title: The effect of VEGF-targeted therapy on biomarker expression in sequential tissue from patients with metastatic clear cell renal cancer.
abstract: OBJECTIVE
  To investigate how biologically relevant markers change in response to antiangiogenic therapy in metastatic clear cell renal cancer (mRCC) and correlate these changes with outcome.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Authors' Affiliations: Barts Cancer Institute, Queen Mary University of London; Experimental Cancer Medicine Centre, University College; The Institute of Cancer Research; Guys and St Thomas' Hospital; The Royal Free Hospital London, London; Edinburgh Urological Cancer Group, University of Edinburgh, Edinburgh; Astra Zeneca, Manchester; School of Medicine, University of St Andrews, Fife, United Kingdom; National Cancer Institute, Amsterdam, the Netherlands; and University of Ghent, Ghent, Belgium.
authors.forename: Kevin
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authors.lastname: Sharpe
authors.forename: Grant D
authors.initials: GD
authors.lastname: Stewart
authors.forename: Alan
authors.initials: A
authors.lastname: Mackay
authors.forename: Christophe
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authors.lastname: Van Neste
authors.forename: Charlotte
authors.initials: C
authors.lastname: Rofe
authors.forename: Dan
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authors.lastname: Berney
authors.forename: Irfan
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authors.lastname: Kayani
authors.forename: Axel
authors.initials: A
authors.lastname: Bex
authors.forename: Elaine
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authors.lastname: Wan
authors.forename: Fiach C
authors.initials: FC
authors.lastname: O'Mahony
authors.forename: Marie
authors.initials: M
authors.lastname: O'Donnell
authors.forename: Simon
authors.initials: S
authors.lastname: Chowdhury
authors.forename: Rukma
authors.initials: R
authors.lastname: Doshi
authors.forename: Colan
authors.initials: C
authors.lastname: Ho-Yen
authors.forename: Marco
authors.initials: M
authors.lastname: Gerlinger
authors.forename: Dawn
authors.initials: D
authors.lastname: Baker
authors.forename: Neil
authors.initials: N
authors.lastname: Smith
authors.forename: Barry
authors.initials: B
authors.lastname: Davies
authors.forename: Anju
authors.initials: A
authors.lastname: Sahdev
authors.forename: Ekaterini
authors.initials: E
authors.lastname: Boleti
authors.forename: Tim
authors.initials: T
authors.lastname: De Meyer
authors.forename: Wim
authors.initials: W
authors.lastname: Van Criekinge
authors.forename: Luis
authors.initials: L
authors.lastname: Beltran
authors.forename: Yong-Jie
authors.initials: YJ
authors.lastname: Lu
authors.forename: David J
authors.initials: DJ
authors.lastname: Harrison
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Reynolds
authors.forename: Tom
authors.initials: T
authors.lastname: Powles
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D055028:Comparative Genomic Hybridization; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019394:Ki-67 Antigen / Q000096:biosynthesis; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A