Potential markers investigated for sunitinib response in patients with metastatic ccRCC
Markers in primary tumors such as CA9, CD31, CD34, and VEGFR1/2 might serve as predictors of a good response to sunitinib treatment in patients with metastatic clear cell renal carcinoma (ccRCC).
"The inactivation of the von Hippel-Lindau gene (VHL) is a common event in ccRCC and finally leads to the induction of HIF1α target genes such as CA9 and VEGF," according a study presented at the 28th Annual European Association of Urology. "Besides VEGF, the VEGF and PDGF receptors also play an important role in angiogenesis that is reflected by the microvessel density (MVD).
“The tyrosine kinase inhibitor (TKI) sunitinib targets the receptors of VEGF and PDGF, among others, and is currently one of the standard treatment options for metastatic ccRCC."
According to the researchers, predictive biomarkers for TKI treatment response are currently lacking. In this study, primary tumors from ccRCC patients, who were later treated with sunitinib, were used for biomarker analyses. In the course of the study, DNA was isolated from cryo-preserved tumor tissue specimens from 20 ccRCC patients and then analyzed for VHL copy number and mutations. Tissue microarrays were prepared from 42 paraffin-embedded malignant and corresponding nonmalignant renal tissue specimens.
Immunohistochemical staining of VHL, CA9, PDGFRα, PDGFRβ, VEGFR1, VEGFR2, VEGFR3, CD31 and CD34 was assessed by a scoring system that included staining intensity, percentage of stained tumor cells, and vessel (endothelial) staining. The objective response rate was evaluated according to the RECIST criteria after 3, 6, and 9 months and after last report (12-54 months) of sunitinib treatment.
Copy number loss was observed in 60% of the patients and mutation of VHL was observed in 50%. A total of 40% of the cases showed both VHL changes. These VHL gene alterations were accompanied by a reduced VHL protein staining and an increased CA9 score.
After 9 months, 45% of the patients responded to sunitinib treatment. Their response was associated with low Fuhrman grade of the primary tumor (P <.05). The vessel staining of VEGFR1/2 was elevated in patients with a response after last report.
Patients with a response after 6 months exhibited an increased MVD and CA9 staining in the primary tumor (P <.05) and their estimated median progression free survival (12 months vs. 8 months; P <.001) and median overall survival (45 months vs. 21 months; P <.001) was longer than for nonresponders. High CA9 protein expression and low PDGFRα protein expression were associated with longer overall survival (P <.01).
This study was presented at the 28th Annual European Association of Urology Congress, which was held March 15-19, 2013, in Milan, Italy.