Comprehensive Molecular Characterization and Response to Therapy in FH-Deficient Renal Cell Carcinoma.

PURPOSE Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare, aggressive form of RCC associated with hereditary leiomyomatosis and RCC syndrome (HLRCC). Evidence for systemic therapy efficacy is lacking. METHODS We studied clinical and genomic characteristics of FH-RCC, including response (ORR) to systemic therapies and next-generation sequencing (NGS). Patients with metastatic FH-RCC, defined by presence of pathogenic germline or somatic FH mutation plus immunohistochemical evidence of FH-loss, were included. RESULTS 28/32 included patients (median age 46; range 20-74; M:F, 20:12) underwent germline testing; 23 (82%) harbored a pathogenic FH germline variant. 5 (16%) were negative for germline FH mutations; all had biallelic somatic FH loss. Somatic NGS (31/32 patients) revealed co-occurring NF2 mutation most frequently (n=5). Compared to clear cell RCC, FH-RCC had lower mutation count (median 2 vs 4; p<0.001) but higher fraction of genome altered (18.7 vs 10.3%; p=0.001).26 patients were evaluable for response to systemic therapy: mTOR/VEGF combination (n=18, ORR 44%), VEGF monotherapy (n=15, ORR 20%), checkpoint inhibitor therapy (n=8, ORR 0%) and mTOR monotherapy (n=4, ORR 0%). No complete responses were seen. Median overall and progression-free survival were 21.9 months (95% CI: 14.3, 33.8) and 8.7 months (95% CI: 4.8, 12.3), respectively. CONCLUSION Although most FH-RCC tumors are due to germline FH alterations, a significant portion result from biallelic somatic FH loss. Both somatic and germline FH-RCC have similar molecular characteristics, with NF2 mutations, low TMB, and high fraction of the genome altered. Although immunotherapy alone produced no objective responses, combination mTOR/VEGF therapy showed encouraging results.