Academic Article, November 2026

The Role of Circulating Tumor DNA (ctDNA) in Ovarian Cancer

Dr. Panjawit Pathumanusorn
Department of Gynecologic Oncology, National Cancer Institute

Introduction & Fundamental Concepts of ctDNA

          Liquid biopsy—the non-invasive molecular profiling of tumor-derived biomarkers in biological fluids—has emerged as a valuable tool in the clinical management of ovarian cancer. Cell-free DNA (cfDNA) consists of extracellular nucleic acid fragments present in blood plasma. In patients with malignancy, a variable fraction of total cfDNA is derived directly from tumor cells and is designated as circulating tumor DNA (ctDNA).

          The release of ctDNA into the peripheral circulation occurs predominantly via cellular turnover processes, including apoptosis, which generates short DNA fragments of approximately 160–180 base pairs (bp), and necrosis, which produces larger fragments exceeding 10,000 bp. A key biological property of ctDNA is its exceptionally short plasma half-life of 4 to 120 minutes due to rapid systemic clearance via the liver, spleen, kidneys, and enzymatic degradation. Consequently, ctDNA functions as a real-time, highly sensitive dynamic biomarker that closely mirrors instantaneous tumor burden and genomic evolution.

Technologies utilized for ctDNA analysis are broadly categorized into two primary approaches:

• Targeted / PCR-Based Assays: Including digital droplet PCR (ddPCR) and quantitative PCR (qPCR), which offer high sensitivity (up to 99%) and specificity (81–100%). These assays are specifically suited for detecting predefined, hotspot somatic mutations (such as TP53, PIK3CA, or KRAS) with rapid turnaround times.

• Next-Generation Sequencing (NGS): Incorporating targeted gene panels, whole exome sequencing (WES), and whole genome sequencing (WGS). NGS platforms enable comprehensive profiling of multi-gene mutational spectra, somatic copy number variations (CNVs), and epigenetic signatures (DNA promoter hypermethylation) in a single workflow.

Screening & Early Diagnosis

• General Population Screening: Currently, population-wide ctDNA screening is not recommended due to limited sensitivity in low-burden, early-stage disease. However, multimodal screening approaches show promise. For instance, the CancerSEEK assay—which combines ctDNA TP53 mutation detection with serum CA-125 levels—achieved a diagnostic sensitivity of 98% and a specificity of 99% in confirmed ovarian cancer cases.

• Differential Diagnosis of Adnexal Masses: Tumor suppressor gene DNA promoter hypermethylation panels (targeting loci such as HOXA9, OPCML, COL23A1, C2CD4D, and WNT6) exhibit high sensitivity and specificity in differentiating benign ovarian cysts from early-stage epithelial ovarian cancer (FIGO Stage I–II), outperforming CA-125 alone.

Therapeutic Guidance & Resistance Detection

• Targeted Therapy Selection: ctDNA analysis enables the detection of both germline and somatic BRCA1/2mutations, particularly when primary tumor tissue is inaccessible or unfeasible for biopsy, guiding the indication for poly (ADP-ribose) polymerase (PARP) inhibitor therapy.

• Detection of Secondary Reversion Mutations: Secondary reversion mutations in BRCA1/2 detected in ctDNA represent a primary mechanism of acquired resistance to PARP inhibitors and platinum-based chemotherapy. Non-invasive identification of reversion events in ctDNA alerts clinicians to therapeutic failure, facilitating timely adaptation of systemic treatment strategies.

Prognosis & Minimal Residual Disease (MRD) Assessment

• Molecular Residual Disease (MRD) Detection: Detectable ctDNA following primary cytoreductive surgery or completion of adjuvant chemotherapy indicates occult molecular residual disease and serves as an independent adverse prognostic factor strongly associated with disease relapse.

• Prognostic Lead Time: Serial ctDNA monitoring enables early prediction of disease recurrence with a mean lead time of 7 to 10 months prior to radiological detection (via CT or PET-CT) or serum CA-125 elevation.

Current Status in Clinical Guidelines & Practice

National Comprehensive Cancer Network (NCCN) and European Society of Gynaecological Oncology (ESGO) Guidelines

          At present, NCCN and ESGO guidelines do not endorse the routine clinical implementation of ctDNA assays for population screening, primary diagnosis, or standard post-treatment surveillance in ovarian cancer. This conservative stance stems from a current lack of assay standardization, inter-laboratory analytical variability, and the absence of prospective randomized controlled trials (RCTs) demonstrating that therapeutic interventions triggered solely by ctDNA detection yield an overall survival (OS) benefit compared to standard CA-125 monitoring and diagnostic imaging.

European Society for Medical Oncology (ESMO) Recommendations

          The ESMO Precision Medicine Working Group notes that validated ctDNA assays may be considered in specific clinical scenarios—specifically, for identifying actionable somatic BRCA1/2 mutations in patients with advanced epithelial ovarian cancer without germline BRCA1/2 mutations when adequate tumor tissue is unavailable or when tissue re-biopsy is unfeasible.

References

1. Laude É, Azaïs H, Ben Sassi M, Bats AS, Taly V, Laurent-Puig P. Clinical value of circulating tumor DNA for patients with epithelial ovarian cancer. Int J Gynecol Cancer. 2025;35(7):101925.

2. Pinton P, et al. Diagnostic accuracy of circulating tumor DNA in ovarian cancer: A systematic review. Int J Gynecol Cancer. 2025;35(8):1018067.

3. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer. Version 1.2026.

4. Pascual J, Attard G, Bidard FC, Curigliano G, De Mattos-Arruda L, Diehn M, et al. ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: a report from the ESMO Precision Medicine Working Group. Ann Oncol. 2022;33(8):750-768.

5. Gao M, Yang PY, Liu RX, Chen C, Chen XF, Li ZL. Application of ctDNA analysis in gynecological tumors. Front Oncol. 2025;15:1664172.

6. Martinelli C, et al. Translational framework of liquid biopsy in gynecological oncology: From biomarker discovery to clinical integration. J Exp Clin Cancer Res. 2025;44:140.