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Predictive role of human equilibrative nucleoside transporter 1 in patients with pancreatic cancer treated by curative resection and gemcitabine-only adjuvant chemotherapy.

ABSTRACT: The predictive roles of human equilibrative nucleoside transporter 1 (hENT-1) in patients who undergo curative resection and adjuvant chemotherapy with gemcitabine alone have not been established. The present study retrospectively analyzed the clinical data from 101 consecutive patients who underwent curative resection and who received gemcitabine adjuvant chemotherapy for the treatment of pancreatic cancer at Kanagawa Cancer Center (Yokohama, Japan) between 2005 and 2014. The associations between the hENT-1 status and the survival and clinicopathological features of the patients were investigated. Of the 101 patients, 60 patients (59.4%) had high levels of hENT-1 expression. A significant association was observed between hENT-1 status and sex; however, for all the other clinicopathological parameters, including tumor and node stages, no differences were observed between the high and low hENT-1 expression groups. The median follow-up period of the present study was 67.3 months. Between the high and low hENT-1 expression groups, there was a statistically significant difference in the 5-year overall survival (OS) rates following surgery (20.6 and 8.9%, respectively; P=0.019). In addition, a significant difference was observed in the recurrence-free survival (RFS) rates at 5 years following surgery (P=0.049). hENT-1 status was one of the important predictive factors for OS and RFS in patients with pancreatic cancer who underwent curative resection followed by adjuvant chemotherapy with gemcitabine. Adjuvant chemotherapy with gemcitabine alone may be insufficient, particularly in patients with certain relevant risk factors.

SUBMITTER: Aoyama T

PROVIDER: S-EPMC5494679 | biostudies-other | 2017 Jul

REPOSITORIES: biostudies-other

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Project description:Gemcitabine is a principal chemotherapeutic agent for biliary tract cancer (BTC). Expression of human equilibrative nucleoside transporter 1 (hENT1) is regarded as a potential predictive biomarker for a gemcitabine response in some cancers. This study was conducted to investigate the association between hENT1 expression and the effects of gemcitabine on BTC cell lines and on patients with advanced BTC receiving gemcitabine-based chemotherapy. A total of four BTC cell lines, HuCCT1, SNU-478, SNU-1079, and SNU-1196, were tested. mRNA and protein expression levels of hENT1 were measured by quantitative reverse-transcription polymerase chain reaction and western blotting, respectively. Cell viability after gemcitabine treatment was measured in a chemosensitivity assay. For clinical assessment, 40 patients with unresectable or recurrent BTC who were treated with gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) between June 2012 and May 2014 were enrolled. Among the four cell lines, SNU1196 showed the highest mRNA and protein levels of hENT1. Expression of hENT1 showed a linear correlation with the log value of the half-maximal inhibitory concentration of gemcitabine. During incubation with gemcitabine, pretreatment with hENT1-specific small interfering RNA (siRNA) resulted in higher cell viability than that in samples pretreated with control siRNA. In a clinical evaluation, the median progression-free survival was 24 and 11 weeks among patients with strong and weak intratumoral hENT1 immunohistochemical staining (P = 0.05), and the median overall survival was 52 and 26 weeks (P = 0.15), respectively. In conclusion, this study showed that increased hENT1 expression is associated with a stronger toxic effect of gemcitabine on BTC cell lines. The clinical outcomes in this study suggest that increased intratumoral hENT1 immunohistochemical staining is a possible biomarker predicting better therapeutic effects of gemcitabine on patients with advanced BTC. Further studies are needed to determine the precise role of hENT1 in BTC.

Project description:BackgroundThe 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.MethodsSeventy-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). Hazard ratios (HRs) of relapse and associated 95% confidence intervals (CIs) were obtained from proportional hazards regression models stratified on quintiles of propensity score.ResultsTwenty-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, p = .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% CI 0.34-2.68; three to four cycles: HR 0.99, 95% CI 0.34-2.90; five to six cycles: HR 0.27, 95% CI 0.10-0.77).ConclusionhENT-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.Implications for practiceGemcitabine is becoming an increasingly used adjuvant modality in cholangiocarcinoma (CC), but limited data are available on predictive biomarkers of response. In this study, patients receiving more than four cycles of adjuvant gemcitabine and harboring Human equilibrative nucleoside transporter 1 (hENT-1, the major transporter involved in gemcitabine intracellular uptake) on tumor cell membrane had a longer disease-free survival compared with patients negative or positive for hENT-1 only in the cytoplasm of tumor cells. Overall these results may lay the basis for further prospective randomized trials based on a larger population of patients and may prove useful for tailoring appropriate gemcitabine-based chemotherapy for CC patients in the adjuvant setting.

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Predictive role of human equilibrative nucleoside transporter 1 in patients with pancreatic cancer treated by curative resection and gemcitabine-only adjuvant chemotherapy.

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