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.

Diagnostic, Predictive and Prognostic Molecular Biomarkers in Pancreatic Cancer: An Overview for Clinicians

“…In a subanalysis of the ESPAC-3 trial population, which was a comparative study between gemcitabine and 5-fluorouracil based chemotherapy in PDAC patients, hENT1 expression was identified as a predictive biomarker of the response to gemcitabine without any hENT-1-dependent difference observed in the fluorouracil group [ 104 ]. Aoyama and colleagues reported that patients with high hENT1 expression in PDAC tissue and treated with curative resection and adjuvant gemcitabine had a higher overall survival at five years (high hENT1: 20.6% vs. low hENT1: 8.9%; p = 0.019) and disease-free survival rates at three years (high hENT1: 23.8% vs. low hENT1: 9.4%; p = 0.024) post-procedure [ 105 ]. In their meta-analysis, Bird et al showed benefits in both disease-free (hazard ratio: 0.58; 95% CI: 0.42–0.79) and overall survival (hazard ratio: 0.52; 95% CI: 0.38–0.72) in PDAC patients with high hENT1 expression and adjuvant gemcitabine chemotherapy after PDAC resection [ 106 ].…”

Molecular characterization of circulating tumor cells in pancreatic ductal adenocarcinoma: potential diagnostic and prognostic significance in clinical practice

“…In addition, cells were incubated with anti-ENT-1 primary antibody (Abcam) and anti-rabbit-alexa fluor 647 conjugated secondary antibody (Cell Signaling) (hENT-1 antibody assessment provided in Supplementary). The staining intensity for hENT-1 in individual CTC and the percentage of hENT-1 positive CTCs were scored based on the immunohistochemical scoring system (28,29). The staining intensity of hENT-1 was divided into four levels: 0, no staining; 1, weakly positive; 2, moderately positive and 3, strongly positive (Figure 1C); the positive percentage was assigned a score ranging from 0 to 3: 0, ≤5% positive cells; 1, 5-25% positive cells; 2, 25-50% positive cells; 3, >50% positive cells.…”

“…Immunohistochemistry (IHC) analyses were performed as previously described (28,29). Formalin-fixed, paraffinembedded (FFPE) tumor tissues from PDAC patients were deparaffinized with xylene, rehydrated with ethanol and boiled for 20 minutes in microwave for antigen retrieval in a 10-mM citrate buffer (pH 6).…”

“…hENT-1 is a nucleoside transporter protein that plays an important role in transporting cytotoxic chemotherapies such as gemcitabine into tumor cells (7,8). Recently, hENT-1 has been reported as a promising predictive biomarker of the treatment outcome of chemotherapy in various cancers (43)(44)(45), including PDAC (9,10,28,29,46). However, there is still no consensus on whether hENT-1 expression in resected tumor specimens correlates to the chemosensitivity of the occult micrometastases (13).…”

Anti-Tumor Activity and Mechanism of Gemcitabine Derivative SZY-200 Assembled from Gemcitabine-Lauric Acid Conjugate on Human Bladder Cancer Cells

“…Human equilibrative nucleoside transporter 1 (hENT1) is the primary facilitative transporter of GEM [6]. High levels of hENT1 were correlated with high GEM concentration in cancer cells and increases drug e cacy [7,8]. Previous studies have indicated that high hENT1 expression was associated with longer overall survival (OS) among patients treated with both palliative and adjuvant GEM [9,10] and vice versa [11,12].…”