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.

Suenaga, Mitsukuni; Schirripa, Marta; Cao, Shu; Zhang, Wu; Yang, Dongyun; Dadduzio, Vincenzo; Salvatore, Lisa; Borelli, Beatrice; Pietrantonio, Filippo; Ning, Yan; Okazaki, Satoshi; Berger, Martin Dave; Miyamoto, Yuji; Gopez, Roel; Barzi, Afsaneh; Yamaguchi, Toshiharu; Loupakis, Fotios; Lenz, Heinz-Josef (2017). 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. European journal of cancer, 86, pp. 197-206. Elsevier 10.1016/j.ejca.2017.08.033

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology

UniBE Contributor:

Berger, Martin Dave

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0959-8049

Publisher:

Elsevier

Language:

English

Submitter:

Nicole Corminboeuf

Date Deposited:

21 Feb 2018 11:19

Last Modified:

27 Oct 2019 21:24

Publisher DOI:

10.1016/j.ejca.2017.08.033

PubMed ID:

28992563

Uncontrolled Keywords:

Metastatic colorectal cancer TAS-102 Thymidine phosphorylase inhibitor Transporter Trifluridine

BORIS DOI:

10.7892/boris.111362

URI:

https://boris.unibe.ch/id/eprint/111362

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