title: IL8 polymorphisms and overall survival in pazopanib- or sunitinib-treated patients with renal cell carcinoma.
abstract: BACKGROUND
  We evaluated germline single nucleotide polymorphisms (SNPs) for association with overall survival (OS) in pazopanib- or sunitinib-treated patients with advanced renal cell carcinoma (aRCC).
  
  
  METHODS
  The discovery analysis tested 27 SNPs within 13 genes from a phase III pazopanib trial (N=241, study 1). Suggestive associations were then pursued in two independent datasets: a phase III trial (COMPARZ) comparing pazopanib vs sunitinib (N=729, study 2) and an observational study of sunitinib-treated patients (N=89, study 3).
  
  
  RESULTS
  In study 1, four SNPs showed nominally significant association (P≤0.05) with OS; two of these SNPs (rs1126647, rs4073) in IL8 were associated (P≤0.05) with OS in study 2. Because rs1126647 and rs4073 were highly correlated, only rs1126647 was evaluated in study 3, which also showed association (P≤0.05). In the combined data, rs1126647 was associated with OS after conservative multiple-test adjustment (P=8.8 × 10(-5); variant vs reference allele hazard ratio 1.32, 95% confidence interval: 1.15-1.52), without evidence for heterogeneity of effects between studies or between pazopanib- and sunitinib-treated patients.
  
  
  CONCLUSIONS
  Variant alleles of IL8 polymorphisms are associated with poorer survival outcomes in pazopanib- or sunitinib-treated patients with aRCC. These findings provide insight in aRCC prognosis and may advance our thinking in development of new therapies.
authors.affiliation: GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK.
authors.forename: C-F
authors.initials: CF
authors.lastname: Xu
authors.affiliation: GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK.
authors.forename: T
authors.initials: T
authors.lastname: Johnson
authors.affiliation: 1] Department of Medical Oncology, Centro Integral Oncológico Clara Campal, Calle de Oña 10, Madrid 28050, Spain [2] Spanish Oncology Genitourinary Group (SOGUG), Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Garcia-Donas
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: T K
authors.initials: TK
authors.lastname: Choueiri
authors.affiliation: Department of Medical Oncology, San Camillo and Forlanini Hospitals, Circonvallazione Gianicolense 87, Rome 00152, Italy.
authors.forename: C N
authors.initials: CN
authors.lastname: Sternberg
authors.affiliation: Monash University Eastern Health Clinical School, 5 Arnold Street, Victoria 3128, Australia.
authors.forename: I D
authors.initials: ID
authors.lastname: Davis
authors.affiliation: GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: N
authors.initials: N
authors.lastname: Bing
authors.affiliation: GlaxoSmithKline, 250 S. Collegeville Road, Collegeville, PA 19426-0989, USA.
authors.forename: K C
authors.initials: KC
authors.lastname: Deen
authors.affiliation: GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Xue
authors.affiliation: GlaxoSmithKline, 250 S. Collegeville Road, Collegeville, PA 19426-0989, USA.
authors.forename: L
authors.initials: L
authors.lastname: McCann
authors.affiliation: 1] Department of Medical Oncology, Centro Integral Oncológico Clara Campal, Calle de Oña 10, Madrid 28050, Spain [2] Hospital Universitario Central de Asturias, Calle Carretera de Rubín, Oviedo 33011, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Esteban
authors.affiliation: GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK.
authors.forename: J C
authors.initials: JC
authors.lastname: Whittaker
authors.affiliation: GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK.
authors.forename: C F
authors.initials: CF
authors.lastname: Spraggs
authors.affiliation: Spanish National Cancer Research Centre and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Calle de Melchor Fernández Almagro 3, Madrid 28029, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Rodríguez-Antona
authors.affiliation: GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: L N
authors.initials: LN
authors.lastname: Pandite
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Motzer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics*; D017326:Clinical Trials, Phase III as Topic; D005260:Female; D006801:Humans; D007191:Indazoles; D007211:Indoles / Q000627:therapeutic use*; D016209:Interleukin-8 / Q000235:genetics*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011743:Pyrimidines / Q000627:therapeutic use*; D011758:Pyrroles / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D013449:Sulfonamides / Q000627:therapeutic use*; D000077210:Sunitinib; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; C508606:CXCL8 protein, human; D007191:Indazoles; D007211:Indoles; D016209:Interleukin-8; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; C516667:pazopanib; D000077210:Sunitinib