A study on the value of ctDNA-based molecular residual disease (MRD) in dynamic monitoring in the clinical treatment of advanced/metastatic renal cell carcinoma.

e16522 Background: While the options for renal cell therapy continue to expand, the traditional methods pose significant challenges in accurately treating and evaluating the effectiveness of interventions for advanced or metastatic renal cell carcinoma (RCC) because of the high tumor heterogeneity. Consequently, there is an escalating demand for precision therapy in clinical settings. The use of molecular markers such as circulating tumor DNA (ctDNA) and ctDNA-based Molecular Residual Disease (MRD) detection through ultra-deep sequencing are emerging as potent biomarkers that can assist clinical treatment decision making. Methods: Patients were recruited with advanced/metastatic Renal Cell Carcinoma would subjected to immunotherapy. Tumor tissues were collected by biopsy or surgery before the initiation of treatment, and plasma samples were drawn at baseline and approximately every three months during treatment. Tissue samples were subjected to Whole Exome Sequencing (WES) at 1000x coverage to obtain individual mutation information, and up to 40 loci were selected to construct a bespoke MRD assay panel. Blood samples underwent 100,000x ultra-deep sequencing to evaluate the tumor molecular signals in peripheral blood. Results: 22 RCC patients (17M:5F) were recruited from 4 to 12, 2023 at a median age of 65 (24 to 82). 21 were diagnosed as clear cell Renal Cell Carcinoma (ccRCC) with 18 metastatic cases, and one is transcription factor E3-Renal Cell Carcinoma (TEF3-RCC). WES resulted in a total of 7,854 mutations across 3,724 genes, including 761 insertions/deletions (InDel), 7,093 single nucleotide variants (SNV), and 3 gene fusions. The highest mutation frequency was observed in VHL (73.68%), followed by PBRM1 (63.16%), ASPA (52.63%), SETD2 (42.11%), TTN (42.11%), and THADA (42.11%). The MRD assay was conducted on 14 patients using a bespoke panel. CtDNA was detected in plasma of 92.9% (13/14) cases at baseline. The concordance with the surgical/biopsy tissue samples was 69.7% (p=0.019, Spearman correlation analysis). For ctDNA-MRD dynamic monitoring, results from 5 PR, 7 SD, and 1 PD patients were available. ctDNA concentrations decreased in 5 PR and 5 SD patients, showing a 100% (5 out of 5) and 71.4% (5 out of 7) concordance with clinical outcomes respectively. Meanwhile, ctDNA levels slightly increased in 2 SD patients and significantly increased in 1 PD patient. Six patients (2 PR, 4 SD) reached MRD-negative levels. Conclusions: The findings from this study illustrate the potential of using circulating tumor DNA (ctDNA) for dynamic monitoring in advanced/metastatic renal cell carcinoma. Furthermore, the levels of ctDNA-Minimal Residual Disease (MRD) may be useful in evaluating the effectiveness of immunotherapy. ctDNA could also serve as a radiological surrogate for assessing the progression of metastatic renal cell carcinoma (mRCC).