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Okazaki, Satoshi; Loupakis, Fotios; Stintzing, Sebastian; Cao, Shu; Zhang, Wu; Yang, Dongyun; Ning, Yan; Sunakawa, Yu; Stremitzer, Stefan; Matsusaka, Satoshi; Berger, Martin D.; Parekh, Anish; West, Jordan D.; Miyamoto, Yuji; Suenaga, Mitsukuni; Schirripa, Marta; Cremolini, Chiara; Falcone, Alfredo; Heinemann, Volker; DePaolo, R. William; Lenz, Heinz-Josef (2016): Clinical Significance of TLR1 I602S Polymorphism for Patients with Metastatic Colorectal Cancer Treated with FOLFIRI plus Bevacizumab. In: Molecular Cancer therapeutics, Vol. 15, No. 7: pp. 1740-1745
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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. (C) 2016 AACR.