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

Hdl Handle:
http://hdl.handle.net/10147/207841
Title:
Sunitinib in urothelial cancer: clinical, pharmacokinetic, and immunohistochemical study of predictors of response.
Authors:
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
Affiliation:
Department of Medical Oncology, The Mater Hospital, Dublin, Ireland.
Citation:
Eur Urol. 2011 Aug;60(2):344-9. Epub 2011 May 25.
Journal:
European urology
Issue Date:
1-Feb-2012
URI:
http://hdl.handle.net/10147/207841
DOI:
10.1016/j.eururo.2011.05.034
PubMed ID:
21645967
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
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
ISSN:
1873-7560 (Electronic); 0302-2838 (Linking)

Full metadata record

DC FieldValue Language
dc.contributor.authorGallagher, David Jen_GB
dc.contributor.authorAl-Ahmadie, Hikmaten_GB
dc.contributor.authorOstrovnaya, Irinaen_GB
dc.contributor.authorGerst, Scott Ren_GB
dc.contributor.authorRegazzi, Ashleyen_GB
dc.contributor.authorGarcia-Grossman, Ilanaen_GB
dc.contributor.authorRiches, Jamieen_GB
dc.contributor.authorGounder, Sivaraman Ken_GB
dc.contributor.authorFlaherty, Anne-Marieen_GB
dc.contributor.authorTrout, Alisaen_GB
dc.contributor.authorMilowsky, Matthew Ien_GB
dc.contributor.authorBajorin, Dean Fen_GB
dc.date.accessioned2012-02-01T11:08:47Z-
dc.date.available2012-02-01T11:08:47Z-
dc.date.issued2012-02-01T11:08:47Z-
dc.identifier.citationEur Urol. 2011 Aug;60(2):344-9. Epub 2011 May 25.en_GB
dc.identifier.issn1873-7560 (Electronic)en_GB
dc.identifier.issn0302-2838 (Linking)en_GB
dc.identifier.pmid21645967en_GB
dc.identifier.doi10.1016/j.eururo.2011.05.034en_GB
dc.identifier.urihttp://hdl.handle.net/10147/207841-
dc.description.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.en_GB
dc.language.isoengen_GB
dc.subject.meshAdaptor Proteins, Signal Transducing/analysisen_GB
dc.subject.meshAngiogenesis Inhibitors/administration & dosage/adverse effects/*pharmacokineticsen_GB
dc.subject.meshBlood Pressure/drug effectsen_GB
dc.subject.meshCarcinoma, Transitional Cell/chemistry/*drug therapy/pathologyen_GB
dc.subject.meshDrug Administration Scheduleen_GB
dc.subject.meshHumansen_GB
dc.subject.meshHypertension/chemically induceden_GB
dc.subject.meshHypoxia-Inducible Factor 1, alpha Subunit/analysisen_GB
dc.subject.mesh*Immunohistochemistryen_GB
dc.subject.meshIndoles/administration & dosage/adverse effects/*pharmacokineticsen_GB
dc.subject.meshLogistic Modelsen_GB
dc.subject.meshNew York Cityen_GB
dc.subject.meshPhosphoproteins/analysisen_GB
dc.subject.meshPhosphorylationen_GB
dc.subject.meshPyrroles/administration & dosage/adverse effects/*pharmacokineticsen_GB
dc.subject.meshRetrospective Studiesen_GB
dc.subject.meshRisk Assessmenten_GB
dc.subject.meshRisk Factorsen_GB
dc.subject.meshTOR Serine-Threonine Kinases/analysisen_GB
dc.subject.meshTissue Array Analysisen_GB
dc.subject.meshTreatment Outcomeen_GB
dc.subject.meshTumor Markers, Biological/analysis/*antagonists & inhibitorsen_GB
dc.subject.meshUrologic Neoplasms/chemistry/*drug therapy/pathologyen_GB
dc.subject.meshUrothelium/chemistry/*drug effects/pathologyen_GB
dc.subject.meshVascular Endothelial Growth Factor Receptor-2/analysis/*antagonists & inhibitorsen_GB
dc.titleSunitinib in urothelial cancer: clinical, pharmacokinetic, and immunohistochemical study of predictors of response.en_GB
dc.contributor.departmentDepartment of Medical Oncology, The Mater Hospital, Dublin, Ireland.en_GB
dc.identifier.journalEuropean urologyen_GB
dc.description.provinceLeinster-

Related articles on PubMed

All Items in Lenus, The Irish Health Repository are protected by copyright, with all rights reserved, unless otherwise indicated.