title: Efflux pump ABCB1 single nucleotide polymorphisms and dose reductions in patients with metastatic renal cell carcinoma treated with sunitinib.
abstract: There is growing evidence that sunitinib plasma levels have an impact on treatment outcome in patients with metastatic renal cell carcinoma (mRCC). We studied the impact of single nucleotide polymorphisms (SNPs) in genes involved in sunitinib pharmacokinetics, and additionally, sunitinib pharmacodynamics on dose reductions of the tyrosine kinase inhibitor.
  
  
  METHODS
  We retrospectively analyzed germ-line DNA retrieved from mRCC patients receiving sunitinib as first-line therapy. We genotyped 11 key SNPs, respectively, in ABCB1, NR1/2, NR1/3 and CYP3A5, involved in sunitinib pharmacokinetics as well as VEGFR1 and VEGFR3, which have been suggested as regulators of sunitinib pharmacodynamics. Association between these SNPs and time-to-dose-reduction (TTDR) was studied by Cox regression.
  
  
  RESULTS
  We identified 96 patients who were treated with sunitinib and from whom germ-line DNA and data on dose reductions were available. We observed an increased TTDR in patients carrying the TT-genotype in ABCB1 rs1125803 compared to patients with CC- or CT-genotypes (19 vs. 7 cycles; p = 0.031 on univariate analysis and p = 0.012 on multivariate analysis) and an increased TTDR in patients carrying the TT/TA-variant in ABCB1 rs2032582 compared to patients with the GG- or GT/GA-variant (19 vs. 7 cycles; p = 0.046 on univariate analysis and p = 0.024 on multivariate analysis).
  
  
  CONCLUSIONS
  mRCC patients carrying the rs1128503 TT-variant or the TT/TA-variant in rs2032582 in ABCB1, which encodes for an efflux pump, do require less dose reductions due to adverse events compared to patients with the wild type or heterozygote variants in these genes.
authors.affiliation: Department of General Medical Oncology and Laboratory for Experimental Oncology, University Hospitals Leuven, Leuven Cancer Institute , KU Leuven, Leuven , Belgium.
authors.forename: Benoit
authors.initials: B
authors.lastname: Beuselinck
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.forename: Thomas
authors.initials: T
authors.lastname: Van Brussel
authors.forename: Pascal
authors.initials: P
authors.lastname: Wolter
authors.forename: Nina
authors.initials: N
authors.lastname: Cardinaels
authors.forename: Steven
authors.initials: S
authors.lastname: Joniau
authors.forename: Evelyne
authors.initials: E
authors.lastname: Lerut
authors.forename: Alexandra
authors.initials: A
authors.lastname: Karadimou
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Couchy
authors.forename: Philippe
authors.initials: P
authors.lastname: Sebe
authors.forename: Alain
authors.initials: A
authors.lastname: Ravaud
authors.forename: Marc
authors.initials: M
authors.lastname: Zerbib
authors.forename: Armelle
authors.initials: A
authors.lastname: Caty
authors.forename: Robert
authors.initials: R
authors.lastname: Paridaens
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
authors.forename: Virginie
authors.initials: V
authors.lastname: Verkarre
authors.forename: Julien
authors.initials: J
authors.lastname: Berger
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Patard
authors.forename: Jessica
authors.initials: J
authors.lastname: Zucman-Rossi
authors.forename: Stéphane
authors.initials: S
authors.lastname: Oudard
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D007680:Kidney Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D012189:Retrospective Studies; D000077210:Sunitinib; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C581309:FLT4 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D040321:Vascular Endothelial Growth Factor Receptor-3; D000077210:Sunitinib