 as a predictive marker of gemcitabine treatment response using Radiation Therapy Oncology Group 9704. Controversy exists about the predictive value of gemcitabine metabolism pathway biomarkers: deoxycytidine kinase (DCK), ribonucleotide reductase 1 (RRM1), RRM2, and p53R2.
  
  
  
  Radiation Therapy Oncology Group 9704 prospectively randomized 538 patients after pancreatic resection to receive either 5-fluorouracil or gemcitabine. Tumor DCK, RRM1, RRM2, and p53R protein expressions were analyzed using a tissue microarray and immunohistochemistry and correlated with treatment outcome (overall survival and disease-free survival) by unconditional logistic regression analysis.
  
  
  
  There were 229 patients eligible for analysis from both the 5-fluorouracil and gemcitabine arms. Only RRM2 protein expression, and not DCK, RRM1, or p53R2 protein expression, was associated with survival in the gemcitabine treatment arm.
  
  
  
  Despite limited data from other nonrandomized treatment data, our data do not support the predictive value of DCK, RRM1, or p53R2. Efforts should focus on human equilibrative nucleoside transporter 1 and possibly RRM2 as valid predictive markers of the treatment response of gemcitabine in pancreatic cancer.
authors.affiliation: From the *Yale Center for Pancreatic Disease, Yale School of Medicine, New Haven, CT; †Statistics and Data Management Center, NRG Oncology, Philadelphia, PA; ‡Department of Medicine, John A Burns School of Medicine, University of Hawaii, Honolulu, HI; §Department of Radiation Oncology, University of Maryland, Baltimore, MD; ∥Oncology Program, Toledo Clinic, Toledo, OH; ¶Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL; #Saint Vincent Comprehensive Cancer Center, New York; and **The Oncology Consortia of Criterium Inc, Saratoga Springs, NY; ††California Cancer Institute, Temple City, CA; ‡‡Graduate Institute of Medical Sciences, College of Medicine, and §§Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; ∥∥Department of Pathology, Cross Cancer Center, University of Alberta, Edmonton, Alberta, Canada; ¶¶Department of Pathology, H. Lee Moffitt Cancer Center, Tampa, FL; ##Karmanos Cancer Institute; and ***Department of Oncology and Cancer Biology Graduate Program, Wayne State University, Detroit, MI; †††Department of Radiation Oncology, Montifiore Medical Center, Bronx, NY; and ‡‡‡Department of Radiation Oncology, The Canberra Hospital, Australian National University, Canberra, Australia.
authors.forename: James J
authors.initials: JJ
authors.lastname: Farrell
authors.forename: Jennifer
authors.initials: J
authors.lastname: Moughan
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Wong
authors.forename: William F
authors.initials: WF
authors.lastname: Regine
authors.forename: Paul
authors.initials: P
authors.lastname: Schaefer
authors.forename: Al B
authors.initials: AB
authors.lastname: Benson
authors.forename: John S
authors.initials: JS
authors.lastname: Macdonald
authors.forename: Xiyong
authors.initials: X
authors.lastname: Liu
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
authors.forename: Raymond
authors.initials: R
authors.lastname: Lai
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zheng
authors.forename: Gerold
authors.initials: G
authors.lastname: Bepler
authors.forename: Chandan
authors.initials: C
authors.lastname: Guha
authors.forename: Hany
authors.initials: H
authors.lastname: Elsaleh
mesh_terms: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine / Q000031:analogs & derivatives; D033721:Equilibrative Nucleoside Transporter 1; D006801:Humans; D010190:Pancreatic Neoplasms; D057285:Precision Medicine; D025521:Tumor Suppressor Proteins; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D033721:Equilibrative Nucleoside Transporter 1; D025521:Tumor Suppressor Proteins; D003841:Deoxycytidine; D000093542:Gemcitabine