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Ann Oncol. 2013 Jun;24(6):1472-8. doi: 10.1093/annonc/mdt018. Epub 2013 Feb 14.

CYP2C8*3 increases risk of neuropathy in breast cancer patients treated with paclitaxel.

Author information

1
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, UNC Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. danhertz@email.unc.edu

Abstract

BACKGROUND:

Paclitaxel-induced neuropathy is an adverse event that often leads to therapeutic disruption and patient discomfort. We attempted to replicate a previously reported association between increased neuropathy risk and CYP2C8*3 genotype.

PATIENTS AND METHODS:

Demographic, treatment, and toxicity data were collected for paclitaxel-treated breast cancer patients who were genotyped for the CYP2C8*3 K399R (rs10509681) variant. A log-rank test was used in the primary analysis of European-American patients. An additional independent replication was then attempted in a cohort of African-American patients, followed by modeling of the entire patient cohort with relevant covariates.

RESULTS:

In the primary analysis of 209 European patients, there was an increased risk of paclitaxel-induced neuropathy related to CYP2C8*3 status [HR (per allele) = 1.93 (95% CI: 1.05-3.55), overall log-rank P = 0.006]. The association was replicated in direction and magnitude of effect in 107 African-American patients (P = 0.043). In the Cox model using the entire mixed-race cohort (n = 411), each CYP2C8*3 allele approximately doubled the patient's risk of grade 2+ neuropathy (P = 0.004), and non-Europeans were at higher neuropathy risk than Europeans of similar genotype (P = 0.030).

CONCLUSIONS:

The increased risk of paclitaxel-induced neuropathy in patients who carry the CYP2C8*3 variant was replicated in two racially distinct patient cohorts.

KEYWORDS:

chemotherapy-induced peripheral neuropathy; cytochrome P450 2C8*3; paclitaxel; pharmacogenetics; race

PMID:
23413280
PMCID:
PMC3660078
DOI:
10.1093/annonc/mdt018
[Indexed for MEDLINE]
Free PMC Article
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