Molecular Subsets in Renal Cancer Determine Outcome to Checkpoint and Angiogenesis Blockade.

Abstract

Integrated multi-omics evaluation of 823 tumors from advanced renal cell carcinoma (RCC) patients identifies molecular subsets associated with differential clinical outcomes to angiogenesis blockade alone or with a checkpoint inhibitor. Unsupervised transcriptomic analysis reveals seven molecular subsets with distinct angiogenesis, immune, cell-cycle, metabolism, and stromal programs. While sunitinib and atezolizumab + bevacizumab are effective in subsets with high angiogenesis, atezolizumab + bevacizumab improves clinical benefit in tumors with high T-effector and/or cell-cycle transcription. Somatic mutations in PBRM1 and KDM5C associate with high angiogenesis and AMPK/fatty acid oxidation gene expression, while CDKN2A/B and TP53 alterations associate with increased cell-cycle and anabolic metabolism. Sarcomatoid tumors exhibit lower prevalence of PBRM1 mutations and angiogenesis markers, frequent CDKN2A/B alterations, and increased PD-L1 expression. These findings can be applied to molecularly stratify patients, explain improved outcomes of sarcomatoid tumors to checkpoint blockade versus antiangiogenics alone, and develop personalized therapies in RCC and other indications.

• Authors: Robert J Motzer, Romain Banchereau, Habib Hamidi, Thomas Powles, David McDermott, Michael B Atkins, Bernard Escudier, Li-Fen Liu, Ning Leng, Alexander R Abbas, Jinzhen Fan, Hartmut Koeppen, Jennifer Lin, Susheela Carroll, Kenji Hashimoto, Sanjeev Mariathasan, Marjorie Green, Darren Tayama, Priti S Hegde, Christina Schiff, Mahrukh A Huseni, Brian Rini
• Journal: Cancer cell (Cancer Cell) Vol. 38 Issue 6 Pg. 803-817.e4 (12 14 2020) ISSN: 1878-3686 [Electronic] United States
• PMID: 33157048 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Angiogenesis Inhibitors
• Antibodies, Monoclonal, Humanized
• Biomarkers, Tumor
• Immune Checkpoint Inhibitors
• Bevacizumab
• atezolizumab
• Sunitinib

Topics

• Angiogenesis Inhibitors (pharmacology, therapeutic use)
• Antibodies, Monoclonal, Humanized (pharmacology, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Bevacizumab (pharmacology, therapeutic use)
• Biomarkers, Tumor (genetics)
• Carcinoma, Renal Cell (drug therapy, genetics)
• Clinical Trials, Phase III as Topic
• Computational Biology (methods)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Immune Checkpoint Inhibitors (pharmacology, therapeutic use)
• Kidney Neoplasms (drug therapy, genetics)
• Prognosis
• Randomized Controlled Trials as Topic
• Sequence Analysis, RNA
• Sunitinib (pharmacology, therapeutic use)
• Treatment Outcome
• Unsupervised Machine Learning