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Pattern recognition receptor polymorphisms as predictors of oxaliplatin benefit in colorectal cancer

Gray, Victoria, Briggs, Sarah, Palles, Claire, Jaegar, Emma, Iveson, Timothy, Kerr, Rachel, Saunders, Mark P., Paul, James, Harkin, Andrea, McQueen, John, Summers, Matthew G., Johnstone, Elaine, Wang, Haitao, Gatcombe, Laura, Maughan, Timothy S., Kaplan, Richard, Escott-Price, Valentina ORCID:, Al-Tassan, Nada A., Meyer, Brian F., Wakil, Salma M., Houlston, Richard S., Cheadle, Jeremy P. ORCID:, Tomlinson, Ian and Church, David N. 2019. Pattern recognition receptor polymorphisms as predictors of oxaliplatin benefit in colorectal cancer. JNCI: Journal of the National Cancer Institute 111 (8) , pp. 828-836. 10.1093/jnci/djy215

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Background Constitutional loss of function (LOF) single nucleotide polymorphisms (SNPs) in pattern recognition receptors FPR1, TLR3, and TLR4 have previously been reported to predict oxaliplatin benefit in colorectal cancer. Confirmation of this association could substantially improve patient stratification. Methods We performed a retrospective biomarker analysis of the Short Course in Oncology Therapy (SCOT) and COIN/COIN-B trials. Participant status for LOF variants in FPR1 (rs867228), TLR3 (rs3775291), and TLR4 (rs4986790/rs4986791) was determined by genotyping array or genotype imputation. Associations between LOF variants and disease-free survival (DFS) and overall survival (OS) were analyzed by Cox regression, adjusted for confounders, using additive, dominant, and recessive genetic models. All statistical tests were two-sided. Results Our validation study populations included 2929 and 1948 patients in the SCOT and COIN/COIN-B cohorts, respectively, of whom 2728 and 1672 patients had functional status of all three SNPs determined. We found no evidence of an association between any SNP and DFS in the SCOT cohort, or with OS in either cohort, irrespective of the type of model used. This included models for which an association was previously reported for rs867228 (recessive model, multivariable-adjusted hazard ratio [HR] for DFS in SCOT = 1.19, 95% confidence interval [CI] = 0.99 to 1.45, P = .07; HR for OS in COIN/COIN-B = 0.92, 95% CI = 0.63 to 1.34, P = .66), and rs4986790 (dominant model, multivariable-adjusted HR for DFS in SCOT = 0.86, 95% CI = 0.65 to 1.13, P = .27; HR for OS in COIN/COIN-B = 1.08, 95% CI = 0.90 to 1.31, P = .40). Conclusion In this prespecified analysis of two large clinical trials, we found no evidence that constitutional LOF SNPs in FPR1, TLR3, or TLR4 are associated with differential benefit from oxaliplatin. Our results suggest these SNPs are unlikely to be clinically useful biomarkers.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Publisher: Oxford University Press
ISSN: 0027-8874
Date of First Compliant Deposit: 10 October 2018
Date of Acceptance: 19 November 2018
Last Modified: 06 May 2023 01:56

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