Beschreibung:
<jats:p> 445 </jats:p><jats:p> Background: Von Hippel Lindau ( VHL) gene function is uniformly lost in clear cell renal cell carcinoma (ccRCC) with consequent accumulation of hypoxia inducible factor 2 alpha (HIF-2α). HIF-2α inhibitors have entered the clinical arena as a new class of agents, alone and in combinations. While VHL loss is thought to result in broad increase of HIF-2α activity, preclinical data suggests that HIF-2α target activation varies across patients. Xenograft response to HIF-2α inhibition helped define an RNA-based HIF-2α target signature (SIG) comprising 277 genes downregulated with treatment (Courtney et al. CCR 2020). We applied this signature in our analysis of two large cohorts. Methods: Retrospective analyses were conducted using two cohorts: 533 tumors from the Cancer Genome Atlas Project (TCGA) with emphasis on early-stage disease and 409 archival tumors collected from patients receiving pazopanib or sunitinib on the phase 3 COMPARZ trial in metastatic RCC. Using single-sample gene set enrichment analysis (ssGSEA), enrichment scores were calculated for HIF-2α-SIG and a previously validated 6 gene tumor angiogenesis SIG (McDermott et al. Nat Med 2020). Individual patients were classified as “high” vs “low” for each (enrichment scores < vs ≥ median). We tested associations of HIF-2α and angiogenesis scores with overall survival (OS) using the Kaplan Meier Method and log-rank comparison. Results: In the TCGA cohort, patients with “high” HIF-2α-SIG had inferior median OS compared to those with “low” levels (69 months [95% CI 53-117] vs 'not reached', log-rank p<0.0001). In the metastatic COMPARZ cohort, “high” HIF-2α-SIG associated adversely with median OS (27 months [95% CI 21-32] vs 36 months [95% CI 28-not reached], log-rank p=0.0240) while angiogenesis scores associated favorably. In both cohorts the majority of HIF-2α “high” patients categorized “low” for angiogenesis and vice versa. Associations amongst HIF-2α-SIG, angiogenesis-SIG, and OS are summarized below (Table). Conclusions: HIF-2α target activation was adversely associated with survival in early and late stage ccRCC while angiogenesis scores correlated favorably. HIF-2α targets other than VEGF appear to have clinical impact and should be explored. HIF-2α-SIG may prove helpful for clinical development of targeted HIF-2α inhibitors and deserves further study.[Table: see text] </jats:p>