In neoadjuvant settings, ctDNA monitoring allows for real-time therapy adjustment. Data from the iSpy platform shows 80% of hormone-positive patients clear ctDNA with half the chemotherapy, enabling de-escalation, while the remaining 20% can be identified for escalated treatment.

A key conceptual shift is viewing ctDNA not as a statistical risk marker, but as direct detection of molecular residual disease (MRD). This framing, similar to how a CT scan identifies metastases, explains its high positive predictive value and justifies its use in making critical treatment decisions.

While not yet validated, ctDNA is being used by clinical experts as a de-escalation tool to provide confidence when stopping long-term maintenance therapies like PARP inhibitors. This novel application focuses on reducing treatment burden rather than solely detecting disease progression.

An expert oncologist advises against ordering ctDNA tests that merely provide a "good or a bad feeling" about prognosis. The most valuable use is when a positive or negative result clearly dictates a clinical action, such as when to stop or restart adjuvant therapy.

Despite significant interest, circulating tumor DNA (ctDNA) is not yet an actionable tool for guiding the duration of maintenance immunotherapy in endometrial cancer. While studies like DuoE show ctDNA levels correlate with outcomes, there is no evidence to support using its clearance to decide when to stop treatment. It remains a prognostic, not a predictive, biomarker for this purpose.

While patients increasingly ask about ctDNA, clinicians are hesitant to use it for treatment decisions in ovarian cancer management. A rising ctDNA level may prompt more vigilant surveillance but does not yet trigger treatment initiation, as its correlation with survival outcomes is unproven.

Despite the promise of liquid biopsies for monitoring, the SERENA-6 trial revealed a significant challenge: fewer than 10% of screened patients developed a detectable ESR1 mutation. This low yield questions the efficiency and broad applicability of this serial screening strategy to guide treatment changes.

Oncologists are more comfortable using a positive ctDNA test to escalate care (e.g., recommend chemo for a low-risk Stage II patient). However, they are more hesitant to use a negative test to de-escalate or withhold standard chemo for higher-risk patients, pending more definitive trial data.

The next wave of ctDNA research focuses on de-escalation. Trials like SIGNAL ER101 and an Alliance cooperative group study will test withholding intensive adjuvant treatments (like CDK4/6 inhibitors) in high-risk, ctDNA-negative patients, initiating therapy only if they turn positive later. This could spare many from toxicity and cost.