The effect of VEGF targeted therapy on biomarker expression in sequential tissue from patients with metastatic clear cell renal cancer

Kevin Sharpe, Grant D Stewart, Alan Mackay, Christophe Van Neste, Charlotte Rofe, Daniel M Berney, Irfan Kayani, Axel Bex, Elaine Wan, Fiach O'Mahony, Marie O'Donnell, Simon Chowdhury, Rukma Doshi, Colan Ho Yen, Marco Gerlinger, Dawn Baker, Neil R Smith, Barry R Davies, Anju Sahdev, Ekaterini BoletiTim de Meyer, Wim Van Criekinge, Luis Beltran, Yong-Jie Lu, David Harrison, Andrew R Reynolds, Thomas Powles

Research output: Contribution to journalArticlepeer-review

Abstract

To investigate how biologically relevant markers change in response to anti-angiogenic therapy in metastatic renal cell carcinoma (mRCC) and correlate these changes with outcome.
Experimental Design: The study used sequential tumor tissue and functional imaging (taken at baseline and 12-16 weeks) obtained from three similar phase II studies. All three studies investigated the role of VEGF tyrosine kinase inhibitors (TKI) before planned nephrectomy in untreated mRCC (n = 85). The effect of targeted therapy on ten biomarkers was measured from sequential tissue. Comparative genomic hybridization (CGH) array and DNA methylation profiling (MethylCap-seq) was performed in matched frozen pairs. Biomarker expression was correlated with early progression (progression as best response) and delayed progression (between 12-16 weeks).

Results: VEGF TKI treatment caused a significant reduction in vessel density (CD31), phospho-S6K expression, PDL-1 expression, and FOXP3 expression (P < 0.05 for each). It also caused a significant increase in cytoplasmic FGF-2, MET receptor expression in vessels, Fuhrman tumor grade, and Ki-67 (P < 0.05 for each). Higher levels of Ki-67 and CD31 were associated with delayed progression (P < 0.05). Multiple samples (n = 5) from the same tumor showed marked heterogeneity of tumor grade, which increased significantly with treatment. Array CGH showed extensive intrapatient variability, which did not occur in DNA methylation analysis.

Conclusion: TKI treatment is associated with dynamic changes in relevant biomarkers, despite significant heterogeneity in chromosomal and protein, but not epigenetic expression. Changes to Ki-67 expression and tumor grade indicate that treatment is associated with an increase in the aggressive phenotype of the tumor. (C)2013 AACR.
Original languageEnglish
Pages (from-to)6294-6934
Number of pages11
JournalClinical Cancer Research
Volume19
Issue number24
Early online date15 Oct 2013
DOIs
Publication statusPublished - 15 Dec 2013

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