title: von Hippel-Lindau gene status and response to vascular endothelial growth factor targeted therapy for metastatic clear cell renal cell carcinoma.
abstract: OBJECTIVE
  The von Hippel-Lindau (VHL) gene is often inactivated (by mutation or promoter hypermethylation) in renal cell carcinoma but the relation to therapeutic outcome is unclear.
  
  
  METHODS
  Patients with metastatic clear cell renal cell carcinoma with available baseline tumor samples who received vascular endothelial growth factor targeted therapy were included in analysis. Patient characteristics, VHL gene status and clinical outcome were documented. Our primary end point was to test for response rate in relation to VHL inactivation. Progression-free survival and overall survival in relation to VHL status were investigated as secondary end points.
  
  
  RESULTS
  A total of 123 patients were evaluable. Response rate, median progression-free survival and median overall survival were 37% (95% CI 28-46), 10.8 (95% CI 7.7-14.8) and 29.8 (CI not estimable) months, respectively. Patients with VHL inactivation had a response rate of 41% vs 31% for those with wild-type VHL (p = 0.34). Patients with loss of function mutations (frameshift, nonsense, splice and in-frame deletions/insertions) had a 52% response rate vs 31% with wild-type VHL (p = 0.04). On multivariate analysis the presence of a loss of function mutation remained an independent prognostic factor associated with improved response. Progression-free survival and overall survival were not significantly different based on VHL status.
  
  
  CONCLUSIONS
  To our knowledge this is the largest analysis investigating the impact of VHL inactivation on the outcome of vascular endothelial growth factor targeted agents in metastatic renal cell carcinoma. We did not find a statistically significant increase in response to vascular endothelial growth factor targeted agents in patients with VHL inactivation. Loss of function mutations identified a population of patients with a greater response. Investigation of downstream markers is under way.
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. toni_choueiri@dfci.harvard.edu
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
authors.forename: Susan A J
authors.initials: SA
authors.lastname: Vaziri
authors.forename: Erich
authors.initials: E
authors.lastname: Jaeger
authors.forename: Paul
authors.initials: P
authors.lastname: Elson
authors.forename: Laura
authors.initials: L
authors.lastname: Wood
authors.forename: Ish Prasad
authors.initials: IP
authors.lastname: Bhalla
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Small
authors.forename: Vivian
authors.initials: V
authors.lastname: Weinberg
authors.forename: Nancy
authors.initials: N
authors.lastname: Sein
authors.forename: Jeff
authors.initials: J
authors.lastname: Simko
authors.forename: Ali-Reza
authors.initials: AR
authors.lastname: Golshayan
authors.forename: Linda
authors.initials: L
authors.lastname: Sercia
authors.forename: Ming
authors.initials: M
authors.lastname: Zhou
authors.forename: Frederic M
authors.initials: FM
authors.lastname: Waldman
authors.forename: Brian I
authors.initials: BI
authors.lastname: Rini
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Bukowski
authors.forename: Ram
authors.initials: R
authors.lastname: Ganapathi
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000077784:Axitinib; D001557:Benzenesulfonates / Q000627:therapeutic use; D000068258:Bevacizumab; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D016009:Chi-Square Distribution; D017931:DNA Primers; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D007191:Indazoles / Q000627:therapeutic use; D007211:Indoles / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009362:Neoplasm Metastasis; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011379:Prognosis; D011725:Pyridines / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use; D000077157:Sorafenib; D000077210:Sunitinib; D015996:Survival Rate; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D006623:von Hippel-Lindau Disease / Q000235:genetics*
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D017931:DNA Primers; D007093:Imidazoles; D007191:Indazoles; D007211:Indoles; D010671:Phenylurea Compounds; D011725:Pyridines; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000068258:Bevacizumab; D000077157:Sorafenib; D000077784:Axitinib; D000077210:Sunitinib