The use of circulating tumor DNA to stratify the risk of recurrence after surgical debulking in epithelial ovarian cancer.

5604 Background: Accurate risk stratification after debulking surgery in ovarian cancer remains challenging. Although surgical debulking status (SDS) and CA125 are standard prognostic markers, patients remain at high risk of recurrence despite optimal debulking and normalization of CA125. Circulating tumor DNA (ctDNA) has emerged as a sensitive biomarker for detecting molecular residual disease (MRD). We evaluated the prognostic value of post-surgical ctDNA compared with SDS and post-surgical CA125 in predicting recurrence. Methods: In a prospectively collected cohort of ovarian cancer patients undergoing standard-of-care treatment, we evaluated 37 patients with a reportable post-surgical MRD before initiation of adjuvant chemotherapy. Tumor-informed, patient-specific panels created from whole genome sequencing of matched tumors and normal samples were used to assess MRD (Precise MRD, Myriad Genetics). Postoperative CA-125 was stratified using a standard clinical cutoff of 35 U/mL. Median follow-up was 30 months (IQR 21.9). Results: Post-operative ctDNA was detected in 75.7% (28/37) of patients with 24.3% (9/37) detected at ultra-low levels ≤100 PPM. Among ctDNA-positive patients, 85.7% (24/28) recurred, compared with no recurrences among ctDNA-negative group (median PFS: 7.6 [3.0-23.2] months vs. not reached; p<0.001). Post-operative CA125 showed a similar trend with elevated-CA125 patients having a shorter median PFS (7.5 [2.8-21.1] vs. 25.1 [9.7-58.0]; p<0.05). Optimal SDS showed a trend toward longer median PFS (Optimal: 22.0 [4.1-58.0] vs. suboptimal: 10.8 [2.8-19.9], p=0.075). Notably, all patients with suboptimal SDS and detectable ctDNA experienced recurrence (4/4). Among patients achieving no gross residual disease (NGR; n=25), ctDNA strongly stratified outcomes: 82.4% (14/17) of ctDNA-positive patients recurred, whereas there we no recurrences in ctDNA-negative patients (median PFS: 4.6 [2.9-38.9] vs. not reached; p<0.001). The median tumor fraction (TF) within this cohort for positive cases was 432.0 PPM (IQR: 49.4–2510.0), where 29.4% (5/17) were detected below 100 PPM. Similarly, within the NGR group, normal-CA125 patients demonstrated a trend toward improved PFS (38.9 [6.9-58.0] vs. 4.6 [2.7-23.2]; p=0.11). Importantly, among patients with normal-CA125 (n=15), ctDNA further discriminated risk: 90% (9/10) of ctDNA-positive patients recurred with a median PFS of 20.3 (4.1-38.9) months, while no recurrences occurred in ctDNA-negative patients (p<0.05). Within this subgroup, the median TF was 235.0 PPM (IQR: 71.4–2640.0), where 26.7% (4/15) were below 100 PPM. Conclusions: Postoperative ctDNA after surgical debulking predicts early recurrence in ovarian cancer, including patients with NGR, supporting its role as a biomarker of MRD and postoperative risk stratification along with CA125.