TY - JOUR
T1 - Comprehensive molecular characterization and response to therapy in fumarate hydratase–deficient renal cell carcinoma
AU - Gleeson, Jack P.
AU - Nikolovski, Ines
AU - Dinatale, Renzo
AU - Zucker, Mark
AU - Knezevic, Andrea
AU - Patil, Sujata
AU - Ged, Yasser
AU - Kotecha, Ritesh R.
AU - Shapnik, Natalie
AU - Murray, Samuel
AU - Russo, Paul
AU - Coleman, Jonathan
AU - Lee, Chung Han
AU - Stadler, Zsofia K.
AU - Ari Hakimi, A.
AU - Feldman, Darren R.
AU - Motzer, Robert J.
AU - Reznik, Ed
AU - Voss, Martin H.
AU - Chen, Ying Bei
AU - Carlo, Maria I.
N1 - Funding Information:
Memorial Sloan Kettering Cancer Center receives research funding through the Core Grant (P30 CA008748) as part of MSK’s Cancer Center Support Grant (CCSG) which is awarded by the NCI. M.I. Carlo is also supported by the Harold Amos Faculty Development Award.
Funding Information:
J.P. Gleeson reports grants from Memorial Sloan Kettering Cancer Center during the conduct of the study. Y. Ged reports personal fees from consulting/ advisory role for Bristol Myers Squibb outside the submitted work. C.H. Lee reports personal fees from Amgen, BMS, Exelixis, Eisai, Merck, Pfizer, and EMD Serono outside the submitted work. Z.K. Stadler reports other from Genetech/ Roche, Novartis, Regeneron, RegenexBio, Adverum, Allergan, Optos Plc, Neu-rogene, and Gyroscope Tx outside the submitted work. D.R. Feldman reports grants from NCI during the conduct of the study; other from Novartis, Astellas, Seattle Genetics, and Decibel outside the submitted work; and royalties for a review article with UpToDate. R.J. Motzer reports grants and personal fees from Pfizer, Novartis, Eisai, Exelixis, Genentech/Roche and personal fees from Merck, Lilly, Incyte, EMD Serono Research and Development Institute, and Aveo outside the submitted work. M.H. Voss reports personal fees from Exelixis, Eisai, Covus, Merck, and Novartis; grants and personal fees from Pfizer, BMS, Bayer, Aveo, and Calithera; and grants from Genentech during the conduct of the study. M.I. Carlo reports grants from NCI-P30 CA008748 and Harold Amos Faculty Development Award during the conduct of the study. No disclosures were reported by the other authors.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/5
Y1 - 2021/5
N2 - 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 ¼ 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 ¼ 0.001). A total of 26 patients were evaluable for response to systemic therapy: mTOR/VEGF combination (n ¼ 18, ORR 44%), VEGF monotherapy (n ¼ 15, ORR 20%), checkpoint inhibitor therapy (n ¼ 8, ORR 0%), and mTOR monotherapy (n ¼ 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.
AB - 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 ¼ 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 ¼ 0.001). A total of 26 patients were evaluable for response to systemic therapy: mTOR/VEGF combination (n ¼ 18, ORR 44%), VEGF monotherapy (n ¼ 15, ORR 20%), checkpoint inhibitor therapy (n ¼ 8, ORR 0%), and mTOR monotherapy (n ¼ 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.
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U2 - 10.1158/1078-0432.CCR-20-4367
DO - 10.1158/1078-0432.CCR-20-4367
M3 - Article
C2 - 33658299
AN - SCOPUS:85105501522
SN - 1078-0432
VL - 27
SP - 2910
EP - 2919
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 10
ER -