Membrane localization of human equilibrative nucleoside transporter 1 in tumor cells may predict response to adjuvant gemcitabine in resected cholangiocarcinoma patients

Giovanni Brandi, Marzia Deserti, Francesco Vasuri, Andrea Farioli, Alessio Degiovanni, Andrea Palloni, Giorgio Frega, Maria A. Barbera, Stefania De Lorenzo, Ingrid Garajova, Mariacristina Dimarco, Antonio D. Pinna, Matteo Cescon, Alessandro Cucchetti, Giorgio Ercolani, Antonietta D’errico-Grigioni, Maria A. Pantaleo, Guido Biasco, Simona Tavolari, G.I.CO. (GRUPPO ITALIANO COLANGIOCARCINOMA)Nicola Silvestris

Research output: Contribution to journalArticle

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Abstract

Background. The use of gemcitabine as an adjuvant modality for cholangiocarcinoma (CC) is increasing, but limited data are available on predictive biomarkers of response. Human equilibrative nucleoside transporter 1 (hENT-1) is the major transporter involved in gemcitabine intracellular uptake. This study investigated the putative predictive role of hENT-1 localization in tumor cells of CC patients undergoing treatment with adjuvant gemcitabine. Methods. Seventy-one consecutive patients with resected CC receiving adjuvant gemcitabine at our center were retrospectively analyzed by immunohistochemistry for hENT-1 localization in tumor cells. The main outcome measure was disease-free survival (DFS). Hazardratios (HRs) of relapse andassociated95% confidence intervals (CIs) were obtained from proportional hazards regression models stratified on quintiles of propensity score. Results. Twenty-three (32.4%) cases were negative for hENT-1, 22 (31.0%) were positive in the cytoplasm only, and 26 (36.6%) showed concomitant cytoplasm/membrane staining. Patients with membrane hENT-1 had a longer DFS (HR 0.49, 95% CI 0.24–0.99, p5.046) than those who were negative or positive only in the cytoplasm of tumor cells. Notably, the association between DFS and membrane hENT-1 was dependent on the number of gemcitabine cycles (one to two cycles: HR 0.96, 95% CI0.34–2.68;threetofourcycles:HR0.99,95%CI0.34–2.90; five to six cycles: HR 0.27, 95% CI 0.10–0.77). Conclusion. hENT-1 localization on tumor cell membrane may predict response to adjuvant gemcitabine in CC patients receiving more than four cycles of chemotherapy. Further prospective randomized trials on larger populations are required to confirm these preliminary results, so that optimal gemcitabine-based chemotherapy may be tailored for CC patients in the adjuvant setting.

Original languageEnglish
Pages (from-to)600-607
Number of pages8
JournalOncologist
Volume21
Issue number5
DOIs
Publication statusPublished - Mar 31 2016

Fingerprint

gemcitabine
Cholangiocarcinoma
Membranes
Neoplasms
Disease-Free Survival
Cytoplasm
Confidence Intervals
Drug Therapy
Propensity Score
human SLC29A1 protein
Proportional Hazards Models
Biomarkers
Immunohistochemistry
Cell Membrane
Outcome Assessment (Health Care)

Keywords

  • Adjuvant gemcitabine
  • Cholangiocarcinoma
  • Human equilibrative nucleoside transporter 1
  • Predictive biomarkers of response to chemotherapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Membrane localization of human equilibrative nucleoside transporter 1 in tumor cells may predict response to adjuvant gemcitabine in resected cholangiocarcinoma patients. / Brandi, Giovanni; Deserti, Marzia; Vasuri, Francesco; Farioli, Andrea; Degiovanni, Alessio; Palloni, Andrea; Frega, Giorgio; Barbera, Maria A.; De Lorenzo, Stefania; Garajova, Ingrid; Dimarco, Mariacristina; Pinna, Antonio D.; Cescon, Matteo; Cucchetti, Alessandro; Ercolani, Giorgio; D’errico-Grigioni, Antonietta; Pantaleo, Maria A.; Biasco, Guido; Tavolari, Simona; G.I.CO. (GRUPPO ITALIANO COLANGIOCARCINOMA) ; Silvestris, Nicola.

In: Oncologist, Vol. 21, No. 5, 31.03.2016, p. 600-607.

