Genetic heterogeneity beyond CYP2C8*3 does not explain differential sensitivity to paclitaxel-induced neuropathy.
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.
Department of Clinical, Social, and Administrative Sciences, University of Michigan College of Pharmacy, 428 Church St, Ann Arbor, MI, 48109, USA, dlhertz@med.umich.edu.
Daniel L
DL
Hertz
Siddharth
S
Roy
John
J
Jack
Alison A
AA
Motsinger-Reif
Amy
A
Drobish
L Scott
LS
Clark
Lisa A
LA
Carey
E Claire
EC
Dees
Howard L
HL
McLeod
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000235:genetics*; D065727:Cytochrome P-450 CYP2C8 / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D017239:Paclitaxel / Q000009:adverse effects* / Q000627:therapeutic use; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
D000970:Antineoplastic Agents; D065727:Cytochrome P-450 CYP2C8; D017239:Paclitaxel