title: Associations between drug metabolism genotype, chemotherapy pharmacokinetics, and overall survival in patients with breast cancer.
abstract: OBJECTIVE
  To evaluate associations between patient survival, pharmacokinetics, and drug metabolism-related genetic polymorphisms in patients receiving a combination chemotherapy regimen for breast cancer.
  
  
  METHODS
  A genotype association study was conducted on 85 chemotherapy-naïve patients with metastatic or inflammatory breast cancer that were evaluated for an extended period after receiving standard-dose chemotherapy followed by high-dose cyclophosphamide, cisplatin, and carmustine. Blood pharmacokinetics were evaluated, and DNA was genotyped for 29 polymorphisms in 17 drug metabolism genes.
  
  
  RESULTS
  Patients with cyclophosphamide plasma exposures above the median (implying slower metabolic activation) had a shorter survival than those below the median (1.8 v 3.8 years, respectively; P = .042). Patients having a variant genotype of cytochrome P450 3A4 displayed higher blood concentrations of parent (inactive) cyclophosphamide with the second and third doses (P = .024 and .028, respectively) in addition to slower cyclophosphamide activation over the three doses (P = .031). Median survival for these patients was 1.3 years compared with 2.7 years for those without the variant (P = .043). Similar results were observed for patients carrying a genetic variant of P450 3A5. Median survival for patients with deletions of glutathione-S-transferase M1 gene was 3.5 v 1.5 years for patients with one or both copies (P = .041). Patients with a polymorphism in a gene regulating metallothionein had lower platinum concentrations and shorter survival (P = .033).
  
  
  CONCLUSIONS
  These data suggest that pretreatment evaluation of drug metabolism genes may explain some interindividual differences in both anticancer drug pharmacokinetics and response. The correlations found here may have implications for other commonly used anticancer drugs.
authors.affiliation: West Virginia University Health Sciences Center, PO Box 9300, Morgantown, WV 26506, USA. wpetros@hsc.wvu.edu
authors.forename: William P
authors.initials: WP
authors.lastname: Petros
authors.forename: Penelope J
authors.initials: PJ
authors.lastname: Hopkins
authors.forename: Susan
authors.initials: S
authors.lastname: Spruill
authors.forename: Gloria
authors.initials: G
authors.lastname: Broadwater
authors.forename: James J
authors.initials: JJ
authors.lastname: Vredenburgh
authors.forename: O Michael
authors.initials: OM
authors.lastname: Colvin
authors.forename: William P
authors.initials: WP
authors.lastname: Peters
authors.forename: Roy B
authors.initials: RB
authors.lastname: Jones
authors.forename: Jeff
authors.initials: J
authors.lastname: Hall
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Marks
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D002330:Carmustine / Q000008:administration & dosage / Q000493:pharmacokinetics; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011379:Prognosis; D016019:Survival Analysis
chemical_list: D003520:Cyclophosphamide; D002945:Cisplatin; D002330:Carmustine