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

Ann Oncol. 2012 Jan;23(1):46-52. doi: 10.1093/annonc/mdr047. Epub 2011 Apr 4.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / therapeutic use
  • Benzenesulfonates / therapeutic use
  • Biomarkers, Tumor / blood*
  • 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-alpha / administration & dosage
  • Kaplan-Meier Estimate
  • Kidney Neoplasms / blood*
  • Kidney Neoplasms / drug therapy
  • Kidney Neoplasms / mortality
  • Niacinamide / analogs & derivatives
  • Phenylurea Compounds
  • Pyridines / therapeutic use
  • Sorafenib
  • Vascular Endothelial Growth Factor A / blood*

Substances

  • Antineoplastic Agents
  • Benzenesulfonates
  • Biomarkers, Tumor
  • Cytokines
  • Interferon-alpha
  • Phenylurea Compounds
  • Pyridines
  • Vascular Endothelial Growth Factor A
  • Niacinamide
  • Sorafenib