Circulating Tumor DNA for Early Prediction of Relapse in Epithelial Ovarian Cancer: A Systematic Review and Meta-analysis

Background: Relapse remains the principal cause of mortality in epithelial ovarian carcinoma, and current surveillance approaches relying on radiologic imaging and protein biomarkers such as cancer antigen 125 (CA 125) frequently detect recurrence only after macroscopic disease has developed. Circulating tumour DNA (ctDNA) has emerged as a promising biomarker of minimal residual disease (MRD), potentially enabling earlier detection of molecular relapse. Material and Methods: We conducted a systematic review and meta-analysis in accordance with PRISMA 2020 guidelines to evaluate the prognostic performance of post treatment ctDNA detection for early relapse prediction in epithelial ovarian cancer. PubMed was searched from January 2010 to October 2025 for prospective and retrospective studies assessing plasma ctDNA after definitive therapy. Eligible studies reported relapse related outcomes and included comparative data with established biomarkers where available. Hazard ratios (HRs) for recurrence were pooled using a random effects model. Diagnostic accuracy was assessed using a hierarchical summary receiver operating characteristic (HSROC) model. Results: Four studies comprising 410 patients met inclusion criteria for quantitative synthesis. Post treatment ctDNA positivity was consistently associated with significantly shorter progression free survival. Pooled analysis demonstrated an approximately three fold increased risk of recurrence among ctDNA positive patients (HR = 2.83; 95% CI 1.82–4.40), with moderate heterogeneity (I² = 68%). Tumour informed assays exhibited substantially stronger prognostic discrimination than tumour naïve panels. Diagnostic meta-analysis showed a pooled sensitivity of 0.71 (95% CI 0.60–0.82) and specificity of 0.92 (95% CI 0.84–0.96), with an area under the curve of 0.91. Across comparative cohorts, ctDNA detected molecular relapse a mean of 6.9 months earlier than radiologic progression and consistently outperformed CA 125 in both lead time and specificity. Conclusion: Post treatment ctDNA is a highly specific and clinically meaningful biomarker of minimal residual disease in epithelial ovarian carcinoma, providing earlier and more accurate relapse detection than conventional protein biomarkers. These findings support the integration of ctDNA into postoperative surveillance strategies and highlight the need for prospective interventional trials to determine whether ctDNA guided management improves survival outcomes.

Keywords: Circulating tumor DNA, Ovarian cancer, Minimal residual disease, Relapse, CA-125, Biomarkers, Recurrence.