Abstract A034: HIF-2-mediated gene expression is highest in metastatic and cluster-exclude clear cell renal cell carcinoma tumors

Abstract Introduction: Hypoxia inducible factor (HIF)-2 inhibitors are FDA-approved for the treatment of metastatic clear cell renal cell carcinoma (ccRCC). In theory, all ccRCC tumors should exhibit HIF-2 stabilization due to VHL silencing. However, many patients fail to respond to HIF-2 inhibitors. A biomarker to identify patients most likely to respond to HIF-2 inhibitors is needed. Methods: In this analysis, we explored a HIF-2 gene expression signature (Courtney et al., Clinical Cancer Research 2020) in two independent cohorts of patients with metastatic ccRCC. The two cohorts include a discovery multi-institutional cohort from VUMC, UTSW, and Rutgers that includes 205 tumor samples, including 12 matched primary:metastatic pairs. As a validation cohort, we utilized samples from the prospective phase 2 OPTIC RCC trial (NCT05361720), which includes 95 samples and 23 matched primary:metastatic pairs. Results: In the discovery cohort, the HIF-2 gene expression signature was higher in metastatic tumors than in primary tumors (p