title: Pazopanib efficacy in renal cell carcinoma: evidence for predictive genetic markers in angiogenesis-related and exposure-related genes.
abstract: OBJECTIVE
  Pazopanib, an oral angiogenesis inhibitor, is approved for the treatment of advanced renal cell carcinoma (RCC). Response to pazopanib monotherapy varies between patients, and no validated biomarkers predictive of treatment outcome have been identified. We tested the hypothesis that this variability is partially dependent on germline genetic variants that may affect pazopanib exposure or angiogenesis pathways.
  
  
  METHODS
  Twenty-seven functional polymorphisms within 13 genes were evaluated in 397 patients with RCC. Genetic association with progression-free survival (PFS) and objective response rate (RR) was analyzed using the Cox proportional hazards model and proportional odds model, respectively.
  
  
  RESULTS
  Three polymorphisms in IL8 and HIF1A and five polymorphisms in HIF1A, NR1I2, and VEGFA showed nominally significant association (P ≤ .05) with PFS and RR, respectively. Compared with the wild-type AA genotype (median PFS, 48 weeks), the IL8 2767TT variant genotype showed inferior PFS (27 weeks, P = .009). The HIF1A 1790AG genotype was associated with inferior PFS and reduced RR, compared with the wild-type GG genotype (median PFS, 20 v 44 weeks; P = .03; RR, 30% v 43%, P = .02). Reductions in RR were detected for the NR1I2 -25385TT genotype, compared with the wild-type CC genotype (37% v 50%, P = .03), and for the VEGFA -1498CC genotype compared with the TT genotypes (33% v 51%).
  
  
  CONCLUSIONS
  Germline variants in angiogenesis- and exposure-related genes may predict treatment response to pazopanib monotherapy in patients with RCC. If validated, these markers may explain why certain patients fail antiangiogenesis therapy and they may support the use of alternative strategies to circumvent this issue.
authors.affiliation: GlaxoSmithKline Medicines Research Centre, Rm 1S101, Gunnels Wood Rd, Stevenage, Hertfordshire, UK. chun-fang.2.xu@gsk.com
authors.forename: Chun-Fang
authors.initials: CF
authors.lastname: Xu
authors.forename: Nan X
authors.initials: NX
authors.lastname: Bing
authors.forename: Howard A
authors.initials: HA
authors.lastname: Ball
authors.forename: Dilip
authors.initials: D
authors.lastname: Rajagopalan
authors.forename: Cora N
authors.initials: CN
authors.lastname: Sternberg
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Hutson
authors.forename: Paul
authors.initials: P
authors.lastname: de Souza
authors.forename: Zhengyu G
authors.initials: ZG
authors.lastname: Xue
authors.forename: Lauren
authors.initials: L
authors.lastname: McCann
authors.forename: Karen S
authors.initials: KS
authors.lastname: King
authors.forename: Leigh J
authors.initials: LJ
authors.lastname: Ragone
authors.forename: John C
authors.initials: JC
authors.lastname: Whittaker
authors.forename: Colin F
authors.initials: CF
authors.lastname: Spraggs
authors.forename: Lon R
authors.initials: LR
authors.lastname: Cardon
authors.forename: Vincent E
authors.initials: VE
authors.lastname: Mooser
authors.forename: Lini N
authors.initials: LN
authors.lastname: Pandite
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D017322:Clinical Trials, Phase II as Topic / Q000706:statistics & numerical data; D018592:Cross-Over Studies; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005819:Genetic Markers; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D007191:Indazoles; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D015337:Multicenter Studies as Topic / Q000706:statistics & numerical data; D009363:Neoplasm Proteins / Q000235:genetics*; D018919:Neovascularization, Physiologic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D020533:Angiogenesis Inhibitors; D005819:Genetic Markers; D007191:Indazoles; D009363:Neoplasm Proteins; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; D020794:Receptor Protein-Tyrosine Kinases