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

Abstract

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. 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. 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 influences 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. 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.

Fig 1

Incidence of grade 2+ neuropathy by CYP2C8 metabolizer status. All patients carrying a CYP2C8*2, *3 or *4 allele were grouped into a low-metabolizer phenotype. As hypothesized, CYP2C8 low-metabolizers had a greater risk of neuropathy (p=0.02).

Fig 2

Incidence of grade 2+ neuropathy by ABCG1 (rs492338) genotype in Caucasian (n=285) (Fig 2A, left) and non-Caucasian (n=124) (Fig 2B, right) patients. The increase in neuropathy risk for patients carrying rs492338 discovered in Caucasians (p=0.0008) could not be replicated in non-Caucasians (p=0.542), suggesting that if the original association is true it may be race-specific.

Fig 3

Stacked bar plots displaying the percentage of Caucasian (green), African (blue), and Asian (red) ancestry, visualized in ascending order of Caucasian genetics stratified by self-reported race. Race was verified by other documentation within the medical record for all patients whose genetic ancestry was <80% concordant with their self-reported race. The self-reported white patients are genetically predominantly Caucasian; however, some patients have substantial African and/or Asian genetic ancestry. Similarly, the self-reported black patients exist on a continuum between almost entirely genetically African and almost entirely genetically Caucasian. Interestingly, Asians are the most genetically homogeneous of the racial groups.

Fig 4

Plot of first two principal components for 412 breast cancer patients and 359 reference samples (YRI=118, JPT=91, CHB=90, CEU=59). The reference samples tightly cluster by race due to genetic homogeneity. The patient samples tend to cluster near the corresponding reference samples but demonstrate substantially greater genetic heterogeneity, particularly for the self-reported black patients who represent a continuum between the African and Caucasian reference populations.