title: Sunitinib in urothelial cancer: clinical, pharmacokinetic, and immunohistochemical study of predictors of response.
abstract: BACKGROUND
  Sunitinib has activity in patients with metastatic urothelial cancer (UC), but most patients do not respond.
  
  
  OBJECTIVE
  To identify predictors of response to sunitinib.
  
  
  METHODS
  Seventy-seven patients with advanced UC received sunitinib on one of two schedules at a single institution. Blood pressure (BP), immunohistochemistry (IHC), and pharmacokinetic (PK) results were correlated with response to sunitinib.
  
  
  METHODS
  BP was assessed on day 1 and 28 of each cycle and on day 14 of cycle 1. IHC was performed on 55 samples from 38 cases using mammalian target of rapamycin and hypoxia-inducible factor (HIF) pathway marker antibodies. Blood samples for PK analysis were collected from 15 patients at three time points. Response was assessed using Response Evaluation Criteria in Solid Tumors criteria.
  
  
  CONCLUSIONS
  Sunitinib-induced hypertension predicted improved response when hypertension was categorized as a discrete (p = 0.02) or continuous variable (p = 0.005 [systolic BP] and p = 0.007 [diastolic BP]). The odds ratio of response was 12.5 (95% confidence interval, 1.95-246.8) for grade 3/4 hypertension compared with grade 0. Response was associated with low HIF-1α expression in primary (p = 0.07) tissue. A nonstatistically significant trend was seen for an association between greater drug concentration and best response. A correlation between expression markers within the same pathways was identified, phosphorylated-4EBP1 and phosphorylated-S6 (p = 6.5 × 10(-9)), and vascular endothelial growth factor receptor 2 and HIF-1α (p = 0.008). Results are limited by small numbers.
  
  
  CONCLUSIONS
  Clinical and molecular biomarkers of response to sunitinib may have clinical relevance and require prospective validation. There is an urgent need for predictive biomarkers to guide the management of UC.
authors.affiliation: Department of Medical Oncology, The Mater Hospital, Dublin, Ireland.
authors.forename: David J
authors.initials: DJ
authors.lastname: Gallagher
authors.forename: Hikmat
authors.initials: H
authors.lastname: Al-Ahmadie
authors.forename: Irina
authors.initials: I
authors.lastname: Ostrovnaya
authors.forename: Scott R
authors.initials: SR
authors.lastname: Gerst
authors.forename: Ashley
authors.initials: A
authors.lastname: Regazzi
authors.forename: Ilana
authors.initials: I
authors.lastname: Garcia-Grossman
authors.forename: Jamie
authors.initials: J
authors.lastname: Riches
authors.forename: Sivaraman K
authors.initials: SK
authors.lastname: Gounder
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Flaherty
authors.forename: Alisa
authors.initials: A
authors.lastname: Trout
authors.forename: Matthew I
authors.initials: MI
authors.lastname: Milowsky
authors.forename: Dean F
authors.initials: DF
authors.lastname: Bajorin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000037:antagonists & inhibitors*; D001794:Blood Pressure / Q000187:drug effects; D002295:Carcinoma, Transitional Cell / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D018797:Cell Cycle Proteins; D004334:Drug Administration Schedule; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis; D007150:Immunohistochemistry; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D016015:Logistic Models; D009519:New York City; D010750:Phosphoproteins / Q000032:analysis; D010766:Phosphorylation; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D000077210:Sunitinib; D058570:TOR Serine-Threonine Kinases / Q000032:analysis; D046888:Tissue Array Analysis; D016896:Treatment Outcome; D014571:Urologic Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D019459:Urothelium / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000032:analysis / Q000037:antagonists & inhibitors*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D010750:Phosphoproteins; D011758:Pyrroles; C546842:MTOR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D058570:TOR Serine-Threonine Kinases; D000077210:Sunitinib