Whole-exome sequencing reveals defective CYP3A4variants predictive for paclitaxel dose-limiting neuropathy

Questions\\ Paclitaxel, a widely-used chemotherapeutic drug, can cause severe peripheral neuropathy, causing dose reductions and treatment suspensions and, when long-lasting, a decrease in the quality of life of patients. Genetic variants altering paclitaxel pharmacokinetics have been proposed to increase the risk for neuropathy, but the major causes of inter-individual differences in susceptibility to paclitaxel toxicity remain unexplained. In this study we used whole-exome sequencing (WES) to identify genetic variants associated with paclitaxel-induced neuropathy and confirmed our results using an independent cohort. Methods \\ Eight patients with severe paclitaxel-induced peripheral neuropathy were selected for WES. An independent cohort of 228 cancer patients with complete data regarding paclitaxel neuropathy was used for variant screening by dHPLC and association analysis. Results \\ WES revealed two patients with rare CYP3A4 variants: a rare premature stop codon (CYP3A4*20 allele) and a novel missense variant (c.1165C>T, p.P389S, named CYP3A4*25). Screening for CYP3A4 variants in the independent series revealed three more CYP3A4*20 carriers and additional variants. All patients with CYP3A4*20 allele had a grade 3 paclitaxel-induced neuropathy. These patients had 2-fold increased risk of paclitaxel-induced neuropathy (P=0.042) and 7-fold higher probability of paclitaxel treatment modifications (P=0.0058) than patients with wild-type CYP3A4. Conclusions \\ CYP3A4 defective variants confer high risk of paclitaxel dose-limiting neuropathy, thus, providing a basis for paclitaxel treatment individualization.