Research output: Contribution to journalArticle

Brandi, G, Deserti, M, Vasuri, F, Farioli, A, Degiovanni, A, Palloni, A, Frega, G, Barbera, MA, De Lorenzo, S, Garajova, I, Dimarco, M, Pinna, AD, Cescon, M, Cucchetti, A, Ercolani, G, D’errico-Grigioni, A, Pantaleo, MA, Biasco, G, Tavolari, S, G.I.CO. (GRUPPO ITALIANO COLANGIOCARCINOMA) & Silvestris, N 2016, 'Membrane localization of human equilibrative nucleoside transporter 1 in tumor cells may predict response to adjuvant gemcitabine in resected cholangiocarcinoma patients', Oncologist, vol. 21, no. 5, pp. 600-607. https://doi.org/10.1634/theoncologist.2015-0356
Brandi, Giovanni ; Deserti, Marzia ; Vasuri, Francesco ; Farioli, Andrea ; Degiovanni, Alessio ; Palloni, Andrea ; Frega, Giorgio ; Barbera, Maria A. ; De Lorenzo, Stefania ; Garajova, Ingrid ; Dimarco, Mariacristina ; Pinna, Antonio D. ; Cescon, Matteo ; Cucchetti, Alessandro ; Ercolani, Giorgio ; D’errico-Grigioni, Antonietta ; Pantaleo, Maria A. ; Biasco, Guido ; Tavolari, Simona ; G.I.CO. (GRUPPO ITALIANO COLANGIOCARCINOMA) ; Silvestris, Nicola. / Membrane localization of human equilibrative nucleoside transporter 1 in tumor cells may predict response to adjuvant gemcitabine in resected cholangiocarcinoma patients. In: Oncologist. 2016 ; Vol. 21, No. 5. pp. 600-607.
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title = "Membrane localization of human equilibrative nucleoside transporter 1 in tumor cells may predict response to adjuvant gemcitabine in resected cholangiocarcinoma patients",
abstract = "Background. The use of gemcitabine as an adjuvant modality for cholangiocarcinoma (CC) is increasing, but limited data are available on predictive biomarkers of response. Human equilibrative nucleoside transporter 1 (hENT-1) is the major transporter involved in gemcitabine intracellular uptake. This study investigated the putative predictive role of hENT-1 localization in tumor cells of CC patients undergoing treatment with adjuvant gemcitabine. Methods. Seventy-one consecutive patients with resected CC receiving adjuvant gemcitabine at our center were retrospectively analyzed by immunohistochemistry for hENT-1 localization in tumor cells. The main outcome measure was disease-free survival (DFS). Hazardratios (HRs) of relapse andassociated95{\%} confidence intervals (CIs) were obtained from proportional hazards regression models stratified on quintiles of propensity score. Results. Twenty-three (32.4{\%}) cases were negative for hENT-1, 22 (31.0{\%}) were positive in the cytoplasm only, and 26 (36.6{\%}) showed concomitant cytoplasm/membrane staining. Patients with membrane hENT-1 had a longer DFS (HR 0.49, 95{\%} CI 0.24–0.99, p5.046) than those who were negative or positive only in the cytoplasm of tumor cells. Notably, the association between DFS and membrane hENT-1 was dependent on the number of gemcitabine cycles (one to two cycles: HR 0.96, 95{\%} CI0.34–2.68;threetofourcycles:HR0.99,95{\%}CI0.34–2.90; five to six cycles: HR 0.27, 95{\%} CI 0.10–0.77). Conclusion. hENT-1 localization on tumor cell membrane may predict response to adjuvant gemcitabine in CC patients receiving more than four cycles of chemotherapy. Further prospective randomized trials on larger populations are required to confirm these preliminary results, so that optimal gemcitabine-based chemotherapy may be tailored for CC patients in the adjuvant setting.",
keywords = "Adjuvant gemcitabine, Cholangiocarcinoma, Human equilibrative nucleoside transporter 1, Predictive biomarkers of response to chemotherapy",
author = "Giovanni Brandi and Marzia Deserti and Francesco Vasuri and Andrea Farioli and Alessio Degiovanni and Andrea Palloni and Giorgio Frega and Barbera, {Maria A.} and {De Lorenzo}, Stefania and Ingrid Garajova and Mariacristina Dimarco and Pinna, {Antonio D.} and Matteo Cescon and Alessandro Cucchetti and Giorgio Ercolani and Antonietta D’errico-Grigioni and Pantaleo, {Maria A.} and Guido Biasco and Simona Tavolari and {G.I.CO. (GRUPPO ITALIANO COLANGIOCARCINOMA)} and Nicola Silvestris",
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T1 - Membrane localization of human equilibrative nucleoside transporter 1 in tumor cells may predict response to adjuvant gemcitabine in resected cholangiocarcinoma patients

AU - Brandi, Giovanni

AU - Deserti, Marzia

AU - Vasuri, Francesco

AU - Farioli, Andrea

AU - Degiovanni, Alessio

AU - Palloni, Andrea

AU - Frega, Giorgio

AU - Barbera, Maria A.

