REAPPRAISAL OF HUMAN EQUILIBRATIVE NUCLEOSIDE TRANSPORTER 1 EXPRESSION AFTER LONG-TERM FOLLOW-UP IN PATIENTS WITH PANCREATIC ADENOCARCINOMA TREATED WITH GEMCITABINE-BASED ADJUVANT CHEMOTHERAPY.
Naru Kondo*, Kenichiro Uemura, Naoya Nakagawa, Kenjiro Okada, Shingo Seo, Yoshiaki Murakami
Department of Surgery, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan
Background: Expression of intratumoral human equilibrative nucleoside transporter 1 (hENT1) has been reported to be associated with chemosensitivity to gemcitabine. However, long term result of its predictive significance has rarely reported.
Objective:
The aim of this study is to investigate impact of intratumoral hENT1 expression on long term survival of patients treated with gemcitabine-based adjuvant chemotherapy (GAC) after surgical resection for pancreatic adenocarcinoma.
Methods: Intratumoral hENT1 expression was investigated by immunohistochemistry for 436 patients who underwent surgical resection for pancreatic adenocarcinoma at Hiroshima University Hospital between 2002 and 2019. Gemcitabine-based adjuvant chemotherapy consisted of intravenous gemcitabine 700 mg/m2 on day 1 and oral S-1 50 mg/m2 for 7 consecutive days in the 2 weeks of treatment cycle. Prognostic impact of hENT1 expression was evaluated by univariate and multivariate analyses stratified by the dosage amount of gemcitabine as adjuvant chemotherapy.
Results: The median follow-up time of patients with censor was 40.1 months (range 6 – 181 months). The median recurrence-free survival (RFS) and overall survival (OS) time for all 436 patients were 28.3 months and 46.7 months, respectively. High hENT1 expression was observed in 275 (63%) patients. Of the 436 patients, 306 (70%) who received more than 5 cycles of GAC were assigned to GAC (+) group, whereas 130 (30%) who received 4 cycles or less were assigned to GAC (-) group. Patients in the GAC (+) group experienced significant longer RFS (P = 0.02) and OS (P< 0.001) that those in the GAC (-) group.
Univariate analysis revealed that patients with high hENT1 expression experienced significantly longer RFS (P = 0.02) and OS (P = 0.002) than those with low hENT1 expression in AGC (+) group. In contrast, hENT1 expression did not affect RFS (P = 0.18) and OS (P = 0.16) in AGC (-) group. Multivariate analyses in the AGC (+) group identified Low hENT1 expression as one of the independent risk factors for poor RFS (P = 0.04) and OS (P = 0.003).
Conclusion: Even after long-term follow-up, predictive significance of intratumoral hENT1 expression was evident in patients with pancreatic adenocarcinoma treated with GAC and enables the stratification of these patients based on their likelihood of long-survival. These findings warrant further investigations as to personalization of pre- and postoperative adjuvant therapy with gemcitabine for pancreatic adenocarcinoma, which can be optimized based on hENT1 expressions.
Patients with high hENT1 expression experienced significantly longer RFS (P = 0.02) than those with low hENT1 expression in AGC (+) group.
Patients with high hENT1 expression experienced significantly longer OS (P = 0.002) than those with low hENT1 expression in AGC (+) group.
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