title: Genotypes of CYP2C8 and FGD4 and their association with peripheral neuropathy or early dose reduction in paclitaxel-treated breast cancer patients.
abstract: BACKGROUND
  The purpose of this study was to evaluate single-nucleotide polymorphisms (SNPs) in genes encoding key metabolising enzymes or involved in pharmacodynamics for possible associations with paclitaxel-induced peripheral neuropathy.
  
  
  METHODS
  The study population consists of 188 women from the multicenter, randomised, phase II ATX trial (BOOG2006-06; EudraCT number 2006-006058-83) that received paclitaxel and bevacizumab without or with capecitabine as first-line palliative therapy of HER2-negative metastatic breast cancer. Genotyping of CYP2C8*3 (c.416G>A), CYP3A4*22 (c.522-191C>T), TUBB2A (c.-101T>C), FGD4 (c.2044-236G>A) and EPHA5 (c.2895G>A) was performed by real-time PCR. Toxicity endpoints were cumulative dose (1) until first onset of grade ⩾1 peripheral neuropathy and (2) until first paclitaxel dose reduction from related toxicity (NCI-CTCAE version 3.0). SNPs were evaluated using the Kaplan-Meier method, the Gehan-Breslow-Wilcoxon test and the multivariate Cox regression analysis.
  
  
  RESULTS
  The rate of grade ⩾1 peripheral neuropathy was 67% (n=126). The rate of dose reduction was 46% (n=87). Age ⩾65 years was a risk factor for peripheral neuropathy (HR=1.87, P<0.008), but not for dose reduction. When adjusted for age, body surface area and total cumulative paclitaxel dose, CYP2C8*3 carriers had an increased risk of peripheral neuropathy (HR=1.59, P=0.045). FGD4 c.2044-236 A-allele carriers had an increased risk of paclitaxel dose reduction (HR per A-allele=1.38, P=0.036) when adjusted for total cumulative paclitaxel dose.
  
  
  CONCLUSIONS
  These findings may point towards clinically useful indicators of early toxicity, but warrant further investigation.
authors.affiliation: Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Siu W
authors.initials: SW
authors.lastname: Lam
authors.affiliation: Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Charlotte N
authors.initials: CN
authors.lastname: Frederiks
authors.affiliation: Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Tahar
authors.initials: T
authors.lastname: van der Straaten
authors.affiliation: Department of Medical Oncology, Isala Clinics, Zwolle, The Netherlands.
authors.forename: Aafke H
authors.initials: AH
authors.lastname: Honkoop
authors.affiliation: Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
authors.affiliation: Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Epie
authors.initials: E
authors.lastname: Boven
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D065727:Cytochrome P-450 CYP2C8 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D017239:Paclitaxel / Q000627:therapeutic use*; D010523:Peripheral Nervous System Diseases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C485164:FGD4 protein, human; D008840:Microfilament Proteins; D065727:Cytochrome P-450 CYP2C8; D017239:Paclitaxel