AU - De Lorenzo, Stefania

AU - Garajova, Ingrid

AU - Dimarco, Mariacristina

AU - Pinna, Antonio D.

AU - Cescon, Matteo

AU - Cucchetti, Alessandro

AU - Ercolani, Giorgio

AU - D’errico-Grigioni, Antonietta

AU - Pantaleo, Maria A.

AU - Biasco, Guido

AU - Tavolari, Simona

AU - G.I.CO. (GRUPPO ITALIANO COLANGIOCARCINOMA)

AU - Silvestris, Nicola

PY - 2016/3/31

Y1 - 2016/3/31

N2 - Background. The use of gemcitabine as an adjuvant modality for cholangiocarcinoma (CC) is increasing, but limited data are available on predictive biomarkers of response. Human equilibrative nucleoside transporter 1 (hENT-1) is the major transporter involved in gemcitabine intracellular uptake. This study investigated the putative predictive role of hENT-1 localization in tumor cells of CC patients undergoing treatment with adjuvant gemcitabine. Methods. Seventy-one consecutive patients with resected CC receiving adjuvant gemcitabine at our center were retrospectively analyzed by immunohistochemistry for hENT-1 localization in tumor cells. The main outcome measure was disease-free survival (DFS). Hazardratios (HRs) of relapse andassociated95% confidence intervals (CIs) were obtained from proportional hazards regression models stratified on quintiles of propensity score. Results. Twenty-three (32.4%) cases were negative for hENT-1, 22 (31.0%) were positive in the cytoplasm only, and 26 (36.6%) showed concomitant cytoplasm/membrane staining. Patients with membrane hENT-1 had a longer DFS (HR 0.49, 95% CI 0.24–0.99, p5.046) than those who were negative or positive only in the cytoplasm of tumor cells. Notably, the association between DFS and membrane hENT-1 was dependent on the number of gemcitabine cycles (one to two cycles: HR 0.96, 95% CI0.34–2.68;threetofourcycles:HR0.99,95%CI0.34–2.90; five to six cycles: HR 0.27, 95% CI 0.10–0.77). Conclusion. hENT-1 localization on tumor cell membrane may predict response to adjuvant gemcitabine in CC patients receiving more than four cycles of chemotherapy. Further prospective randomized trials on larger populations are required to confirm these preliminary results, so that optimal gemcitabine-based chemotherapy may be tailored for CC patients in the adjuvant setting.

AB - Background. The use of gemcitabine as an adjuvant modality for cholangiocarcinoma (CC) is increasing, but limited data are available on predictive biomarkers of response. Human equilibrative nucleoside transporter 1 (hENT-1) is the major transporter involved in gemcitabine intracellular uptake. This study investigated the putative predictive role of hENT-1 localization in tumor cells of CC patients undergoing treatment with adjuvant gemcitabine. Methods. Seventy-one consecutive patients with resected CC receiving adjuvant gemcitabine at our center were retrospectively analyzed by immunohistochemistry for hENT-1 localization in tumor cells. The main outcome measure was disease-free survival (DFS). Hazardratios (HRs) of relapse andassociated95% confidence intervals (CIs) were obtained from proportional hazards regression models stratified on quintiles of propensity score. Results. Twenty-three (32.4%) cases were negative for hENT-1, 22 (31.0%) were positive in the cytoplasm only, and 26 (36.6%) showed concomitant cytoplasm/membrane staining. Patients with membrane hENT-1 had a longer DFS (HR 0.49, 95% CI 0.24–0.99, p5.046) than those who were negative or positive only in the cytoplasm of tumor cells. Notably, the association between DFS and membrane hENT-1 was dependent on the number of gemcitabine cycles (one to two cycles: HR 0.96, 95% CI0.34–2.68;threetofourcycles:HR0.99,95%CI0.34–2.90; five to six cycles: HR 0.27, 95% CI 0.10–0.77). Conclusion. hENT-1 localization on tumor cell membrane may predict response to adjuvant gemcitabine in CC patients receiving more than four cycles of chemotherapy. Further prospective randomized trials on larger populations are required to confirm these preliminary results, so that optimal gemcitabine-based chemotherapy may be tailored for CC patients in the adjuvant setting.

KW - Adjuvant gemcitabine

KW - Cholangiocarcinoma

KW - Human equilibrative nucleoside transporter 1

KW - Predictive biomarkers of response to chemotherapy

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