The prognostic role of circulating tumor DNA (ctDNA) clearance as a biomarker in localized and metastatic renal cell carcinoma (RCC): A single-center experience.
Authors: Ayanambakkam Adanma , Maryam Bibi , Vallabhaneni Priyanka , Andanamala Haripriya , Nagalapuram Vishnu , Glover Joshua Caleb , Gunter Tyler , Stratton Kelly Lynn , Cookson Michael , Cross Brian , Patel Sanjay , McIntosh Andrew G. , Abushukair Hassan M , Phan Minh Duc , Nipp Ryan David , Basu Arnab , McKay Rana R. 
Published: February 2025

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Background:
The use of ctDNA-based molecular residual disease detection represents a promising prognostic biomarker in multiple solid tumors, yet limited data exist in RCC. This study aims to prospectively assess the utility of longitudinal ctDNA monitoring in localized and metastatic RCC.
Methods:
We conducted a retrospective analysis on the use of longitudinal ctDNA testing in a single academic center for patients with RCC from 2022 - 2024. We used a clinically validated, personalized, tumor-informed, multiple PCR-NGS assay (Signatera, Natera, Inc.) to detect and quantify ctDNA. A total of 229 plasma samples from 69 patients were analyzed. Clinical data were collected on pathologic subtype, tumor stage and grade including the presence of sarcomatoid/rhabdoid features and type of treatment. ctDNA dynamics were categorized as follows : clearance, decrease, or increase in ctDNA levels. Treating physicians were not blinded to ctDNA results, no treatment decisions were made based on ctDNA dynamics.
Results:
A total of 69 patients (mean age=62, 23% female) with RCC were included in the analysis, (median: 3 samples/patient), with 33 (48%) having localized RCC and 36 (52%) having metastatic RCC (mRCC). Clear cell RCC was the predominant subtype, present in 61 (88%) patients. Among 33 patients with localized disease, 8 (24%) patients were on surveillance, and 25 (76%) patients received adjuvant pembrolizumab. Among 36 patients with mRCC, 32 (89%) patients were on systemic therapy and 4 (11%) patients were on surveillance. Among those with localized RCC, 1 (3%) patient was ctDNA positive 12 months after nephrectomy and, subsequently developed metastatic disease 1 month from ctDNA detection. Thirty-two (97%) patients with localized RCC and ctDNA negative results remained relapse-free with a median follow-up of 9 months. Among patients with mRCC, 22 (61%) patients were ctDNA positive, 12 (55%) achieved ctDNA clearance (10 after systemic therapy and 2 spontaneously on surveillance). Of these, 10 (83%) remained progression-free at a median follow-up of 11.5 months, while 2 had rise in ctDNA levels after clearance, correlating with disease progression. At median follow-up of 15 months (range 2 to 70 months), all 4 patients with radiographic progression had rising ctDNA levels (median lead time 4 weeks). One patient had rising ctDNA without evidence of radiographic progression.
Conclusions:
Our findings highlight the potential of ctDNA detection and dynamics as a valuable prognostic biomarker for patients with both localized and metastatic RCC. These results support further prospective studies to establish the clinical utility of ctDNA clearance as a predictive marker in metastatic RCC.