Metastasis remains the main reason for renal cell carcinoma (RCC)-associated mortality. Tyrosine kinase inhibitors (TKI) impart clinical benefit for most RCC patients but the determinants of response are poorly understood. We report an integrated genomic and transcriptomic analysis of metastatic clear cell RCC (ccRCC) patients treated with TKI therapy and identify predictors of response. Patients in the COMPARZ phase III trial received first-line sunitinib or pazopanib with comparable efficacy. RNA-based analyses revealed four distinct molecular subgroups associated with response and survival. Characterization of these subgroups identified mutation profiles, angiogenesis and macrophage infiltration programs to be powerful predictors of outcome with TKI therapy. Notably, predictors differed by the type of TKI received. Our study emphasizes the clinical significance of angiogenesis and immune tumor microenvironment and suggests the critical effects its various aspects have on TKI efficacy vary by agent. This has broad implications for optimizing precision treatment of RCC.
Cancer discovery. 2019 Jan 08 [Epub ahead of print]
A Ari Hakimi, Martin H Voss, Fengshen Kuo, Alejandro Sanchez, Ming Liu, Briana G Nixon, Lynda Vuong, Irina Ostrovnaya, Ying-Bei Chen, Victor Reuter, Nadeem Riaz, Yuan Cheng, Parul Patel, Mahtab Marker, Albert Reising, Ming O Li, Timothy A Chan, Robert J Motzer
Surgery - Urology Service, Memorial Sloan Kettering Cancer Center ., GU oncology, Memorial Sloan Kettering Cancer Center., Immunogenomics & Precision Oncology Platform, Memorial Sloan Kettering Cancer Center., Urology, Memorial Sloan Kettering Cancer Center., Immunology program, Memorial Sloan Kettering Cancer Center., Immunogenomics and Precision Oncology Platform, MSKCC., Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center., Department of Pathology, Memorial Sloan Kettering Cancer Center., Pathology, Memorial Sloan Kettering Cancer Center., Radiation Oncology, Memorial Sloan Kettering Cancer Center., Novartis Pharma AG., Oncology, Novartis Oncology., Statistics, Novartis Oncology., Oncology Precision Medicine, Novartis Oncology., Memorial Sloan Kettering Cancer Center., Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center., Department of Medicine, Memorial Sloan Kettering Cancer Center.