James J Farrell1, Jennifer Moughan, Jonathan L Wong, William F Regine, Paul Schaefer, Al B Benson, John S Macdonald, Xiyong Liu, Yun Yen, Raymond Lai, Zhong Zheng, Gerold Bepler, Chandan Guha, Hany Elsaleh. 1. 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.
Abstract
OBJECTIVES: 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. METHODS:Radiation Therapy OncologyGroup 9704 prospectively randomized 538 patients after pancreatic resection to receive either5-fluorouracil or gemcitabine. Tumor DCK, RRM1, RRM2, andp53R 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. RESULTS: There were 229 patients eligible for analysis from both the5-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. CONCLUSIONS: 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.
RCT Entities:
OBJECTIVES: There is a need for validated predictive markers of gemcitabine response to guide precision medicine treatment in pancreatic cancer. We previously validated humanequilibrative 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. METHODS: Radiation Therapy Oncology Group 9704 prospectively randomized 538 patients after pancreatic resection to receive either 5-fluorouracil or gemcitabine. TumorDCK, 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. RESULTS: 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. CONCLUSIONS: 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 humanequilibrative nucleoside transporter 1 and possibly RRM2 as valid predictive markers of the treatment response of gemcitabine in pancreatic cancer.
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