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

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.

Figures

Figure 1.

Incidence curve for grade 2+ neuropathy across genotype groups in the European-American cohort (n = 209). The highest risk was seen in the variant homozygotes and the lowest risk in the wild-type homozygotes.

Figure 2.

Incidence curve for grade 2+ neuropathy across genotype groups in the African-American cohort (n = 107). Higher risk was seen in the carriers of the CYP2C8*3 variant when compared with the wild-type homozygotes (P = 0.043). There were no homozygous variant individuals in this cohort.

Figure 3.

Incidence curve for grade 2+ neuropathy across genotype groups in the mixed-race cohort (n = 411) indicating an approximate doubling of grade 2+ neuropathy risk for each *3 variant a patient carries, supporting an additive genetic effect.

Figure 4.

Incidence curve for grade 2+ neuropathy across racial groups in the entire mixed-race cohort (n = 411). After adjusting for CYP2C8*3 and age, non-European Americans (n = 124) were at higher risk of grade 2+ neuropathy than European Americans (n = 287) (P = 0.030).