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Potential role of polymorphisms in the transporter genes ENT1 and MATE1/OCT2 in predicting TAS-102 efficacy and toxicity in patients with refractory metastatic colorectal cancer

  • Mitsukuni Suenaga
    Affiliations
    Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
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  • Marta Schirripa
    Affiliations
    Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
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  • Shu Cao
    Affiliations
    Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
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  • Wu Zhang
    Affiliations
    Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
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  • Dongyun Yang
    Affiliations
    Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
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  • Vincenzo Dadduzio
    Affiliations
    Medical Oncology 1 Unit, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Via Gattamelata 64, 35128 Padua, Italy
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  • Lisa Salvatore
    Affiliations
    Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Via Roma 67, 56126 Pisa, Italy
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  • Beatrice Borelli
    Affiliations
    Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Via Roma 67, 56126 Pisa, Italy
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  • Filippo Pietrantonio
    Affiliations
    Medical Oncology Department, Fondazione IRCCS, Istituto Nazionale Dei Tumori, Via Venezian 1, 20133 Milan, Italy
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  • Yan Ning
    Affiliations
    Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
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  • Satoshi Okazaki
    Affiliations
    Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
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  • Martin D. Berger
    Affiliations
    Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
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  • Yuji Miyamoto
    Affiliations
    Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
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  • Roel Gopez Jr.
    Affiliations
    Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
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  • Afsaneh Barzi
    Affiliations
    Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
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  • Toshiharu Yamaguchi
    Affiliations
    Gastroenterology Center, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, 135-8550, Tokyo, Japan
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  • Fotios Loupakis
    Affiliations
    Medical Oncology 1 Unit, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Via Gattamelata 64, 35128 Padua, Italy
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  • Heinz-Josef Lenz
    Correspondence
    Corresponding author: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Ave, Suite 3456, Los Angeles, CA 90033, USA.
    Affiliations
    Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
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Published:October 06, 2017DOI:https://doi.org/10.1016/j.ejca.2017.08.033

      Highlights

      • Trifluridine (FTD) is a cytotoxic component of the metastatic colorectal cancer drug TAS-102.
      • FTD rapid degradation is inhibited by thymidine phosphorylase inhibitor (TPI).
      • Germline polymorphisms of the nucleoside transporter ENT1 regulate the FTD influx/efflux.
      • Transporters multidrug and toxin extrusion 1 (MATE1) and organic cation transporter 2 (OCT2) are involved in TPI excretion.
      • Combined polymorphisms of transporter genes ENT1, MATE1 and OCT2 classify the clinical outcome.

      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.

      Keywords

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