Association of pre-operative circulating tumor DNA (ctDNA) status with clinicopathologic characteristics in patients (pts) with localized renal cell carcinoma (RCC).

Abstract

532 Background: Clinicopathologic nomograms, such as UISS, Leibovich, and SSIGN models, are used to estimate recurrence risk in localized RCC. However, these tools demonstrate limited predictive accuracy as they were developed in retrospective cohorts and lack integration of molecular or immune biomarkers. There is growing interest in ctDNA as a biomarker for risk stratification in RCC. Pre-operative ctDNA positivity has been associated with clinical features linked to worse outcomes, underscoring its utility in detecting aggressive disease pre-surgery. Here, we present preliminary analyses on correlation between ctDNA status and clinicopathologic characteristics in an institutional cohort of RCC. Methods: Of the 92 pts with available tissue specimens and pre-operative plasma collected between March 2023 and December 2024, five with metastatic disease at the time of nephrectomy were excluded. ctDNA in plasma samples was detected using a personalized, tumor-informed 16-plex mPCR-NGS assay (Signatera, Natera, Inc.). Ridge penalized multivariable logistic regression was performed to identify association between pre-operative ctDNA status and other clinical characteristics. Results: Of the 87 pts included in the study, clinical data (clinical stage, ISUP nucleolar grade, histology, tumor size) and pre-operative ctDNA results were available for 79 pts, (71% male, 90% clear cell). At the time of this analysis, median follow-up was 12 months (range: 1 –27.4 months). Before nephrectomy, 39.2% (31/79) tested positive, and 60.7% (48/79) were ctDNA-negative. Multivariate analyses revealed that pre-operative ctDNA-positivity was associated with a significantly larger mean tumor size compared to ctDNA-negativity (6.2 cm vs. 4.0 cm; OR: 1.38, 95% CI: 1.04 – 1.85, p=0.026). Additionally, ctDNA-positivity was significantly associated with advanced disease stage (stage III/IV [pT1-T2 with N or pT3 or pT4 and/or N1]; OR: 4.60, 95% CI: 1.58 – 14.42, p 0.005) when compared to pts with early stage disease (stage I/II, pT1 or pT2), but not with higher grade (grade III-IV vs. lower grade I-II; OR: 1.01 95% CI: 0.37 – 2.72, p=0.988). In the 31 pts who tested ctDNA positive pre-operatively, 26 had follow-up post-operative ctDNA collected. Two of these pts remained persistently positive post-operatively and presented with metastatic disease within 6 months. Conclusions: Pre-nephrectomy ctDNA positivity correlates with tumor size and stage, suggesting that ctDNA reflects underlying tumor burden and biology. Ongoing analyses will assess clearance with nephrectomy and post-operative longitudinal testing to define prognostic and clinical utility of ctDNA. Integrating ctDNA with tumor features in large contemporary datasets may refine current risk models and enable ctDNA-guided adaptive perioperative trials in localized RCC.