Docetaxel-Induced Toxicities in Patients With Breast Cancer With CYP3A4*22 Alleles

PURPOSE Docetaxel-related toxicities can limit cancer treatment and be fatal. It is metabolized by the cytochrome P450 3A4 enzyme. We evaluated the association of rare reduced-function CYP3A4 variants with grade 3-4 docetaxel-induced toxicity. METHODS We analyzed data from the SUCCESS-A breast cancer study available from the Database for Genotypes and Phenotypes. In our retrospective, case-control analysis of the data, 3,208 patients were enrolled in the original study, received docetaxel, and had genetic data and associated docetaxel-induced toxicity outcomes available. CYP3A4 genotypes were not originally determined for individuals in the SUCCESS-A study, so we imputed CYP3A4 genotypes using the TOPMed imputation server. The development of grade 3-4 docetaxel-induced hematological toxicities in patients with two copies of the reduced-function CYP3A4*22 allele were compared with those with normal function alleles. RESULTS Eight individuals had imputed CYP3A4*22 / *22 genotypes. Six of them (75%) experienced grade 3-4 toxicities. In comparison, 56% of the CYP3A4*1 / *1 (normal function alleles) participants (n = 1,628; P = .31, odds ratio [OR], 2.41 [95% CI, 0.43 to 24.49) and 50.9% (n = 145) of the CYP3A4*1 / *22 participants developed grade 3-4 toxicities ( P = .11, OR, 1.23 [95% CI, 0.96 to 1.58]). CONCLUSION Although not statistically significant, patients with the rare CYP3A4*22 / *22 genotypes may be at increased risks of severe toxicities.