Gastroenterology

Gastroenterology

Volume 136, Issue 1, January 2009, Pages 187-195
Gastroenterology

Clinical—Liver, Pancreas, and Biliary Tract
Human Equilibrative Nucleoside Transporter 1 Levels Predict Response to Gemcitabine in Patients With Pancreatic Cancer

https://doi.org/10.1053/j.gastro.2008.09.067Get rights and content

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.

Section snippets

Patient Selection and Consent

Patients entering RTOG 9704 gave consent for use of formalin-fixed tissue for future planned translational research as part of the formal informed consent process. The RTOG tissue bank received tumor blocks from a total of 229 of the 538 patients who had undergone surgical resection and were entered in the RTOG 9704 prospective adjuvant treatment trial. Tissue microarrays (TMAs) were constructed from these blocks. Clinicopathologic factors were obtained as part of the patients' enrollment in

Patient Population

The study opened July 20, 1998, and closed on July 26, 2002, with a total of 538 patients, and the final results have been published.19 Eighty-seven percent and 86% of patients assigned to the 5-FU group completed chemotherapy and radiotherapy, respectively, as planned. Ninety percent and 88% of patients assigned to the gemcitabine group completed chemotherapy and radiotherapy, respectively, as planned. Of the 268 patients entered in the gemcitabine arm, 91 were eligible and had analyzable

Discussion

This current study studied hENT1 in a phase III adjuvant therapy trial in early stage pancreas cancer. Patients were randomized to receive gemcitabine or 5-FU as part of their systemic therapy. Although slightly less than 50% of the patients entered into the trial had tissue available for hENT1 analysis, the missing data are not expected to bias our results because there were no significant imbalances between patient and tumor baseline characteristics (including tumor and nodal stage) in the

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    The authors disclose the following: Funded by a RTOG Seed Grant and a National Institutes of Health K12 Career Development Award in Clinical Pharmacology (J.J.F.) and by an American Society of Therapeutic Radiology and Oncology Junior Faculty Award (H.E.).

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