Sunitinib in urothelial cancer: clinical, pharmacokinetic, and immunohistochemical study of predictors of response.
AuthorsGallagher, David J
Gerst, Scott R
Gounder, Sivaraman K
Milowsky, Matthew I
Bajorin, Dean F
AffiliationDepartment of Medical Oncology, The Mater Hospital, Dublin, Ireland.
MeSHAdaptor 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
Hypoxia-Inducible Factor 1, alpha Subunit/analysis
Indoles/administration & dosage/adverse effects/*pharmacokinetics
New York City
Pyrroles/administration & dosage/adverse effects/*pharmacokinetics
TOR Serine-Threonine Kinases/analysis
Tissue Array Analysis
Tumor Markers, Biological/analysis/*antagonists & inhibitors
Urologic Neoplasms/chemistry/*drug therapy/pathology
Vascular Endothelial Growth Factor Receptor-2/analysis/*antagonists & inhibitors
MetadataShow full item record
CitationEur Urol. 2011 Aug;60(2):344-9. Epub 2011 May 25.
AbstractBACKGROUND: 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.