Bruno Vincenzi1, Silvia Stacchiotti2, Paola Collini3, Francesco Pantano1, Carla Rabitti4, Giuseppe Perrone4, Michele Iuliani5, Alfonso Baldi5, Giuseppe Badalamenti6, Roberta Sanfilippo2, Daniele Santini1, Andrea Onetti Muda4, Alessandro Gronchi7, Paolo Casali2, Angelo Paolo Dei Tos8, Giuseppe Tonini1. 1. Medical Oncology, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 200, 00128 Rome, Italy. 2. Sarcoma Unit Cancer Medicine Department, Fondazione IRCCS Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy. 3. Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy. 4. Human Pathology, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 200, 00128 Rome, Italy. 5. Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples, Via A. Vivaldi 43, 81100 Caserta, Italy. 6. Department of Surgical and Oncological Sciences, University of Palermo, Via del Vespro 131, 90127 Palermo, Italy. 7. Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy. 8. Department of Pathology and Molecular Genetics, Treviso General Hospital, Piazza Ospedale 1, 31100 Treviso, Italy.
Abstract
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-ΔCt 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.
BACKGROUND: The expression of humanequilibrative 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-ΔCt 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 angiosarcomapatients treated with gemcitabine. CONCLUSIONS: Our study suggests that higher hENT1 expression are associated to gemcitabine efficacy both in patients with advanced leiomyosarcoma and angiosarcoma.
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