Simple genetic test cuts severe cancer drug toxicity risk in half
Researchers have developed a predictive model that identifies colorectal cancer patients at high risk of life-threatening reactions to standard chemotherapy drugs, based on genetic variants in the DPYD gene. The finding could prevent hospitalizations and deaths while allowing oncologists to confidently treat low-risk patients with standard doses, reshaping how cancer centers manage chemotherapy safety.
Originaltitel: A predictive model for life-threatening fluoropyrimidine toxicity based on DPYD sequencing in colorectal cancer.
: 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<0.01) in silico-predicted deleterious variants (OR 3.20 [95%CI 1.43-7.14] if one allele). Model performance was supported by discrimination (AUC=0.76, 95%CI 0.73-0.78), calibration, and internal validation. Crude sensitivity of DPYD testing increased from 11.2% for *2A/*13/p.D949V to 47.5% when including the 44 variants. An exploratory analysis of 1,138 stage III CRC patients revealed, for the first time, that carriers of deleterious DPYD variants exhibited significantly longer overall survival: HR=0.65 [95%CI 0.43-0.98] for p. V732I and 0.62 [95%CI 0.43-0.90] for p. M166V.DPYD sequencing identified additional relevant variants and improved the sensitivity of DPYD testing. An online calculator (https://fluoropyrimidine-toxicity-predictor.gustaveroussy.fr/) is provided to estimate the individual probability of developing life-threatening toxicity, based on clinical covariates and extended DPYD genotype.