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.
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.
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.
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.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021 Mar 03 [Epub ahead of print]
Jack P Gleeson, Ines Nikolovski, Renzo G DiNatale, Mark Zucker, Andrea Knezevic, Sujata Patil, Yasser Ged, Ritesh R Kotecha, Natalie Shapnik, Samuel Murray, Paul Russo, Jonathan Coleman, Chung-Han Lee, Zsofia K Stadler, A Ari Hakimi, Darren R Feldman, Robert J Motzer, Ed Reznik, Martin H Voss, Ying-Bei Chen, Maria I Carlo
Genitourinary Oncology, Memorial Sloan Kettering Cancer Center., Radiology, Memorial Sloan Kettering Cancer Center., Surgery - Urology Service, Memorial Sloan Kettering Cancer Center., Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center., Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center., Quantitative Health Sciences, Cleveland Clinic., Genitourinary Oncology, Johns Hopkins Medicine., Department of Medicine, Memorial Sloan Kettering Cancer Center., Memorial Sloan Kettering Cancer Center., Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center., Surgery- Urology service, Memorial Sloan Kettering., Surgery, Urology Service, Memorial Sloan Kettering Cancer Center., Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College., Medicine, Memorial Sloan Kettering Cancer Center., Computational Oncology, Memorial Sloan Kettering Cancer Center., GU oncology, Memorial Sloan Kettering Cancer Center., Department of Pathology, Memorial Sloan Kettering Cancer Center., Medicine, Memorial Sloan Kettering Cancer Center .