A cytokine and angiogenic factor (CAF) analysis in plasma for selection of sorafenib therapy in patients with metastatic renal cell carcinoma

• Published in: Annals of oncology Vol. 23; no. 1; pp. 46 - 52
• Main Authors: Zurita, A.J., Jonasch, E., Wang, X., Khajavi, M., Yan, S., Du, D.Z., Xu, L., Herynk, M.H., McKee, K.S., Tran, H.T., Logothetis, C.J., Tannir, N.M., Heymach, J.V.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.01.2012; Oxford University Press
• Subjects: Antineoplastic agents; Antineoplastic Agents - therapeutic use; Benzenesulfonates - therapeutic use; Biological and medical sciences; Biomarkers, Tumor - blood; CAF profiling; Carcinoma, Renal Cell - blood; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - mortality; Cluster Analysis; Cytokines - blood; Disease-Free Survival; Enzyme-Linked Immunosorbent Assay; Humans; interferon; Interferon-alpha - administration & dosage; Kaplan-Meier Estimate; Kidney Neoplasms - blood; Kidney Neoplasms - drug therapy; Kidney Neoplasms - mortality; Kidneys; Medical sciences; Nephrology. Urinary tract diseases; Niacinamide - analogs & derivatives; Original; Pharmacology. Drug treatments; Phenylurea Compounds; Pyridines - therapeutic use; RCC combinations; renal cell carcinoma; Sorafenib; Tumors of the urinary system; Vascular Endothelial Growth Factor A - blood; CAF profiling; renal cell carcinoma; RCC combinations; sorafenib; interferon; Antineoplastic agent; Biological fluid; Carcinoma; Angiogenic factor; Selection; Metastasis; Blood plasma; Angiogenesis; Grawitz tumor; Advanced stage; Antiangiogenic agent; Kidney disease; Human; Urinary system disease; Tyrosine kinase inhibitor; Cell antiviral factor; Cytokine; Enzyme inhibitor; Patient; Malignant tumor; Treatment; Analysis; Sorafenib; Kidney cancer; Interferon; Multikinase inhibitor; Cancer
• ISSN: 0923-7534; 1569-8041
• DOI: 10.1093/annonc/mdr047

We investigated cytokines and angiogenic factors (CAFs) in patients with metastatic renal cell carcinoma (mRCC) treated in a randomized phase II clinical trial of sorafenib versus sorafenib+ interferon-α (IFN-α) that yielded no differences in progression-free survival (PFS). We aimed to link the CAF profile to PFS and select candidate predictive and prognostic markers for further study. The concentrations of 52 plasma CAFs were measured pretreatment (n = 69), day 28, and day 56 using multiplex bead arrays and enzyme-linked immunosorbent assay. We investigated the association between baseline levels of CAFs with PFS and posttreatment changes. Unsupervised CAF clustering analysis revealed two distinct mRCC patient groups with elevated proangiogenic or proinflammatory mediators. A six-marker baseline CAF signature [osteopontin, vascular endothelial growth factor (VEGF), carbonic anhydrase 9, collagen IV, VEGF receptor-2, and tumor necrosis factor-related apoptosis-inducing ligand] correlated with PFS benefit (hazard ratio 0.20 versus 2.25, signature negative versus positive, respectively; P = 0.0002). While changes in angiogenic factors were frequently attenuated by the sorafenib+ IFN combination, most key immunomodulatory mediators increased. Using CAF profiling, we identified two mRCC patient groups, a candidate plasma signature for predicting PFS benefit, and distinct marker changes occurring with each treatment. This platform may provide valuable insights into renal cell carcinoma biology and the molecular consequences of targeted therapies.