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

Gray, V. et al. (2019) Pattern recognition receptor polymorphisms as predictors of oxaliplatin benefit in colorectal cancer. Journal of the National Cancer Institute, 111(8), pp. 828-836. (doi: 10.1093/jnci/djy215) (PMID:30649440) (PMCID:PMC6695319)

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Abstract

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. 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. 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). 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:Articles
Additional Information:This work was supported by The Oxford NIHR Comprehensive Biomedical Research Centre, Cancer Research UK (C6199/A10417 and C399/A2291), the European Union Seventh Framework Programme (FP7/207– 2013) grant 258236 collaborative project SYSCOL, European Research Council project EVOCAN, and core funding to the Wellcome Trust Centre for Human Genetics from the Wellcome Trust (090532/Z/09/Z). The SCOT trial was supported by the Medical Research Council (transferred to NETSCC—Efficacy and Mechanism Evaluation; grant reference G0601705), the Swedish Cancer Society, and Cancer Research UK Core Clinical Trials Unit Funding (funding reference C6716/A9894). The TRIAL sponsor was NHS Greater Glasgow & Clyde and University of Glasgow (Eudract reference 2007–003957–10; ISRCTN number 23516549). COIN and COIN-B were coordinated by the Medical Research Council Clinical Trials Unit and conducted with the support of the National Institutes of Health Research Cancer Research Network. COIN and COIN-B translational studies were supported by the Bobby Moore Fund from Cancer Research UK, Tenovus, the Kidani Trust, Cancer Research Wales, and the National Institute for Social Care and Health Research Cancer Genetics Biomedical Research Unit. SB is funded by an MRC Clinical Research Training Fellowship. CP is funded by a University of Birmingham Fellowship. NAA, BFM, and SMW were funded and supported by KFSHRC. RSH is supported by Cancer Research UK. DNC is funded by a Health Foundation/Academy of Medical Sciences Clinician Scientist Fellowship. The cost of open access publication was provided by core funding to the Wellcome Centre for Human Genetics from the Wellcome Trust (203141/Z/16/Z).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Paul, Mr James and Mcqueen, Mr John and Harkin, Mrs Andrea
Authors: Gray, V., Briggs, S., Palles, C., Jaeger, E., Iveson, T., Kerr, R., Saunders, M. P., Paul, J., Harkin, A., Mcqueen, J., Summers, M. G., Johnstone, E., Wang, H., Gatcombe, L., Maughan, T. S., Kaplan, R., Escott-Price, V., Al-Tassan, N. A., Meyer, B. F., Wakil, S. M., Houlston, R. S., Cheadle, J. P., Tomlinson, I., and Church, D. N.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Journal of the National Cancer Institute
Publisher:Oxford University Press
ISSN:1460-2105
ISSN (Online):1460-2105
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Journal of the National Cancer Institute 111(8):828-836
Publisher Policy:Reproduced under a Creative Commons License

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