Circulating tumor DNA (ctDNA) has emerged as an important tool in cancer research, offering new ways to detect disease, predict outcomes, and guide treatment. In ovarian and Endometrial Cancer, ctDNA may strengthen clinical decision-making, but its routine use still depends on stronger evidence and better therapies for high-risk disease.
ctDNA in Ovarian Cancer
Detecting Poor-Prognosis Disease and Recurrence
Studies remain limited, but data show clear potential. A recent meta-analysis reported that patients with detectable or high ctDNA levels had shorter progression-free and overall survival. High ctDNA after cytoreductive surgery also signaled worse outcomes. In several small studies, ctDNA identified recurrence earlier than CA-125 testing and imaging, sometimes by months. ctDNA levels also reflected disease volume at the start of chemotherapy, and the inability to suppress mutant p53 fractions predicted earlier treatment failure.
Despite these promising signals, meaningful clinical benefit requires more effective therapies. Earlier intervention based solely on CA-125 did not improve survival in earlier trials, and ctDNA-driven intervention will need strong evidence before entering routine care.
Identifying Therapeutic Targets
In ovarian cancer, ctDNA testing is mainly useful for identifying BRCA1/2 mutations and therapy resistance. Standard tumor sequencing can miss some germline variants, so germline testing remains essential. ctDNA may also detect resistance pathways, such as BRCA reversion mutations associated with PARP inhibitor resistance, helping clinicians avoid ineffective and potentially harmful treatments.
Improving Screening
Ovarian cancer still lacks an effective screening strategy. Combining cfDNA methylation analysis with CA-125 has shown high sensitivity and specificity in detecting advanced cancers. Early detection, however, remains challenging, and studies in high-risk groups have shown limited success.
New methods, including ultra-deep sequencing of cervical cytology samples, have revealed promising early signals. Pap test samples sometimes detect p53 mutations more reliably than blood, suggesting future possibilities for monitoring clonal changes in people at high inherited risk.
ctDNA in Endometrial Cancer
Detecting Poor-Prognosis Disease and Recurrence
In endometrial cancer, high cfDNA or detectable ctDNA at diagnosis has been linked with advanced stage and poorer outcomes. ctDNA has also identified recurrence before symptoms or imaging. Retrospective testing using a commercial ctDNA assay found somatic mutations in most patients, and specific combinations—such as p53 with PIK3CA mutations—predicted poorer survival. As with ovarian cancer, improved prognostication must translate into better outcomes before ctDNA becomes standard practice.
Identifying Therapeutic Targets
ctDNA may help identify actionable biomarkers, such as MSI-H status, which predicts response to immunotherapy. While tumor samples typically provide this information, molecular changes between primary and metastatic disease can occur. In such cases, ctDNA may offer a noninvasive alternative to biopsy for reassessing tumor biology.
Improving Screening
Rising global incidence and mortality underscore the need for effective screening in endometrial cancer. ctDNA is often undetectable in early disease, limiting its value. However, MSI-H signals can sometimes be found in uterine aspirates or cfDNA, offering potential for monitoring individuals with Lynch syndrome. Pap-derived ctDNA has also shown higher detection rates than plasma, even in early-stage disease. Tracking molecular changes—such as PTEN loss and later PIK3CA mutations—may eventually support early detection strategies.
Conclusion
ctDNA research is advancing rapidly and offers meaningful potential for earlier detection, better prognostication, and more precise treatment in ovarian and endometrial cancers. Still, its role in routine practice must be guided by strong prospective data and therapies capable of improving patient outcomes.
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