P3.03-035 Prognostic Role of hENT1 and RRM1 in Patients with Advanced Pleural Mesothelioma Treated with Second Line Gemcitabine Based Regimens: Topic: Mesothelioma Clinical

Abstract

Nucleoside transporter proteins mediates the transport of nucleosides and nucleoside analog drugs across the plasma membrane. The human equilibrative nucleoside transporter 1 (hENT1) is a nucleoside transporter protein that mediates cellular entry of gemcitabine, cytarabine, and fludarabine. The hENT1 expression has been demonstrated to be related with prognosis and activity of gemcitabine-based therapy in breast, ampullary, lung, and pancreatic cancer. In the same way, RRM1 encodes the regulatory subunit of ribonucleotide reductase and is a molecular target of gemcitabine. Previous studies showed increased RRM1 expression on continuous exposure of cell lines to gemcitabine and suggested improved survival for patients with low RRM1 expression. We measured hENT1 and RRM1 messenger RNA (mRNA) levels by quantitative real-time reverse transcription-polymerase chain reaction in tumor samples from 29 patients with advanced pleural mesothelioma (APM) treated in second line with gemcitabine based chemotherapy correlating these data with clinical parameters and disease outcomes (overall response rate-ORR, progression free survival-PFS and overall survival-OS). The median age was 60-yo (r, 33-70 years), 15 patients were males (51%), 34% of cases undergone debulking surgery and the median follow-up was 13.4 months (95% CI 6.4-34). All patients were treated with Pem based chemotherapy in first line achieving a PFS of 8.1 months (95% CI 3.7-12.6), while PFS with second-line Gem based chemotherapy was 6.3 months (95% CI 3.6-8.8). 62% and 34.5% of patients had low levels of mRNA for hENT1 and RRM1, respectively. On univariate survival analysis, the hENT1 expression was associated with OS (p=0.001) and PFS (p=0.022). Specifically, those patients with overexpression of hENT1 showed a shorter OS p=0.021) and a shorter PFS (p=0.033). In contrast, mRNA expression of RRM1 did not influence the OS (p = 0.44) but it modifies positively the PFS (p=0.034). Multivariate analysis found that combined hENT1 (p=0.001) and RMM1 (p=0.012) predict survival in patients with APM treated with Gem based regimens. hENT1 mRNA expression carries prognostic information in patients with APM and combined with RRM1 holds promise as a predictive biomarkers in gemcitabine treated patients.