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

Suenaga, M; Schirripa, M; Cao, S; Zhang-Wu, Xiaxia; Yang, D; Murgioni, S; Rossini, D; Marmorino, F; Mennitto, A; Ning, Y; Okazaki, S; Berger, Martin Dave; Miyamoto, Y; Gopez, R; Barzi, A; Yamaguchi, T; Loupakis, F; Lenz, H-J (2017). Genetic variants of DNA repair-related genes predict efficacy of TAS-102 in patients with refractory metastatic colorectal cancer. Annals of oncology, 28(5), pp. 1015-1022. Oxford University Press 10.1093/annonc/mdx035

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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 = 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 = 0.024) and OS (15.6 vs. 6.3 months, HR 0.25, 95% CI: 0.08-0.79, P = 0.012) than those with the G/G variant. In multivariable analysis, ATM rs609429 remained significant for OS (P = 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.

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:

0923-7534

Publisher:

Oxford University Press

Language:

English

Submitter:

Nicole Corminboeuf

Date Deposited:

13 Feb 2018 16:26

Last Modified:

25 Oct 2019 08:05

Publisher DOI:

10.1093/annonc/mdx035

PubMed ID:

28453695

Uncontrolled Keywords:

ATM DNA repair TAS-102 cell cycle checkpoint metastatic colorectal cancer

BORIS DOI:

10.7892/boris.111404

URI:

https://boris.unibe.ch/id/eprint/111404

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