Adam C. ElNaggar

Surgical and Blood-Based Minimal Residual Disease in Patients with Ovarian Cancer after First-line Therapy: Clinical Outcomes and Translational Opportunities

Abstract Purpose: Minimal residual disease (MRD) after first-line treatment of advanced-stage ovarian cancer remains a long-standing barrier to cure. We investigated the prognostic and translational value of MRD detection by second-look laparoscopy (SLL) and ctDNA at the completion of first-line therapy. Experimental Design: Patients with high-grade epithelial ovarian cancer who had a complete clinical response to first-line therapy and underwent SLL and plasma collection for ctDNA were included. Progression-free survival (PFS) and overall survival (OS) were estimated based on MRD and clinicopathologic status. Spatial transcriptomics (GeoMx and Visium) and proteomics (CODEX) profiling were performed on serial samples from select patients. Results: Forty of 95 (42.1%) patients had surgically detected MRD, which was associated with worse PFS (median PFS 7.4 vs. 23.8 months; P < 0.001) and OS (median OS 33.9 vs. not reached; P < 0.001). SLL positivity was an independent negative prognostic factor for OS (HR, 4.40; 95% confidence interval, 1.37–14.21; P = 0.013) in multivariable analysis. Among 44 patients who underwent SLL and had ctDNA testing, 34% (15/44) were ctDNA-positive, which was associated with worse PFS (6.4 vs. 28.1 months; P < 0.001) and OS (32.4 months vs. not reached; P = 0.008). We demonstrated the feasibility of spatial multiomics in studying MRD and their ability to provide hypothesis-generating observations, implicating the upregulation of the hypoxia signaling pathway, expression of multiple druggable targets (CDK6, GLS, MSLN, ERBB2), and immune exclusion in MRD lesions. Conclusions: Approximately half of patients in clinical remission after first-line therapy have assessable MRD, which can inform prognosis, therapeutic target discovery, and clinical trials.

Using Circulating Tumor DNA–Based Molecular Residual Disease Detection for Postoperative Monitoring in Early-Stage Uterine Cancer

PURPOSE Clinical decision making for adjuvant treatment in early-stage uterine cancer (UC) following surgery is typically directed by clinicopathological risk factors. There is an unmet need for a clinically relevant biomarker to improve individualized risk stratification and help monitor response to adjuvant therapy. Here, we sought to analyze circulating tumor DNA (ctDNA) as a prognostic biomarker in patients with early-stage UC. METHODS Retrospective analysis of ctDNA results from real-world data was performed for 61 patients (233 plasma time points) diagnosed with early-stage UC. ctDNA status and dynamics were assessed using a clinically validated, personalized, tumor-informed ctDNA assay (Signatera), and its association with recurrence-free survival (RFS) was evaluated. RESULTS ctDNA positivity was associated with significantly reduced RFS postoperatively (hazard ratio [HR], 7.6; P = .003) and postdefinitive therapy (HR, 25.4; P = .0009) and was the most significant factor associated with recurrence when compared with other clinicopathological and molecular risk factors. Notably, of patients who recurred and for whom clinical outcomes were available, 100% were ctDNA-positive before or at the time of recurrence, whereas none of the serially ctDNA-negative patients experienced relapse. CONCLUSION Our data demonstrate the feasibility of monitoring ctDNA in the postoperative and adjuvant settings in early-stage UC. Analysis of ctDNA, in addition to other risk factors, may help identify patients at the highest risk of recurrence, inform surveillance strategies, and support treatment decision-making for these patients.