Analyses of potential predictive markers and survival data for a response to sunitinib in patients with metastatic renal cell carcinoma

• Published in: PloS one Vol. 8; no. 9; p. e76386
• Main Authors: Dornbusch, Juana, Zacharis, Aristeidis, Meinhardt, Matthias, Erdmann, Kati, Wolff, Ingmar, Froehner, Michael, Wirth, Manfred P, Zastrow, Stefan, Fuessel, Susanne
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 27-09-2013; Public Library of Science (PLoS)
• Subjects: Angiogenesis; Angiogenesis Inhibitors - antagonists & inhibitors; Angiogenesis Inhibitors - therapeutic use; Antigens, Neoplasm - metabolism; Apoptosis; Biomarkers; Biomarkers, Tumor - metabolism; Cancer therapies; Carbonic Anhydrase IX; Carbonic Anhydrases - metabolism; Carcinoma, Renal Cell - drug therapy; CD34 antigen; Cell cycle; Cell growth; Clear cell-type renal cell carcinoma; Copy number; Deactivation; Deoxyribonucleic acid; DNA; DNA microarrays; DNA Mutational Analysis; Gene expression; Hazards; Hippel-Lindau gene; Humans; Hypertension; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Immunohistochemistry; Inactivation; Indoles - therapeutic use; Ki-67 Antigen - metabolism; Kidney cancer; Kidney Neoplasms - drug therapy; Kinases; Markers; Medical prognosis; Metastases; Metastasis; Mutation; Neoplasia; Neovascularization, Pathologic - metabolism; Patients; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism; Platelet-derived growth factor; Predictions; Prognosis; Proportional Hazards Models; Protein expression; Protein-tyrosine kinase; Proteins; Pyrroles - therapeutic use; Receptors; Regression analysis; Signal transduction; Sunitinib; Survival; Survivin; Therapy; Time Factors; Tissue Array Analysis; Tissues; Tumors; Tyrosine; Urology; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-1 - metabolism; VHL protein; Von Hippel-Lindau Tumor Suppressor Protein - metabolism; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0076386

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.
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.
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.
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.