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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.
- Source :
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European journal of cancer (Oxford, England : 1990) [Eur J Cancer] 2017 Nov; Vol. 86, pp. 197-206. Date of Electronic Publication: 2017 Oct 06. - Publication Year :
- 2017
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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.<br />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.<br />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.<br />Conclusions: The combination of ENT1, MATE1 and OCT2 SNPs may serve as a predictive and prognostic marker in mCRC patients treated with TAS-102.<br /> (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Subjects :
- Antineoplastic Agents adverse effects
Antineoplastic Agents pharmacokinetics
California
Colorectal Neoplasms genetics
Colorectal Neoplasms pathology
Disease-Free Survival
Drug Combinations
Equilibrative Nucleoside Transporter 1 metabolism
Female
Gene Frequency
Genotype
Humans
Italy
Japan
Male
Neoplasm Metastasis
Organic Cation Transport Proteins metabolism
Organic Cation Transporter 2 metabolism
Pharmacogenetics
Pharmacogenomic Testing
Phenotype
Predictive Value of Tests
Pyrrolidines
Retrospective Studies
Thymine
Treatment Outcome
Trifluridine adverse effects
Trifluridine pharmacokinetics
Uracil adverse effects
Uracil pharmacokinetics
Uracil therapeutic use
Antineoplastic Agents therapeutic use
Colorectal Neoplasms drug therapy
Equilibrative Nucleoside Transporter 1 genetics
Organic Cation Transport Proteins genetics
Organic Cation Transporter 2 genetics
Pharmacogenomic Variants
Polymorphism, Single Nucleotide
Trifluridine therapeutic use
Uracil analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0852
- Volume :
- 86
- Database :
- MEDLINE
- Journal :
- European journal of cancer (Oxford, England : 1990)
- Publication Type :
- Academic Journal
- Accession number :
- 28992563
- Full Text :
- https://doi.org/10.1016/j.ejca.2017.08.033