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Analyses of Potential Predictive Markers and Survival Data for a Response to Sunitinib in Patients with Metastatic Renal Cell Carcinoma

BACKGROUND: Patients with metastatic clear cell renal cell carcinoma (ccRCC) are frequently treated with tyrosine kinase inhibitors (TKI) such as sunitinib. It inhibits angiogenic pathways by mainly targeting the receptors of VEGF and PDGF. In ccRCC, angiogenesis is characterized by the inactivation...

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Autores principales: Dornbusch, Juana, Zacharis, Aristeidis, Meinhardt, Matthias, Erdmann, Kati, Wolff, Ingmar, Froehner, Michael, Wirth, Manfred P., Zastrow, Stefan, Fuessel, Susanne
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3785463/
https://www.ncbi.nlm.nih.gov/pubmed/24086736
http://dx.doi.org/10.1371/journal.pone.0076386
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author Dornbusch, Juana
Zacharis, Aristeidis
Meinhardt, Matthias
Erdmann, Kati
Wolff, Ingmar
Froehner, Michael
Wirth, Manfred P.
Zastrow, Stefan
Fuessel, Susanne
author_facet Dornbusch, Juana
Zacharis, Aristeidis
Meinhardt, Matthias
Erdmann, Kati
Wolff, Ingmar
Froehner, Michael
Wirth, Manfred P.
Zastrow, Stefan
Fuessel, Susanne
author_sort Dornbusch, Juana
collection PubMed
description BACKGROUND: Patients with metastatic clear cell renal cell carcinoma (ccRCC) are frequently treated with tyrosine kinase inhibitors (TKI) such as sunitinib. It inhibits angiogenic pathways by mainly targeting the receptors of VEGF and PDGF. In ccRCC, angiogenesis is characterized by the inactivation of the von Hippel-Lindau gene (VHL) which in turn leads to the induction of HIF1α target genes such as CA9 and VEGF. Furthermore, the angiogenic phenotype of ccRCC is also reflected by endothelial markers (CD31, CD34) or other tumor-promoting factors like Ki67 or survivin. METHODS: Tissue microarrays from primary tumor specimens of 42 patients with metastatic ccRCC under sunitinib therapy were immunohistochemically stained for selected markers related to angiogenesis. The prognostic and predictive potential of theses markers was assessed on the basis of the objective response rate which was evaluated according to the RECIST criteria after 3, 6, 9 months and after last report (12–54 months) of sunitinib treatment. Additionally, VHL copy number and mutation analyses were performed on DNA from cryo-preserved tumor tissues of 20 ccRCC patients. RESULTS: Immunostaining of HIF-1α, CA9, Ki67, CD31, pVEGFR1, VEGFR1 and -2, pPDGFRα and -β was significantly associated with the sunitinib response after 6 and 9 months as well as last report under therapy. Furthermore, HIF-1α, CA9, CD34, VEGFR1 and -3 and PDGRFα showed significant associations with progression-free survival (PFS) and overall survival (OS). In multivariate Cox proportional hazards regression analyses high CA9 membrane staining and a response after 9 months were independent prognostic factors for longer OS. Frequently observed copy number loss and mutation of VHL gene lead to altered expression of VHL, HIF-1α, CA9, and VEGF. CONCLUSIONS: Immunoexpression of HIF-1α, CA9, Ki67, CD31, pVEGFR1, VEGFR1 and -2, pPDGFRα and -β in the primary tumors of metastatic ccRCC patients might support the prediction of a good response to sunitinib treatment.
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spelling pubmed-37854632013-10-01 Analyses of Potential Predictive Markers and Survival Data for a Response to Sunitinib in Patients with Metastatic Renal Cell Carcinoma Dornbusch, Juana Zacharis, Aristeidis Meinhardt, Matthias Erdmann, Kati Wolff, Ingmar Froehner, Michael Wirth, Manfred P. Zastrow, Stefan Fuessel, Susanne PLoS One Research Article BACKGROUND: Patients with metastatic clear cell renal cell carcinoma (ccRCC) are frequently treated with tyrosine kinase inhibitors (TKI) such as sunitinib. It inhibits angiogenic pathways by mainly targeting the receptors of VEGF and PDGF. In ccRCC, angiogenesis is characterized by the inactivation of the von Hippel-Lindau gene (VHL) which in turn leads to the induction of HIF1α target genes such as CA9 and VEGF. Furthermore, the angiogenic phenotype of ccRCC is also reflected by endothelial markers (CD31, CD34) or other tumor-promoting factors like Ki67 or survivin. METHODS: Tissue microarrays from primary tumor specimens of 42 patients with metastatic ccRCC under sunitinib therapy were immunohistochemically stained for selected markers related to angiogenesis. The prognostic and predictive potential of theses markers was assessed on the basis of the objective response rate which was evaluated according to the RECIST criteria after 3, 6, 9 months and after last report (12–54 months) of sunitinib treatment. Additionally, VHL copy number and mutation analyses were performed on DNA from cryo-preserved tumor tissues of 20 ccRCC patients. RESULTS: Immunostaining of HIF-1α, CA9, Ki67, CD31, pVEGFR1, VEGFR1 and -2, pPDGFRα and -β was significantly associated with the sunitinib response after 6 and 9 months as well as last report under therapy. Furthermore, HIF-1α, CA9, CD34, VEGFR1 and -3 and PDGRFα showed significant associations with progression-free survival (PFS) and overall survival (OS). In multivariate Cox proportional hazards regression analyses high CA9 membrane staining and a response after 9 months were independent prognostic factors for longer OS. Frequently observed copy number loss and mutation of VHL gene lead to altered expression of VHL, HIF-1α, CA9, and VEGF. CONCLUSIONS: Immunoexpression of HIF-1α, CA9, Ki67, CD31, pVEGFR1, VEGFR1 and -2, pPDGFRα and -β in the primary tumors of metastatic ccRCC patients might support the prediction of a good response to sunitinib treatment. Public Library of Science 2013-09-27 /pmc/articles/PMC3785463/ /pubmed/24086736 http://dx.doi.org/10.1371/journal.pone.0076386 Text en © 2013 Dornbusch et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Dornbusch, Juana
Zacharis, Aristeidis
Meinhardt, Matthias
Erdmann, Kati
Wolff, Ingmar
Froehner, Michael
Wirth, Manfred P.
Zastrow, Stefan
Fuessel, Susanne
Analyses of Potential Predictive Markers and Survival Data for a Response to Sunitinib in Patients with Metastatic Renal Cell Carcinoma
title Analyses of Potential Predictive Markers and Survival Data for a Response to Sunitinib in Patients with Metastatic Renal Cell Carcinoma
title_full Analyses of Potential Predictive Markers and Survival Data for a Response to Sunitinib in Patients with Metastatic Renal Cell Carcinoma
title_fullStr Analyses of Potential Predictive Markers and Survival Data for a Response to Sunitinib in Patients with Metastatic Renal Cell Carcinoma
title_full_unstemmed Analyses of Potential Predictive Markers and Survival Data for a Response to Sunitinib in Patients with Metastatic Renal Cell Carcinoma
title_short Analyses of Potential Predictive Markers and Survival Data for a Response to Sunitinib in Patients with Metastatic Renal Cell Carcinoma
title_sort analyses of potential predictive markers and survival data for a response to sunitinib in patients with metastatic renal cell carcinoma
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3785463/
https://www.ncbi.nlm.nih.gov/pubmed/24086736
http://dx.doi.org/10.1371/journal.pone.0076386
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