HUMAN ENT1 IS PREDICTIVE OF RESPONSE IN PATIENTS WITH PANCREATIC CANCER TREATED WITH GEMCITABINE

Abstract

Background: Human equilibrative nucleoside transporter (hENT1) is responsible for gemcitabine transport into cells. Small retrospective studies in pancreatic cancer suggest that hENT1 tumor levels may have prognostic and predictive value. We studied hENT 1 protein expression in a cohort of pancreatic adenocarcinoma patients from the RTOG 9704: a large prospective randomized adjuvant treatment trial. Methods: RTOG 9704 randomized 538 patients after surgical resection to treatment containing either 5-FU or gemcitabine. A tissue microarray was constructed using three separate cores from 225 resected pancreatic tumors from RTOG 9704. HENT1 Immunohistochemistry was performed and scored as having no staining, low staining or high staining (>50% cells positive) Associations between hENT1 protein expression, either dichotomized (no staining vs. low and high staining) or ungrouped (no staining vs. low vs high staining) with tumor demographic details and treatment outcome (overall survival and disease free survival), were analyzed by unconditional logistic regression analysis using the Chi-square test and the Cox proportional hazards model. Both treatment arms of the study were analyzed. Results: Of the 538 patients entered into RTOG 9704, 198 from both arms of the study were eligible and had analyzable hENT1. hENT1 expression was not associated with overall or disease-free survival in a univariate or multivariate model when evaluating patients treated with 5-FU alone and comparing the dichotomized hENT1 level variable (No staining vs. Low, High (>50%) and the ungrouped hENT1 level variable (No staining, Low and High (>50%).Of the 268 patients entered on the Gemcitabine arm, 91 were eligible and had analyzable hENT1. Univariate and multivariate analyses for hENT1 is shown in Table 1 (expressed as hazard ratio (HR) (95% confidence intervals).TABLE 1: hENT1 and Survival in Pancreatic Adenocarcinoma treated with GemcitabineConclusion: In this prospective randomized trial, hENT1 protein expression is associated with a statistically significant improvement in overall survival and disease free survival in pancreatic cancer patients receiving gemcitabine, but not in those not receiving gemcitabine. This prospective data suggests that hENT1, a gemcitabine transporter, is a useful mechanistic predictive marker of response to gemcitabine in patients with pancreatic cancer.