Farrell James J, Elsaleh Hany, Garcia Miguel, Lai Raymond, Ammar Ali, Regine William F, Abrams Ross, Benson A Bowen, Macdonald John, Cass Carol E, Dicker Adam P, Mackey John R
Division of Digestive Diseases, University of California Los Angeles School of Medicine, Los Angeles, California 90405, USA.
Gastroenterology. 2009 Jan;136(1):187-95. doi: 10.1053/j.gastro.2008.09.067. Epub 2008 Oct 7.
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.
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.
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% CI, 0.21-0.73; P= .003). hENT1 expression was not associated with survival in the group given 5-FU.
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.
人平衡核苷转运体（hENT1）蛋白可将吉西他滨转运至细胞内。胰腺癌的小型回顾性研究表明，hENT1蛋白或信使核糖核酸水平可能具有预后价值。我们在大型前瞻性随机辅助治疗试验RTOG9704的一组胰腺腺癌患者中研究了hENT1水平的预测价值。
在RTOG9704中，538例患者在手术切除后被随机分配至接受吉西他滨或5-氟尿嘧啶（5-FU）治疗的组中。对RTOG9704中229例切除的胰腺肿瘤组织芯片进行hENT1免疫组织化学检测，并将其评分分为无染色、低染色或高染色。使用卡方检验和Cox比例风险模型，通过无条件逻辑回归分析hENT1蛋白与治疗结果之间的关联。
在接受吉西他滨治疗的组中，单因素（风险比[HR]，0.51；95%置信区间[CI]，0.29 - 0.91；P = .02；HR，0.57；95% CI，0.32 - 1.00；P = .05）和多因素模型中，hENT1表达与总生存期和无病生存期相关（HR，0.40；95% CI，0.22 - 0.75；P = .004；HR，0.39；95% CI，0.21 - 0.73；P = .003）。hENT1表达与接受5-FU治疗组的生存期无关。
在这项前瞻性随机试验中，hENT1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延长相关，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，吉西他滨转运体hENT1是切除的胰腺癌患者从吉西他滨治疗中获益的分子和机制相关的预测标志物。
