Prediction of gemcitabine benefit after curative-intent resection of pancreatic adenocarcinoma using HENT1 and dCK protein expression.

Abstract

4024 Background: In resected pancreatic adenocarcinoma (PA), gemcitabine was shown to improve both DFS and OS, equally to 5FU. In vitro, gemcitabine efficacy is linked to expression of the human equilibrative nucleoside transporter 1(hENT1), deoxycytidine kinase (dCK) and ribonucleotide reductase subunit1 (RRM1) proteins. This study evaluated association of these three proteins with efficacy of gemcitabine in resected PA. Methods: Patients with resected PA and no prior neoadjuvant therapy were accrued in 5 university hospitals. hENT1, dCK and RRM1 protein expression were semi-quantitatively assessed by immunohistochemistry using tissue microarray analysis and applying scoring systems as previously reported. The primary clinical end-point was overall survival (OS). The association of clinico-pathological parameters and protein expression with OS was evaluated by log-rank testing and Cox proportional regression. For statistical analysis, biomarkers expression was dichotomized as followed: hENT1 high vslow, dCK high vs low, RRM1 positive vs negative. Results: 434 patients with resected PA were analysed with a median OS of 30.4 months (95% CI: 26.0-34.8); 142 patients (32.7%) did not receive any adjuvant treatment; 243 (56%) were treated with an adjuvant gemcitabine-based therapy (Gem), and 49 (11.3%) with an adjuvant non gemcitabine-based therapy. In patients who did not received Gem (n=191), hENT1, RRM1 and dCK expression were not associated with OS in univariate and multivariate analysis. There was a significant interaction for OS between Gem and hENT1 (p=0.001), and Gem and dCK (p=0.001). In multivariate models adjusted for center, tumor grade, maximum tumor size, lymph nodes, and resection margins, Gem was associated with better OS in hENT1 high (n=163; HR: 0.44, 95%CI: 0.28-0.69, p<0.001) and in dCK high tumors (n=302; HR: 0.57, 95% CI:0.41-0.78, p=0.001). By contrast, in dCK low (n= 114, p=0.73) and in hENT1 low (n=249, p=0.66) tumors, patients derived no benefit from gemcitabine. Conclusions: In this multicenter study, hENT1 and dCK high expressions may predict benefit from gem-based chemotherapy after curative-intent surgery in PA.