M Suenaga1, M Schirripa1, S Cao2, W Zhang1, D Yang2, S Murgioni3, D Rossini4, F Marmorino4, A Mennitto5, Y Ning1, S Okazaki1, M D Berger1, Y Miyamoto1, R Gopez1, A Barzi1, T Yamaguchi6, F Loupakis3, H-J Lenz1. 1. Department of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA. 2. Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA. 3. Medical Oncology 1 Unit, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padova, Italy. 4. Polo Oncologico, Istituto Toscano Tumori, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. 5. Medical Oncology Department, Fondazione Istituti di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy. 6. Gastroenterology Center, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
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 = 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.
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 ATMrs609429 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 XRCC3rs861539 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, ATMrs609429 remained significant for OS (P = 0.020). In the validation cohort, patients having ATMrs609429 with any G allele showed longer OS and PFS; the G/A variant in XRCC3rs861539 showed longer OS, though without statistical significance. Conclusion: Genetic variants in the HR pathway may predict clinical outcome in mCRC patients receiving TAS-102.
Authors: Ian Hickson; Yan Zhao; Caroline J Richardson; Sharon J Green; Niall M B Martin; Alisdair I Orr; Philip M Reaper; Stephen P Jackson; Nicola J Curtin; Graeme C M Smith Journal: Cancer Res Date: 2004-12-15 Impact factor: 12.701
Authors: Robert J Mayer; Eric Van Cutsem; Alfredo Falcone; Takayuki Yoshino; Rocio Garcia-Carbonero; Nobuyuki Mizunuma; Kentaro Yamazaki; Yasuhiro Shimada; Josep Tabernero; Yoshito Komatsu; Alberto Sobrero; Eveline Boucher; Marc Peeters; Ben Tran; Heinz-Josef Lenz; Alberto Zaniboni; Howard Hochster; James M Cleary; Hans Prenen; Fabio Benedetti; Hirokazu Mizuguchi; Lukas Makris; Masanobu Ito; Atsushi Ohtsu Journal: N Engl J Med Date: 2015-05-14 Impact factor: 91.245
Authors: Johannes J M Kwakman; G Vink; J H Vestjens; L V Beerepoot; J W de Groot; R L Jansen; F L Opdam; H Boot; G J Creemers; J M van Rooijen; M Los; A J E Vulink; H Schut; E van Meerten; A Baars; P Hamberg; E Kapiteijn; D W Sommeijer; C J A Punt; M Koopman Journal: Int J Clin Oncol Date: 2017-12-04 Impact factor: 3.402
Authors: Vincenzo Sforza; Erika Martinelli; Claudia Cardone; Giulia Martini; Stefania Napolitano; Pietro Paolo Vitiello; Pasquale Vitale; Nicoletta Zanaletti; Alfonso Reginelli; Maurizio Di Bisceglie; Tiziana Pia Latiano; Anna Maria Bochicchio; Fabiana Cecere; Francesco Selvaggi; Fortunato Ciardiello; Teresa Troiani Journal: ESMO Open Date: 2017-09-21