Pattern Recognition Receptor Polymorphisms as Predictors of Oxaliplatin Benefit in Colorectal Cancer

Abstract

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.

Immunogenic cell death pathway polymorphisms for predicting oxaliplatin efficacy in metastatic colorectal cancer

“…Although FPR1 , TLR3 , and TLR4 are also key PRR-encoding genes, these genes were not included in this study because they were not predictive of oxaliplatin efficacy in patients with CRC in another large biomarker study. 19 The candidate SNPs for this study were arbitrarily selected according to the following criteria: (1) minor allele frequency in Caucasians of at least 10% in the Ensemble Genome Browser ( https://www.ensembl.org ), (2) having potential biological functions based on public databases ( https://snpinfo.niehs.nih.gov ; https://www.ncbi.nlm.nih.gov ), and (3) tag SNPs chosen from HapMap genotype data with an r 2 threshold of 0.8 ( https://snpinfo.niehs.nih.gov ). In total, 10 SNPs were selected, as presented in online supplementary table S2 .…”

“…Although FPR1, TLR3, and TLR4 are also key PRR-encoding genes, these genes were not included in this study because they were not predictive of oxaliplatin efficacy in patients with CRC in another large biomarker study. 19 The candidate SNPs for this study were arbitrarily selected according to the following criteria: (1) To formally assess the predictive value, the treatmentby-SNP interaction was tested within each trial using the HR calculated in the multivariate analyzes. All analyzes were two-sided at a significance level of 0.05 and were performed using SAS V.9.4 software.…”

What Should We Do Better? Lessons from Negative Results of a Biomarker Validation Study

“…The negative results of this study raise, once again, the issue of the level of evidence of positive genotyping results obtained in small dataset and retrospective series of patients. The authors, in fact, argue that the discordance between their results and those from previous studies may be explained by the increased risk of false-positive associations in smaller cohorts, and in the case of FPR1, an apparent misclassification of the functional and LOF alleles in previous analyses (11). However, they recognize that a limitation of their work is the lack of testing for an association between the selected SNPs and outcome in specific molecular subgroups, particularly those with enhanced immunogenicity such as MMR-d tumors.…”

“…Several other candidate gene polymorphisms have been proposed as predictors for clinical outcome in CRC patients treated with platinum-based regimens (9,10). In this issue of JNCI, Gray and colleagues report the results of a validation analysis of pattern recognition receptor polymorphisms as predictors of oxaliplatin benefit in CRC (11). The authors aimed to verify previous evidence on the predictive value of common loss of function (LOF) polymorphisms in FPR1 (rs867228), TLR3 (rs3775291), and TLR4 (rs4986790/rs4986791) in patients treated with anthracycline-and oxaliplatin-based chemotherapy (12)(13)(14).…”

“…Conflicting results from different studies and lack of prospective validation warrant caution in the generalization of positive preliminary SNPs data, as Gray and colleagues' study exemplifies (11). Nevertheless, the constant effort in dissecting the pharmacogenomic basis of drug activity and efficacy is paramount to improve patient selection and drive personalized treatment strategies and novel drug development.…”