Active angiogenesis in metastatic renal cell carcinoma predicts clinical benefit to sunitinib-based therapy.
BACKGROUND
Sunitinib represents a widely used therapy for metastatic renal cell carcinoma patients. Even so, there is a group of patients who show toxicity without clinical benefit. In this work, we have analysed pivotal molecular targets involved in angiogenesis (vascular endothelial growth factor (VEGF)-A, VEGF receptor 2 (KDR), phosphorylated (p)KDR and microvascular density (MVD)) to test their potential value as predictive biomarkers of clinical benefit in sunitinib-treated renal cell carcinoma patients.


METHODS
Vascular endothelial growth factor-A, KDR and pKDR-Y1775 expression as well as CD31, for MVD visualisation, were determined by immunohistochemistry in 48 renal cell carcinoma patients, including 23 metastatic cases treated with sunitinib. Threshold was defined for each biomarker, and univariate and multivariate analyses for progression-free survival (PFS) and overall survival (OS) were carried out.


RESULTS
The HistoScore mean value obtained for VEGF-A was 121.6 (range, 10-300); for KDR 258.5 (range, 150-300); for pKDR-Y1775 10.8 (range, 0-65) and the mean value of CD31-positive structures for MVD visualisation was 49 (range, 10-126). Statistical differences for PFS (P=0.01) and OS (P=0.007) were observed for pKDR-Y1775 in sunitinib-treated patients. Importantly, pKDR-Y1775 expression remained significant after multivariate Cox analysis for PFS (P=0.01; HR: 5.35, 95% CI, 1.49-19.13) and for OS (P=0.02; HR: 5.13, 95% CI, 1.25-21.05).


CONCLUSIONS
Our results suggest that the expression of phosphorylated (i.e., activated) KDR in tumour stroma might be used as predictive biomarker for the clinical outcome in renal cell carcinoma first-line sunitinib-treated patients.
Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain.
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del Puerto-Nevado
Department of Pathology, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain.
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Rojo
Department of Pathology, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain.
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Zazo
Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain.
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Caramés
Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain.
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Rubio
Department of Pathology, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain.
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Vega
Department of Pathology, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain.
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Chamizo
Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain.
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Casado
Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain.
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Martínez-Useros
Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain.
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Rincón
Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain.
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Rodríguez-Remírez
Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain.
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Borrero-Palacios
Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain.
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Cristóbal
Department of Pathology, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain.
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Madoz-Gúrpide
Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain.
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Aguilera
Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain.
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García-Foncillas
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000098:blood supply* / Q000188:drug therapy / Q000401:mortality / Q000556:secondary; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D008297:Male; D055806:Microvessels / Q000473:pathology; D008875:Middle Aged; D015999:Multivariate Analysis; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D016016:Proportional Hazards Models; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D007211:Indoles; D010750:Phosphoproteins; D011758:Pyrroles; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077210:Sunitinib