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.
RCT Entities:
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.
Authors: Robert J Motzer; Thomas E Hutson; Piotr Tomczak; M Dror Michaelson; Ronald M Bukowski; Olivier Rixe; Stéphane Oudard; Sylvie Negrier; Cezary Szczylik; Sindy T Kim; Isan Chen; Paul W Bycott; Charles M Baum; Robert A Figlin Journal: N Engl J Med Date: 2007-01-11 Impact factor: 91.245
Authors: James C Yang; Leah Haworth; Richard M Sherry; Patrick Hwu; Douglas J Schwartzentruber; Suzanne L Topalian; Seth M Steinberg; Helen X Chen; Steven A Rosenberg Journal: N Engl J Med Date: 2003-07-31 Impact factor: 91.245
Authors: Brian I Rini; Susan Halabi; Jonathan E Rosenberg; Walter M Stadler; Daniel A Vaena; San-San Ou; Laura Archer; James N Atkins; Joel Picus; Piotr Czaykowski; Janice Dutcher; Eric J Small Journal: J Clin Oncol Date: 2008-10-20 Impact factor: 44.544
Authors: Samuel E Deprimo; Carlo L Bello; John Smeraglia; Charles M Baum; Dominic Spinella; Brian I Rini; M Dror Michaelson; Robert J Motzer Journal: J Transl Med Date: 2007-07-02 Impact factor: 5.531
Authors: Nicholas J Farber; Christopher J Kim; Parth K Modi; Jane D Hon; Evita T Sadimin; Eric A Singer Journal: Transl Cancer Res Date: 2017-06 Impact factor: 1.241
Authors: Wenxin Xu; Maneka Puligandla; Judith Manola; Andrea J Bullock; Daniel Tamasauskas; David F McDermott; Michael B Atkins; Naomi B Haas; Keith Flaherty; Robert G Uzzo; Janice P Dutcher; Robert S DiPaola; Rupal S Bhatt Journal: Clin Cancer Res Date: 2019-08-30 Impact factor: 12.531
Authors: Nilofer Azad; Minshu Yu; Ben Davidson; Peter Choyke; Clara C Chen; Bradford J Wood; Aradhana Venkatesan; Ryan Henning; Kathy Calvo; Lori Minasian; Daniel C Edelman; Paul Meltzer; Seth M Steinberg; Christina M Annunziata; Elise C Kohn Journal: Mol Cell Proteomics Date: 2013-02-28 Impact factor: 5.911
Authors: Taofeek K Owonikoko; Mohammad S Hossain; Chandar Bhimani; Zhengjia Chen; Sungjin Kim; Suresh S Ramalingam; Shi-Yong Sun; Dong M Shin; Edmund K Waller; Fadlo R Khuri Journal: Cancer Date: 2013-01-22 Impact factor: 6.860