Polymorphisms in Pattern Recognition Receptors as Predictors of Oxaliplatin Benefit in Colorectal Cancer
In a study reported in the Journal of the National Cancer Institute, Gray et al found that constitutional loss of function single-nucleotide polymorphisms in the pattern recognition receptors FPR1, TLR3, and TLR4 were not associated with preferential benefit of oxaliplatin in colorectal cancer. As noted by the investigators, loss of function single-nucleotide polymorphisms in these receptors have previously been reported to predict oxaliplatin benefit in this setting.
Study Details
The study was a retrospective biomarker analysis of the SCOT and COIN/COIN-B trials. The SCOT trial compared oxaliplatin-based adjuvant chemotherapy with previous standard of care in high-risk stage II disease or stage III disease. The COIN/COIN-B trial assessed the addition of cetuximab to oxaliplatin-based therapy in metastatic colorectal cancer.
Patient status for loss of function variants in FPR1 (rs867228), TLR3 (rs3775291), and TLR4 (rs4986790/rs4986791) was assessed by genotyping array or genotype imputation. Associations between loss of function variants and disease-free and overall survival in the SCOT cohort and overall survival in the COIN/COIN-B cohort were analyzed by Cox regression analysis adjusted for confounders using additive, dominant, and recessive genetic models.
Absence of Associations
The study populations for the current analysis included 2,929 and 1,948 patients in the SCOT and COIN/COIN-B cohorts, with 2,728 and 1,672 patients having data on functional status for all three single-nucleotide polymorphisms.
On multivariate analysis in the SCOT cohort, no significant association was found between any of the single-nucleotide polymorphisms and disease-free survival (hazard ratios [HRs] range = 0.86–1.58, P ≥ .07, across single-nucleotide polymorphisms and genetic models) or overall survival (HRs = 0.81–1.82, P ≥ .24) on any genetic model. On multivariate analysis in the COIN/COIN-B cohort, no significant association was found for any of the single-nucleotide polymorphisms and overall survival (HRs = 0.92–2.91, P ≥ .07) on any genetic model.
The absence of significant association was found in models for which a significant association was previously reported for FPR1 rs867228 and TLR4 rs4986790. Thus, in the current analysis, for rs867228 using the recessive model, multivariate hazard ratios were 1.19 (P = .07) for disease-free survival in the SCOT cohort and 0.92 (P = .66) for overall survival in the COIN/COIN-B cohort. For rs4986790 using the dominant model, hazard ratios were 0.86 (P = .27) for disease-free survival in the SCOT cohort and 1.08 (P = .40) for overall survival in the COIN/COIN-B cohort.
The investigators concluded, “In this … analysis of two large clinical trials, we found no evidence that constitutional loss of function single-nucleotide polymorphisms in FPR1, TLR3, or TLR4 are associated with differential benefit from oxaliplatin. Our results suggest these single-nucleotide polymorphisms are unlikely to be clinically useful biomarkers.”
David N. Church, DPhil, of the Wellcome Centre for Human Genetics, University of Oxford, is the corresponding author for the Journal of the National Cancer Institute article.
Disclosure: The study was supported by The Oxford NIHR Comprehensive Biomedical Research Centre, Cancer Research UK, European Union Seventh Framework Programme, European Research Council, and core funding to the Wellcome Trust Centre for Human Genetics from the Wellcome Trust. The study authors’ full disclosures can be found at academic.oup.com.
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