81 Tumor-Informed Circulating Tumor DNA Monitoring in Fumarate Hydratase–Deficient Renal Cell Carcinoma

Vollständiger Abstract

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Abstract Background Fumarate hydratase (FH)–deficient renal cell carcinoma (RCC) is a rare and aggressive subtype associated with hereditary leiomyomatosis and RCC (HLRCC) syndrome. These tumors are characterized by early onset, frequent de novo metastatic presentation, and poor prognosis. Treatment standards are poorly defined, and no validated molecular biomarkers exist for real-time disease monitoring. Circulating tumor DNA (ctDNA) is showing promise as a liquid biomarker in clear cell RCC, but its feasibility and clinical utility in FH-deficient RCC have not been evaluated. The distinct metabolic biology of FH-deficient tumors, driven by fumarate accumulation and the Warburg effect, may influence ctDNA shedding differently than other RCC subtypes. Methods We retrospectively identified patients with pathologically confirmed FH-deficient RCC who underwent serial ctDNA assessments with the Signatera assay (Natera, Inc.) at Memorial Sloan Kettering Cancer Center (October 2021–February 2026). Signatera assay is a tumor-informed, personalized multiplex PCR–based target capture assay tracking up to 16 patient-specific somatic variants. Draws were grouped as surveillance (post-resection, no systemic therapy) or treatment response (on active systemic therapy). Standard-of-care imaging at each draw was categorized as no evidence of disease (NED), stable disease, disease response, or progression based on clinical radiology report and treating-clinician assessment. Draws were classified as concordant (ctDNA-positive with progression; ctDNA-negative with NED/stable/response), discordant (ctDNA-positive with non-progression, or ctDNA-negative with progression), or indeterminate (no contemporaneous imaging or unclassifiable). ctDNA-attributed clinical actions were captured by chart review. Results Thirteen patients (median age 37; 77% male) contributed 60 longitudinal ctDNA draws (median 2 per patient; range 1–16); 19 draws in the surveillance (4 patients) and 41 in the treatment-response cohort (9 patients). ctDNA was detected in 25/60 draws (42%). In the surveillance cohort, detection was 1/19 (5%; single positive at 0.04 MTM/mL); 2 draws were indeterminate, and concordance was 100% (17/17 evaluable). No patients converted from ctDNA-negative to positive during surveillance. In the treatment-response cohort, detection was 24/41 (59%; median burden 4.19 MTM/mL, range 0.13–317.46); 4 draws were indeterminate, and concordance was 81% (30/37 evaluable). Among 32 evaluable ctDNA-negative draws, 30 (94%) corresponded to non-progressive imaging (18 NED, 12 stable). Of 22 evaluable ctDNA-positive draws, 12 (55%) coincided with imaging progression and 10 (45%) occurred with stable or responding disease, raising the possibility of molecular lead time. ctDNA prompted clinical action in 12/60 draws (20%): therapy change after imaging confirmation (n = 5), systemic therapy initiation (n = 2), surgery (n = 2), dose modification (n = 1), treatment resumption (n = 1), and diagnostic workup (n = 1); two involved CT-to-FDG-PET/CT escalation that revealed disease not apparent on CT. Conclusions Tumor-informed ctDNA monitoring using the Signatera assay can be implemented in FH-deficient RCC and demonstrates meaningful clinical actionability in the postoperative non-metastatic and advanced disease setting. ctDNA may complement standard imaging by enabling earlier molecular detection of disease progression and prompting escalation of imaging modality, particularly to FDG-PET/CT. Prospective validation with standardized testing protocols is needed to define the role of ctDNA in the management of this aggressive RCC subtype.