title: Genetic polymorphisms associated with a prolonged progression-free survival in patients with metastatic renal cell cancer treated with sunitinib.
abstract: OBJECTIVE
  The objective of this study was to identify genetic polymorphisms related to the pharmacokinetics and pharmacodynamics of sunitinib that are associated with a prolonged progression-free survival (PFS) and/or overall survival (OS) in patients with clear-cell metastatic renal cell cancer (mRCC) treated with sunitinib.
  
  
  METHODS
  A retrospective multicenter pharmacogenetic association study was performed in 136 clear-cell mRCC patients treated with sunitinib. A total of 30 polymorphisms in 11 candidate genes, together with clinical characteristics were tested univariately for association with PFS as primary and OS as secondary outcome. Candidate variables with P < 0.1 were analyzed in a multivariate Cox regression model.
  
  
  RESULTS
  Multivariate analysis showed that PFS was significantly improved when an A-allele was present in CYP3A5 6986A/G [hazard ratio (HR), 0.27; P = 0.032], a CAT copy was absent in the NR1I3 haplotype (5719C/T, 7738A/C, 7837T/G; HR, 1.76; P = 0.017) and a TCG copy was present in the ABCB1 haplotype (3435C/T, 1236C/T, 2677G/T; HR, 0.52; P = 0.033). Carriers with a favorable genetic profile (n = 95) had an improved PFS and OS as compared with noncarriers (median PFS and OS: 13.1 versus 7.5 months and 19.9 versus 12.3 months). Next to the genetic variants, the Memorial Sloan-Kettering Cancer Center prognostic criteria were associated with PFS and OS (HR, 1.99 and 2.27; P < 0.001).
  
  
  CONCLUSIONS
  This exploratory study shows that genetic polymorphisms in three genes involved in sunitinib pharmacokinetics are associated with PFS in mRCC patients treated with this drug. These findings advocate prospective validation and further elucidation of these genetic determinants in relation to sunitinib exposure and efficacy.
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Astrid A M
authors.initials: AA
authors.lastname: van der Veldt
authors.forename: Karel
authors.initials: K
authors.lastname: Eechoute
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
authors.forename: Jourik
authors.initials: J
authors.lastname: Gietema
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
authors.forename: Nielka P
authors.initials: NP
authors.lastname: van Erp
authors.forename: Alfons J M
authors.initials: AJ
authors.lastname: van den Eertwegh
authors.forename: John B
authors.initials: JB
authors.lastname: Haanen
authors.forename: Ron H J
authors.initials: RH
authors.lastname: Mathijssen
authors.forename: Judith A M
authors.initials: JA
authors.lastname: Wessels
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000090702:Constitutive Androstane Receptor; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011758:Pyrroles / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000077210:Sunitinib
chemical_list: D000090702:Constitutive Androstane Receptor; D007211:Indoles; C000716327:NR1I3 protein, human; D011758:Pyrroles; D000077210:Sunitinib