Mitsukuni Suenaga1, Marta Schirripa1, Shu Cao2, Wu Zhang1, Dongyun Yang2, Vincenzo Dadduzio3, Lisa Salvatore4, Beatrice Borelli4, Filippo Pietrantonio5, Yan Ning1, Satoshi Okazaki1, Martin D Berger1, Yuji Miyamoto1, Roel Gopez1, Afsaneh Barzi1, Toshiharu Yamaguchi6, Fotios Loupakis3, Heinz-Josef Lenz7. 1. Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA. 2. Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA. 3. Medical Oncology 1 Unit, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Via Gattamelata 64, 35128 Padua, Italy. 4. Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Via Roma 67, 56126 Pisa, Italy. 5. Medical Oncology Department, Fondazione IRCCS, Istituto Nazionale Dei Tumori, Via Venezian 1, 20133 Milan, Italy. 6. Gastroenterology Center, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, 135-8550, Tokyo, Japan. 7. Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA. Electronic address: lenz@med.usc.edu.
Abstract
BACKGROUND: Trifluridine (FTD) is an active cytotoxic component of the metastatic colorectal cancer (mCRC) drug TAS-102, and thymidine phosphorylase inhibitor (TPI) inhibits the rapid degradation of FTD. We tested whether single nucleotide polymorphisms (SNPs) in genes involved in FTD metabolism and TPI excretion could predict outcome in patients with mCRC treated with TAS-102. PATIENTS AND METHODS: We investigated three different cohorts: a training cohort (n = 52) and a testing cohort (n = 129) both receiving TAS-102 and a control cohort (n = 52) receiving regorafenib. SNPs of TK1, ENT1, CNT1, MATE1, MATE2 and OCT2 were analysed by polymerase chain reaction-based direct DNA sequencing. RESULTS: In the training cohort, patients with any ENT1 rs760370 G allele had a significantly longer progression-free survival (PFS; 3.5 versus 2.1 months, respectively, hazard ratio [HR] 0.44, P = 0.004) and overall survival (OS; 8.7 versus 5.3 months, respectively, HR 0.27, P = 0.003) than the A/A genotype. These findings were validated in the testing cohort (P = 0.021 and 0.009 for PFS and OS, respectively). In addition, the combination of ENT1 rs760370, MATE1 rs2289669 and OCT2 rs316019 SNPs significantly stratified patients with the risk of PFS and OS in both cohorts (P < 0.001 for PFS and OS in the training cohort; P = 0.053 and 0.025 for PFS and OS, respectively, in the testing cohort). No significant differences were observed in the control group. CONCLUSIONS: The combination of ENT1, MATE1 and OCT2 SNPs may serve as a predictive and prognostic marker in mCRC patients treated with TAS-102.
BACKGROUND:Trifluridine (FTD) is an active cytotoxic component of the metastatic colorectal cancer (mCRC) drug TAS-102, and thymidine phosphorylase inhibitor (TPI) inhibits the rapid degradation of FTD. We tested whether single nucleotide polymorphisms (SNPs) in genes involved in FTD metabolism and TPI excretion could predict outcome in patients with mCRC treated with TAS-102. PATIENTS AND METHODS: We investigated three different cohorts: a training cohort (n = 52) and a testing cohort (n = 129) both receiving TAS-102 and a control cohort (n = 52) receiving regorafenib. SNPs of TK1, ENT1, CNT1, MATE1, MATE2 and OCT2 were analysed by polymerase chain reaction-based direct DNA sequencing. RESULTS: In the training cohort, patients with any ENT1rs760370 G allele had a significantly longer progression-free survival (PFS; 3.5 versus 2.1 months, respectively, hazard ratio [HR] 0.44, P = 0.004) and overall survival (OS; 8.7 versus 5.3 months, respectively, HR 0.27, P = 0.003) than the A/A genotype. These findings were validated in the testing cohort (P = 0.021 and 0.009 for PFS and OS, respectively). In addition, the combination of ENT1rs760370, MATE1rs2289669 and OCT2rs316019 SNPs significantly stratified patients with the risk of PFS and OS in both cohorts (P < 0.001 for PFS and OS in the training cohort; P = 0.053 and 0.025 for PFS and OS, respectively, in the testing cohort). No significant differences were observed in the control group. CONCLUSIONS: The combination of ENT1, MATE1 and OCT2 SNPs may serve as a predictive and prognostic marker in mCRC patients treated with TAS-102.
Authors: Kyla M Smith; Melissa D Slugoski; Shaun K Loewen; Amy M L Ng; Sylvia Y M Yao; Xing-Zhen Chen; Edward Karpinski; Carol E Cass; Stephen A Baldwin; James D Young Journal: J Biol Chem Date: 2005-05-03 Impact factor: 5.157
Authors: Henriette E Meyer zu Schwabedissen; Celine Verstuyft; Heyo K Kroemer; Laurent Becquemont; Richard B Kim Journal: Am J Physiol Renal Physiol Date: 2010-01-06
Authors: Irene V Bijnsdorp; Godefridus J Peters; Olaf H Temmink; Masakazu Fukushima; Frank A Kruyt Journal: Int J Cancer Date: 2010-05-15 Impact factor: 7.396