Genetic variants of DNA repair-related genes predict efficacy of TAS-102 in patients with refractory metastatic colorectal cancer

M. Suenaga, M. Schirripa, S. Cao, W. Zhang, D. Yang, S. Murgioni, D. Rossini, F. Marmorino, A. Mennitto, Y. Ning, S. Okazaki, M. D. Berger, Y. Miyamoto, R. Gopez Jr, A. Barzi, T. Yamaguchi, F. Loupakis, H.-J. Lenz

Research output: Contribution to journalArticle

Abstract

Background: Tri-phosphorylated trifluridine (FTD) incorporation into DNA is TAS-102’s main anti-tumor action. We tested
whether genetic polymorphisms in homologous recombination (HR) and cell cycle checkpoint pathway for DNA repair is associated
with outcomes in refractory metastatic colorectal cancer (mCRC) patients treated with TAS-102.
Patients and methods: We analyzed genomic DNA extracted from 233 samples of three cohorts: an evaluation cohort of
52 patients receiving TAS-102, a validation cohort of 129 patients receiving TAS-102 and a control cohort of 52 patients
receiving regorafenib. Single nucleotide polymorphisms of genes involved in HR (ATM, BRCA1, BRCA2, XRCC3, FANCD2, H2AX,
RAD51) and cell cycle checkpoint (ATR, CHEK1, CHEK2, CDKN1A, TP53, CHE1, PIN1, PCNA) were analyzed by PCR-based direct
sequencing.
Results: In univariate analysis for the evaluation cohort, patients with any G allele in ATM rs609429 had longer overall survival
(OS) than those with the C/C variant (8.7 vs. 4.4 months, HR 0.37, 95% CI: 0.14–0.99, P ¼ 0.022). Patients carrying any A allele in
XRCC3 rs861539 had significantly longer progression-free survival (PFS) (3.8 vs. 2.3 months, HR 0.44, 95% CI: 0.21–0.92,
P ¼ 0.024) and OS (15.6 vs. 6.3 months, HR 0.25, 95% CI: 0.08–0.79, P ¼ 0.012) than those with the G/G variant. In multivariable
analysis, ATM rs609429 remained significant for OS (P ¼ 0.020). In the validation cohort, patients having ATM rs609429 with any
G allele showed longer OS and PFS; the G/A variant in XRCC3 rs861539 showed longer OS, though without statistical
significance.
Conclusion: Genetic variants in the HR pathway may predict clinical outcome in mCRC patients receiving TAS-102.
Original languageUndefined/Unknown
Pages (from-to)1015-1022
Number of pages8
JournalAnnals of Oncology
Volume28
Issue number5
Early online dateFeb 9 2017
Publication statusPublished - May 1 2017

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