Thumbnail Image
Publication

Sunitinib in urothelial cancer: clinical, pharmacokinetic, and immunohistochemical study of predictors of response.

Gallagher, David J
; 
Al-Ahmadie, Hikmat
; 
Ostrovnaya, Irina
; 
Gerst, Scott R
; 
Regazzi, Ashley
; 
Garcia-Grossman, Ilana
; 
Riches, Jamie
; 
Gounder, Sivaraman K
; 
Flaherty, Anne-Marie
; 
Trout, Alisa
... show 2 more
Author
Gallagher, David J
 Al-Ahmadie, Hikmat
 Ostrovnaya, Irina
 Gerst, Scott R
 Regazzi, Ashley
 Garcia-Grossman, Ilana
 Riches, Jamie
 Gounder, Sivaraman K
 Flaherty, Anne-Marie
 Trout, Alisa
 Milowsky, Matthew I
 Bajorin, Dean F
Advisors
Editors
Other Contributors
Departments
Department of Medical Oncology, The Mater Hospital, Dublin, Ireland.
Date
2012-02-01T11:08:47Z
Date Submitted
Keywords
Other Subjects
Subject Mesh
Adaptor Proteins, Signal Transducing/analysis
Angiogenesis Inhibitors/administration & dosage/adverse effects/*pharmacokinetics
Blood Pressure/drug effects
Carcinoma, Transitional Cell/chemistry/*drug therapy/pathology
Drug Administration Schedule
Humans
Hypertension/chemically induced
Hypoxia-Inducible Factor 1, alpha Subunit/analysis
*Immunohistochemistry
Indoles/administration & dosage/adverse effects/*pharmacokinetics
Logistic Models
New York City
Phosphoproteins/analysis
Phosphorylation
Pyrroles/administration & dosage/adverse effects/*pharmacokinetics
Retrospective Studies
Risk Assessment
Risk Factors
TOR Serine-Threonine Kinases/analysis
Tissue Array Analysis
Treatment Outcome
Tumor Markers, Biological/analysis/*antagonists & inhibitors
Urologic Neoplasms/chemistry/*drug therapy/pathology
Urothelium/chemistry/*drug effects/pathology
Vascular Endothelial Growth Factor Receptor-2/analysis/*antagonists & inhibitors
Planned Date
Start Date
Collaborators
Principal Investigators
Alternative Titles
Publisher
URI
https://hdl.handle.net/10147/207841
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. DESIGN, SETTING, AND PARTICIPANTS: 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. MEASUREMENTS: 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. RESULTS AND LIMITATIONS: 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-1alpha 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 x 10(-9)), and vascular endothelial growth factor receptor 2 and HIF-1alpha (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.
Language
eng
Citation
Eur Urol. 2011 Aug;60(2):344-9. Epub 2011 May 25.
ISSN
1873-7560 (Electronic)
0302-2838 (Linking)
eISSN
ISBN
DOI
10.1016/j.eururo.2011.05.034
PMID
21645967
PMCID
Sponsorships
Funding Sources
Funding Amounts
Grant Identifiers
Methodology
Duration
Ethical Approval