title: Clinical Significance of TLR1 I602S Polymorphism for Patients with Metastatic Colorectal Cancer Treated with FOLFIRI plus Bevacizumab.
abstract: The purpose of this study was to evaluate the clinical significance of single-nucleotide polymorphisms in TLR1, TLR2, TLR6, and TAK1 in patients with metastatic colorectal cancer (mCRC). We genotyped 9 SNPs of TLR1, TLR2, TLR6, and TAK1 in mCRC patients treated with first-line FOLFIRI (combination therapy of irinotecan, 5-fluorouracil, and folinic acid) plus bevacizumab, using a discovery cohort (TRIBE trial, n = 228) and a validation cohort (FIRE-3 trial, n = 297), and analyzed for the association with response rate (RR), progression-free survival (PFS), and overall survival (OS). There was a significant association of TLR1 rs5743618 (T1805G) with the clinical outcome. In the TRIBE cohort, a homozygous wild-type genotype (T/T) associated with a significantly lower RR compared with variant T/G and G/G genotypes (43% vs. 62%, P = 0.025), and this observation was validated in the FIRE-3 cohort (46% vs. 65%, P = 0.021). In addition, those patients with the T/T genotype had significantly worse PFS (median, 8.2 vs. 10.5 months; HR, 1.57; 95% CI, 1.09-2.28, P = 0.014) and OS (median: 19.9 vs. 27.9 months; HR, 1.63; 95% CI, 1.14-2.35, P = 0.007), compared with those with other genotypes in the TRIBE cohort. These differences remained statistically significant in multivariate analysis. Our data suggest that TLR1 rs5743618 could serve as a predictor of clinical response to FOLFIRI plus bevacizumab in patients with mCRC. Mol Cancer Ther; 15(7); 1740-5. ©2016 AACR.
authors.affiliation: Department of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okazaki
authors.affiliation: U.O. Oncologia Medica 2, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy.
authors.forename: Fotios
authors.initials: F
authors.lastname: Loupakis
authors.affiliation: Department of Medical Oncology and Comprehensive Cancer Center, University of Munich, Munich, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Stintzing
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Shu
authors.initials: S
authors.lastname: Cao
authors.affiliation: Department of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Wu
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Dongyun
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ning
authors.affiliation: Department of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sunakawa
authors.affiliation: Department of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Stefan
authors.initials: S
authors.lastname: Stremitzer
authors.affiliation: Department of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsusaka
authors.affiliation: Department of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Berger
authors.affiliation: Department of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Anish
authors.initials: A
authors.lastname: Parekh
authors.affiliation: Department of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Jordan D
authors.initials: JD
authors.lastname: West
authors.affiliation: Department of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Miyamoto
authors.affiliation: Department of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Mitsukuni
authors.initials: M
authors.lastname: Suenaga
authors.affiliation: Department of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Marta
authors.initials: M
authors.lastname: Schirripa
authors.affiliation: U.O. Oncologia Medica 2, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cremolini
authors.affiliation: U.O. Oncologia Medica 2, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Falcone
authors.affiliation: Department of Medical Oncology and Comprehensive Cancer Center, University of Munich, Munich, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Heinemann
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California.
authors.forename: R William
authors.initials: RW
authors.lastname: DePaolo
authors.affiliation: Department of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California. lenz@usc.edu.
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D011905:Genes, ras; D005838:Genotype; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D019233:Retreatment; D051194:Toll-Like Receptor 1 / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D051194:Toll-Like Receptor 1; D000068258:Bevacizumab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin