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

Abstract

BackgroundPatients 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.MethodsTissue 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.ResultsImmunostaining 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.ConclusionsImmunoexpression 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.

A decade of pharmacogenomics research on tyrosine kinase inhibitors in metastatic renal cell cancer: a systematic review

“…Dornbusch et al [56] evaluated the immunoexpression of tumor protein markers in 42 patients with mRCC. They concluded that HIF-1a, CA9, Ki67, CD31, pVEGFR1, VEGFR1 and -2, pPDGFR-a and -b were associated with the response to sunitinib (P < 0.05) [56].…”

Wide spetcrum mutational analysis of metastatic renal cell cancer: a retrospective next generation sequencing approach

“…In addition, there is no clear-cut evidence that the ccRCC or the non-ccRCC histotypes respond differently to specific target therapies [9, 11]…”

Curcumin Promotes Cell Cycle Arrest and Inhibits Survival of Human Renal Cancer Cells by Negative Modulation of the PI3K/AKT Signaling Pathway

“…RCC is resistant to chemo-and radiotherapy; thus, surgical resection is still the first choice treatment of RCC [4]. As RCC is difficult to recognize clinically, nearly 30 % of the patients present with distant metastases at the time of the diagnosis [5,6]. Up to now, the prognosis for advanced or metastatic RCC is poor [7].…”