Human Equilibrative Nucleoside Transporter 1 Levels Predict Response to Gemcitabine in Patients With Pancreatic Cancer
Human Equilibrative Nucleoside Transporter 1 Levels Predict Response to Gemcitabine in Patients With Pancreatic Cancer
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DOI：
10.1053/j.gastro.2008.09.067
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发表时间：
2009-01-01
期刊：
影响因子：
29.4
通讯作者：
Mackey, John R.
中科院分区：
文献类型：
--
作者：
Farrell, James J.;Elsaleh, Hany;Mackey, John R.
背景与目的：人平衡型核苷转运蛋白（hENT 1）将吉西他滨转运到细胞内。在胰腺癌中的小型回顾性研究表明，hENT 1蛋白或信使RNA水平可能具有预后价值。我们研究了hENT 1水平在胰腺癌队列中的预测价值。来自大型前瞻性随机辅助治疗试验RTOG 9704的患者。研究方法：在RTOG 9704中，538例患者在手术切除后被随机分配到吉西他滨组或5-氟尿嘧啶（5-FU）组。在来自RTOG 9704的229个切除的胰腺肿瘤的组织微阵列上进行hENT 1的免疫组织化学，并将其评分为无染色、低染色或高染色。采用卡方检验和考克斯比例风险模型，通过非条件logistic回归分析分析hENT 1蛋白和治疗结果之间的关联。结果如下：在单变量分析中，HENT 1表达与总生存期和无病生存期相关。（风险比[HR]，0.51; 95%置信区间[CI]，0.29-0.91; P = 0.02; HR，0.57; 95% CI，0.32-1.00; P = 0.05）和多变量模型（HR，0.40; 95% CI，0.22-0.75; P = .004; HR，0.39; 95% CI，0.21-0.73; P = .003）。hENT 1表达与5-FU组的生存率无关。结论：在这项前瞻性随机试验中，hENT 1蛋白表达与接受吉西他滨治疗的胰腺癌患者的总生存期和无病生存期增加相关，但与接受5-FU治疗的患者无关。这些发现得到了临床前数据的支持;因此，吉西他滨转运蛋白hENT 1是切除胰腺癌患者从吉西他滨获益的分子和机制相关预测标志物。
Background & Aims: The human equilibrative nucleoside transporter (hENT1) protein transports gemcitabine into cells. Small retrospective studies in pancreatic cancer suggest that levels of hENT1 protein or messenger RNA may have prognostic value. We studied the predictive value of hENT1 levels in a cohort of pancreatic adenocarcinoma. patients from the large prospective randomized adjuvant treatment trial RTOG9704. Methods: In RTOG9704, 538 patients were assigned randomly, after surgical resection, to groups that were given either gemcitabine or 5-fluorouracil (5-FU). Immunohistochemistry for hENT1 was performed on a tissue microarray of 229 resected pancreatic tumors from RTOG9704 and scored as having no staining, low staining, or high staining. Associations between hENT1 protein and treatment outcome were analyzed by unconditional logistic regression analysis using the chi-square test and the Cox proportional hazards model. Results: HENT1 expression was associated with overall and disease-free survival in a univariate (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.29-0.91; P = .02; and HR, 0.57; 95% CI, 0.32-1.00; P = .05) and multivariate model in the group given gemcitabine (HR, 0.40; 95% CI, 0.22-0.75; P = .004; and HR, 0.39; 95% Cl, 0.21-0.73; P = .003). hENT1 expression was not associated with survival in the group given 5-FU. Conclusions: In this prospective randomized trial, hENT1 protein expression was associated with increased overall survival and disease-free survival in pancreatic cancer patients who received gemcitabine, but not in those who received 5-FU. These findings are supported by preclinical data; the gemcitabine transporter hENT1 is therefore a molecular and mechanistically relevant predictive marker of benefit from gemcitabine in patients with resected pancreatic cancer.