title: 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.
  
  
  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.
authors: 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
authors: D L
authors: DL
authors: Hertz
authors: S
authors: S
authors: Roy
authors: A A
authors: AA
authors: Motsinger-Reif
authors: A
authors: A
authors: Drobish
authors: L S
authors: LS
authors: Clark
authors: H L
authors: HL
authors: McLeod
authors: L A
authors: LA
authors: Carey
authors: E C
authors: EC
authors: Dees
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D015331:Cohort Studies; D065727:Cytochrome P-450 CYP2C8; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D017239:Paclitaxel / Q000009:adverse effects*; D020364:Paraneoplastic Polyneuropathy / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics*; D012307:Risk Factors; D016896:Treatment Outcome; D044465:White People / Q000235:genetics*; D055815:Young Adult
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D017239:Paclitaxel
keywords: chemotherapy-induced peripheral neuropathy; cytochrome P450 2C8*3; paclitaxel; pharmacogenetics; race