title: Investigation of novel circulating proteins, germ line single-nucleotide polymorphisms, and molecular tumor markers as potential efficacy biomarkers of first-line sunitinib therapy for advanced renal cell carcinoma.
abstract: OBJECTIVE
  Sunitinib is a first-line advanced renal cell carcinoma (RCC) standard of care. In a randomized phase II trial comparing sunitinib treatment schedules, separate exploratory biomarker analyses investigated the correlations of efficacy with selected serum, germ line single-nucleotide polymorphism (SNP), or tumor markers.
  
  
  METHODS
  Advanced RCC patients received first-line sunitinib 50 mg/day on the approved 4-week-on-2-week-off schedule (n = 146) or 37.5 mg/day continuous dosing (n = 146). The following correlation analyses were performed: (1) response evaluation criteria in solid tumors-defined tumor response with serum soluble protein levels via two distinct multiplex (n < 1,000) platforms; (2) response and time-to-event outcomes with germ line SNPs in vascular endothelial growth factor (VEGF)-A and VEGF receptor (VEGFR)3 genes; and (3) response and time-to-event outcomes with tumor immunohistochemistry status for hypoxia-inducible factor 1-alpha (HIF-1α) and carbonic anhydrase-IX or tumor Von Hippel-Lindau (VHL) gene inactivation status.
  
  
  RESULTS
  Lower baseline angiopoietin-2 (Ang-2) and higher baseline matrix metalloproteinase-2 (MMP-2) levels were identified by both platforms as statistically significantly associated with tumor response. There were no significant correlations between VEGF-A or VEGFR3 SNPs and outcomes. Progression-free survival was longer for HIF-1α percent of tumor expression groups 0-2 (HIF-1α low) versus 3-4 (HIF-1α high; p = 0.034). There were no significant correlations between outcomes and each VHL inactivation mechanism [mutation (86% of VHL-inactive patients), methylation (14%), and large deletion (7%)] or mechanisms combined.
  
  
  CONCLUSIONS
  Serum Ang-2 and MMP-2 and tumor HIF-1α were identified as relevant baseline biomarkers of sunitinib activity in advanced RCC, warranting further research into their prognostic versus predictive value.
authors.affiliation: Department of Medicine, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Motzer
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Hutson
authors.forename: Gary R
authors.initials: GR
authors.lastname: Hudes
authors.forename: Robert A
authors.initials: RA
authors.lastname: Figlin
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Martini
authors.forename: Patricia A
authors.initials: PA
authors.lastname: English
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.forename: Olga
authors.initials: O
authors.lastname: Valota
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Williams
mesh_terms: D000328:Adult; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D042702:Angiopoietin-2 / Q000097:blood*; D000951:Antigens, Neoplasm / Q000097:blood / Q000235:genetics; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000097:blood / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D016903:Drug Monitoring / Q000379:methods; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000097:blood / Q000235:genetics; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000097:blood*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000077210:Sunitinib; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000097:blood / Q000235:genetics
chemical_list: D020533:Angiogenesis Inhibitors; D042702:Angiopoietin-2; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D040321:Vascular Endothelial Growth Factor Receptor-3; D020778:Matrix Metalloproteinase 2; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; D000077210:Sunitinib
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