Comprehensive Molecular Characterization and Response to Therapy in Fumarate Hydratase-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. Evidence for systemic therapy efficacy is lacking.

EXPERIMENTAL DESIGN

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 mutation plus IHC evidence of FH loss, were included.

RESULTS

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 germline variant. Five (16%) were negative for germline mutations; all had biallelic somatic loss. Somatic NGS (31/32 patients) revealed co-occurring mutation most frequently ( = 5). Compared with clear-cell RCC, FH-RCC had a lower mutation count (median 2 vs. 4; < 0.001) but higher fraction of genome altered (18.7% vs. 10.3%; = 0.001). A total of 26 patients were evaluable for response to systemic therapy: mTOR/VEGF combination ( = 18, ORR 44%), VEGF monotherapy ( = 15, ORR 20%), checkpoint inhibitor therapy ( = 8, ORR 0%), and mTOR monotherapy ( = 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.

CONCLUSIONS

Although most FH-RCC tumors are due to germline alterations, a significant portion result from biallelic somatic 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.