Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer
Gastroenterology, 2009•Elsevier
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 …
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 …
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% CI, 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.
Elsevier