精准医学与胰腺癌：吉西他滨通路研究方法
Precision Medicine and Pancreatic Cancer: A Gemcitabine Pathway Approach.
作者信息
Farrell James J, Moughan Jennifer, Wong Jonathan L, Regine William F, Schaefer Paul, Benson Al B, Macdonald John S, Liu Xiyong, Yen Yun, Lai Raymond, Zheng Zhong, Bepler Gerold, Guha Chandan, Elsaleh Hany
机构信息
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.
出版信息
Pancreas. 2016 Nov;45(10):1485-1493. doi: 10.1097/MPA.0000000000000710.
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 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.
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 human equilibrative nucleoside transporter 1 and possibly RRM2 as valid predictive markers of the treatment response of gemcitabine in pancreatic cancer.
目的
需要经过验证的吉西他滨反应预测标志物来指导胰腺癌的精准医学治疗。我们之前使用放射治疗肿瘤学组9704研究，验证了人类平衡核苷转运体1作为吉西他滨治疗反应的预测标志物。关于吉西他滨代谢途径生物标志物：脱氧胞苷激酶（DCK）、核糖核苷酸还原酶1（RRM1）、RRM2和p53R2的预测价值存在争议。
方法
放射治疗肿瘤学组9704对538例胰腺切除术后的患者进行前瞻性随机分组，分别接受5-氟尿嘧啶或吉西他滨治疗。使用组织微阵列和免疫组织化学分析肿瘤中DCK、RRM1、RRM2和p53R蛋白表达，并通过无条件逻辑回归分析将其与治疗结果（总生存期和无病生存期）相关联。
结果
5-氟尿嘧啶组和吉西他滨组分别有229例患者符合分析条件。在吉西他滨治疗组中，只有RRM2蛋白表达与生存相关，而DCK、RRM1或p53R2蛋白表达与生存无关。
结论
尽管来自其他非随机治疗数据的数据有限，但我们的数据不支持DCK、RRM1或p53R2的预测价值。应将工作重点放在人类平衡核苷转运体1上，并可能将RRM2作为胰腺癌中吉西他滨治疗反应的有效预测标志物。
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