Human equilibrative nucleoside transporter 1 gene expression is associated with gemcitabine efficacy in advanced leiomyosarcoma and angiosarcoma

Background: The expression of human equilibrative nucleoside transporter 1 (hENT1), the major gemcitabine transporter into cells, has been thoroughly investigated as a predictive marker of response to gemcitabine in pancreatic cancer and biliary tract cancers. Since gemcitabine is widely used in the treatment of leiomyosarcoma and angiosarcoma, we investigated the correlation between hENT1 expression and gemcitabine efficacy in these sarcoma subtypes. Methods: We retrospectively identified 71 patients affected by advanced angiosarcoma (26) or leiomyosarcoma (45) treated within five Italian referral centres for sarcoma; among them, 49 patients (15 angiosarcoma, 34 leiomyosarcoma) were treated with gemcitabine. All tumour samples were analysed for hENT1 expression by real-time PCR. Median 2-(Delta Ct) value was used as the cutoff to dichotomise patients into 'high' expression and 'low' expression groups. Kaplan-Meier analysis was performed to estimate progression-free survival (PFS) and overall survival (OS). Results: We found a significant association between high hENT1 expression levels and favourable outcome in terms of PFS and OS compared to cases with low hENT1 expression in leiomyosarcoma treated with gemcitabine (PFS: 6.8 vs 3.2 months, P = 0.004; OS: 14.9 vs 8.5 months, P = 0.007). In addition, hENT1 overexpression correlated with a significant improvement in PFS (9.3 vs 4.5 months; P = 0.02) and OS (20.6 vs 10.8 months; P = 0.001) in angiosarcoma patients treated with gemcitabine. Conclusions: Our study suggests that higher hENT1 expression are associated to gemcitabine efficacy both in patients with advanced leiomyosarcoma and angiosarcoma.