Correlation Between Molecular Subclassifications of Clear Cell Renal Cell Carcinoma and Targeted Therapy Response

Thai H. Ho, Toni K. Choueiri, Kai Wang, Jose A. Karam, Zachary Chalmers, Garrett Frampton, Julia A. Elvin, Adrienne Johnson, Xueli Liu, Yulan Lin, Richard W. Joseph, Melissa L. Stanton, Vincent A. Miller, Philip J. Stephens, Jeffrey S. Ross, Siraj M. Ali, Sumanta K. Pal

Vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR)-directed therapies are the standard of care in metastatic clear cell renal cell carcinoma (mccRCC) but are not used based on molecular subclassifications of ccRCC. To determine if an association exists between genomic alterations (GAs) detected by comprehensive genomic profiling (CGP) in the course of clinical care and the response to anti-VEGF receptor (VEGFR) and anti-MTOR pathway targeted therapies in a cohort of patients with treated mccRCC. CGP, using a Clinical Laboratory Improvement Amendments-certified platform, was performed on 31 formalin-fixed, paraffin-embedded tissue specimens (84% from cytoreductive nephrectomies) obtained from patients with metastatic renal cell carcinoma who had received VEGFR and/or mTOR inhibitors. Duration of treatment (DOT) and extent and duration of clinical response were obtained from review of medical records. All classes of GAs-base substitutions, short insertions, deletions, gene fusions, rearrangements, and copy number-were assessed via hybrid capture-based CGP. Descriptive statistics were used to determine the frequency of GAs in groups segregated by the DOT with VEGF-directed agents. The most common GAs detected in this series were in VHL (70%), PBRM1 (48%), SETD2 (32%), TSC1 (29%), MLL (19%), TERT (16%), ARID1B (16%), and KDM5C (16%). Across 61 administrations of VEGF-directed therapy in 27 patients, exceptional responses (DOT >21 mo) were more frequent among patients with GAs in KDM5C, PBRM1, and VHL. Conversely, these patients also featured a lower frequency of GA associated with response to mTOR-directed therapy, such as TSC1. Molecular subclassifications may affect response to VEGF-directed therapy. The predictive and prognostic nature of these molecular subclassifications in the metastatic setting should be explored in an extended series. Comprehensive genomic profiling in the course of clinical care in the community oncology setting can delineate subgroups of patients with advanced kidney cancer who stand to benefit more from specific molecular-targeted agents.