Plasma membrane localization of human equilibrative nucleoside transporter 1 (hENT-1) to predict better outcome of adjuvant gemcitabine in cholangiocarcinoma (CC) patients.

Background: The role of adjuvant chemotherapy in CC is controversial and, to date, no standard treatment has been established in this setting. Some institutions offer gemcitabine (GEM) as adjuvant strategy to radically resected CC patients. The efficient uptake of this drug into cells requires the expression and plasma membrane localization of hENT-1. A recent study showed that a high hENT-1 expression closely associated with better survivals in macroscopically (R0 + R1) resected CC patients treated with adjuvant GEM plus S-1. In the present study, we analyzed the relationship between hENT-1 expression/localization and disease free survival (DFS) in CC patients undergone surgery and treated with adjuvant GEM. Methods: A total of 71 CC patients (44 intra-hepatic and 27 extra-hepatic) operated between 2002 and 2011 (46 R0 and 25 R1) and treated with adjuvant GEM (1000 mg/m2, 1-8-15/21 days planned for 6 months) in our institution were enrolled and retrospectively analyzed for hENT-1 expression/localization by immunohistochemistry. Main outcome measure was DFS. Hazard ratios (HR) of relapse and associated 95% confidence intervals (95% CIs) were obtained from proportional hazards regression models stratified on quintiles of propensity score (estimated from baseline covariates). Results: 26/71 patients (36.6%) showed a high hENT-1 plasma membrane expression. During a median follow-up of 18.1 months (IQR 9.1–36.2) 49 relapses were observed. Patients with a high expression of hENT-1 showed a reduced risk of relapse (HR 0.50, 95%CI 0.26–0.99, p=0.047). Noteworthy, the effect of hENT-1 appeared to increase across tertiles of duration of gemcitabine-based adjuvant chemotherapy (lower tertile, 102 days: HR 0.87, 95%CI 0.30–2.53; middle tertile, 103–170 days: HR 0.68, 95%CI 0.22–2.06; higher tertile, 171 days: 0.20, 95%CI 0.04–0.94). Conclusions: High plasma membrane hENT-1 expression was associated with a longer DFS among CC patients. The interaction between hENT-1 expression and duration of chemotherapy deserves further investigations, as it could be useful to tailor optimal GEM-based adjuvant chemotherapies.