Comprehensive molecular characterization and response to therapy in fumarate hydratase-deficient renal cell carcinoma Journal Article
| Authors: | Gleeson, J. P.; Nikolovski, I.; Dinatale, R.; Zucker, M.; Knezevic, A.; Patil, S.; Ged, Y.; Kotecha, R. R.; Shapnik, N.; Murray, S.; Russo, P.; Coleman, J.; Lee, C. H.; Stadler, Z. K.; Ari Hakimi, A.; Feldman, D. R.; Motzer, R. J.; Reznik, E.; Voss, M. H.; Chen, Y. B.; Carlo, M. I. |
| Article Title: | Comprehensive molecular characterization and response to therapy in fumarate hydratase-deficient renal cell carcinoma |
| Abstract: | 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 FH 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 FH germline variant. Five (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 1⁄4 5). Compared with clear-cell RCC, FH-RCC had a lower mutation count (median 2 vs. 4; P < 0.001) but higher fraction of genome altered (18.7% vs. 10.3%; P 1⁄4 0.001). A total of 26 patients were evaluable for response to systemic therapy: mTOR/VEGF combination (n 1⁄4 18, ORR 44%), VEGF monotherapy (n 1⁄4 15, ORR 20%), checkpoint inhibitor therapy (n 1⁄4 8, ORR 0%), and mTOR monotherapy (n 1⁄4 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 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 tumor mutational burden, and high fraction of genome altered. Although immunotherapy alone produced no objective responses, combination mTOR/VEGF therapy showed encouraging results. © 2021 American Association for Cancer Research. |
| Journal Title: | Clinical Cancer Research |
| Volume: | 27 |
| Issue: | 10 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2021-05-15 |
| Start Page: | 2910 |
| End Page: | 2919 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-20-4367 |
| PUBMED: | 33658299 |
| PROVIDER: | scopus |
| PMCID: | PMC8127353 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 June 2021 -- Source: Scopus |
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