Human Equilibrative Nucleoside Transporter 1 Levels Predict Response to Gemcitabine in Patients With Pancreatic Cancer

James J. Farrell*, Hany Elsaleh, Miguel Garcia, Raymond Lai, Ali Ammar, William F. Regine, Ross Abrams, A. Bowen Benson, John Macdonald, Carol E. Cass, Adam P. Dicker, John R. Mackey

*Corresponding author for this work

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)187-195
Number of pages9
JournalGastroenterology
Volume136
Issue number1
DOIs
StatePublished - Jan 2009

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gemcitabine
Pancreatic Neoplasms
Fluorouracil
Confidence Intervals
Staining and Labeling
Disease-Free Survival
Nucleoside Transport Proteins
Proteins
Survival
Protein Transport
Chi-Square Distribution
Proportional Hazards Models
human SLC29A1 protein
Adenocarcinoma
Retrospective Studies
Logistic Models
Immunohistochemistry
Regression Analysis

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Farrell, J. J., Elsaleh, H., Garcia, M., Lai, R., Ammar, A., Regine, W. F., ... Mackey, J. R. (2009). Human Equilibrative Nucleoside Transporter 1 Levels Predict Response to Gemcitabine in Patients With Pancreatic Cancer. Gastroenterology, 136(1), 187-195. https://doi.org/10.1053/j.gastro.2008.09.067
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. / Human Equilibrative Nucleoside Transporter 1 Levels Predict Response to Gemcitabine in Patients With Pancreatic Cancer. In: Gastroenterology. 2009 ; Vol. 136, No. 1. pp. 187-195.
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title = "Human Equilibrative Nucleoside Transporter 1 Levels Predict Response to Gemcitabine in Patients With Pancreatic Cancer",
abstract = "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.",
author = "Farrell, {James J.} and Hany Elsaleh and Miguel Garcia and Raymond Lai and Ali Ammar and Regine, {William F.} and Ross Abrams and Benson, {A. Bowen} and John Macdonald and Cass, {Carol E.} and Dicker, {Adam P.} and Mackey, {John R.}",
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Farrell, JJ, Elsaleh, H, Garcia, M, Lai, R, Ammar, A, Regine, WF, Abrams, R, Benson, AB, Macdonald, J, Cass, CE, Dicker, AP & Mackey, JR 2009, 'Human Equilibrative Nucleoside Transporter 1 Levels Predict Response to Gemcitabine in Patients With Pancreatic Cancer', Gastroenterology, vol. 136, no. 1, pp. 187-195. https://doi.org/10.1053/j.gastro.2008.09.067

Human Equilibrative Nucleoside Transporter 1 Levels Predict Response to Gemcitabine in Patients With Pancreatic Cancer. / 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.

In: Gastroenterology, Vol. 136, No. 1, 01.2009, p. 187-195.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Human Equilibrative Nucleoside Transporter 1 Levels Predict Response to Gemcitabine in Patients With Pancreatic Cancer

AU - Farrell, James J.

AU - Elsaleh, Hany

AU - Garcia, Miguel

AU - Lai, Raymond

AU - Ammar, Ali

AU - Regine, William F.

AU - Abrams, Ross

AU - Benson, A. Bowen

AU - Macdonald, John

AU - Cass, Carol E.

AU - Dicker, Adam P.

AU - Mackey, John R.

PY - 2009/1

Y1 - 2009/1

N2 - 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.

AB - 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.

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