Genetic heterogeneity beyond CYP2C8*3 does not explain differential sensitivity to paclitaxel-induced neuropathy

PURPOSE: The development of paclitaxel-induced peripheral neuropathy (PIPN) is influenced by drug exposure and patient genetics. The purpose of this analysis was to expand on a previous reported association of CYP2C8*3 and PIPN risk by investigating additional polymorphisms in CYP2C8 and in hundreds of other genes potentially relevant to paclitaxel pharmacokinetics. METHODS: Clinical data was collected prospectively in an observational registry of newly diagnosed breast cancer patients. Patients treated with paclitaxel-containing regimens were genotyped using the Affymetrix DMET(™) Plus chip. Patients who carried the CYP2C8*2, *3 or *4 variant were collapsed into a low-metabolizer CYP2C8 phenotype for association with PIPN. Separately, all SNPs that surpassed quality control were assessed individually and as a composite of genetic ancestry for associations with PIPN. RESULTS: 412 paclitaxel-treated patients and 564 genetic markers were included in the analysis. The risk of PIPN was significantly greater in the CYP2C8 low-metabolizer group (HR=1.722, p=0.018), however, the influence of the *2 and *4 SNPs were not independently significant (*2: p=0.847, *4: p=0.408). One intronic SNP in ABCG1 (rs492338) surpassed the exploratory significance threshold for an association with PIPN in the Caucasian cohort (p=0.0008) but not in the non-Caucasian replication group (p=0.54). Substantial genetic variability was observed within self-reported racial groups but this genetic variability was not associated with risk of grade 2+ PIPN. CONCLUSIONS: The pharmacogenetic heterogeneity within a cohort of breast cancer patients is dramatic, though we did not find evidence that this heterogeneity directly influences the risk of PIPN beyond the contribution of CYP2C8*3