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

Abstract

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