1. Molecular Subsets in Renal Cancer Determine Outcome to Checkpoint and Angiogenesis Blockade.
- Author
-
Motzer, Robert J., Banchereau, Romain, Hamidi, Habib, Powles, Thomas, McDermott, David, Atkins, Michael B., Escudier, Bernard, Liu, Li-Fen, Leng, Ning, Abbas, Alexander R., Fan, Jinzhen, Koeppen, Hartmut, Lin, Jennifer, Carroll, Susheela, Hashimoto, Kenji, Mariathasan, Sanjeev, Green, Marjorie, Tayama, Darren, Hegde, Priti S., and Schiff, Christina
- Subjects
- *
PROGRAMMED cell death 1 receptors , *RENAL cancer , *NEOVASCULARIZATION , *RENAL cell carcinoma , *FATTY acid oxidation , *KIDNEY tumors , *RETROLENTAL fibroplasia - 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. • Genomics of 823 RCC tumors, including 134 sarcomatoid tumors, reveals 7 subtypes • Subtype specific angiogenesis, immune, metabolic, stromal, and cell-cycle profiles • Differential prevalence of PBRM1 , KDM5C , CDKN2A/2B , and TP53 alterations in subsets • Differential outcomes to VEGF blockade alone or in combination with anti-PD-L1 Motzer et al. perform integrative multi-omics analyses of 823 renal cancer tumors from a randomized clinical trial. A robust molecular classification scheme, based on transcriptional and gene alteration profiles and differential clinical outcomes to VEGF blockade alone or in combination with anti-PD-L1, informs personalized treatment strategies and future therapeutic development in RCC. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF