Abstract 1144: Tumor genomic features and postsurgical ctDNA status in patients with stage I-IV uterine cancer

Abstract Introduction: Molecular residual disease (MRD) detection using personalized, tumor-informed circulating tumor DNA (ctDNA) is a promising biomarker for early detection of recurrence and treatment response in uterine cancer (UC). However, the biological and genomic correlates of ctDNA positivity remain poorly understood in this setting. This study aimed to evaluate the prevalence and dynamics of ctDNA in UC patients, and associations with key genomic alterations derived from Altera™ comprehensive genomic profiling. Methods: A retrospective cohort of 200 UC patients with available post-surgical ctDNA testing (Signatera™, Natera, Inc.) and Altera™ profiling from the same primary tumor tissue were analyzed. Inclusion criteria required blood collection within 2 months of surgery, and availability of at least one additional timepoint during adjuvant or surveillance period. Associations between ctDNA status/dynamics and Altera-reported genomic results were assessed. Results: Among 200 evaluable UC patients, 43% (86/200) were ctDNA-positive (+) and 57% (114/200) were ctDNA-negative (-) within the MRD window. When stratified by stage, 15% (12/82) of early-stage (ES, stages I-II) and 63% (74/118) of late-stage (LS, stages III-IV) patients were ctDNA(+), indicating a higher MRD burden in advanced/aggressive disease. Genomic correlation analyses demonstrated that during the MRD window, ctDNA status was significantly associated with MSI-H/MSS status (chi-square test, p0.05). ctDNA positivity rate was 78% (66/85) and 22% (19/85) among MSS and MSI patients, respectively. POLE exonuclease mutations (N=11; ctDNA(+): 18% 2/11; ctDNA(-): 82% 9/11) were seen in 55% (6/11) of MSS and 45% (5/11) of MSI-H patients. Among MSS patients with POLE mutations (N=6), 17% (1/6) were ctDNA(+) and 83% (5/6) were ctDNA(-). Similarly, among MSI-H patients with POLE mutations (N=5), 20% (1/5) were ctDNA(+) and 80% (4/5) were ctDNA(-). Notably, all MSS patients without an MMR alteration were ctDNA(+). When analyzed longitudinally, 93% (14/15) of MMR-altered ctDNA(-) patients remained serially ctDNA(-) throughout adjuvant/surveillance period, while 50% (4/8) of MMR-altered ctDNA(+) patients cleared ctDNA. Conversely, in the non-altered MMR group, 81% (18/95) of ctDNA(-) patients remained serially ctDNA(-), and 27% (21/77) of ctDNA(+) patients cleared ctDNA. Conclusions: Post-surgical ctDNA status and dynamics are associated with disease stage and genomic features. Overall, ctDNA status within the MRD window was associated with MSI status. Post-surgical lack of ctDNA positivity and sustained clearance of ctDNA in the adjuvant period were associated with POLE alterations and/or MMR-altered phenotype, consistent with better prognosis. Given high prognostic value of ctDNA status and dynamics, integrating ctDNA-based MRD monitoring may aid in recurrence risk assessment and guide adjuvant therapy decisions. Citation Format: Tara Berman, Bhakti Dwivedi, Carly B. Scalise, Punashi Dutta, Adam ElNaggar, Minetta Liu, Casey Cosgrove. Tumor genomic features and postsurgical ctDNA status in patients with stage I-IV uterine cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1144.