A predictive model for life-threatening fluoropyrimidine toxicity based on DPYD sequencing in colorectal cancer

ABSTRACT

: Deleterious DPYD variants are the primary identified cause of severe fluoropyrimidine-related toxicity. The objective was to improve the sensitivity of current DPYD genotyping recommendations and develop a predictive model for severe toxicity.: This pooled analysis included colorectal cancer (CRC) patients from seven prospective studies. Full DPYD sequencing was performed. Depending on their minor allele frequency (MAF), relevant DPYD variants were identified using Bolasso, or SKAT coupled with in silico functionality predictions. The primary end-point was 12-week grade 4-5 fluoropyrimidine-related hematological and digestive toxicities. Multivariate logistic regression models were developed.Of 4,496 eligible patients, 3,437 were analyzed (267 events). The final model included patient/treatment characteristics, variants *2A/*13/p.D949V, common variants rs1801160 (p.V732I (*6), OR 1.93 [95%CI 1.37-2.70] if heterozygous) and rs2297595 (p.M166V, OR 1.49 [95%CI 1.13-1.96] if heterozygous), and aggregation of all very rare (MAF