The prognostic value of a positive ctDNA test in urothelial cancer intensifies throughout the treatment journey. Failure to clear ctDNA after neoadjuvant therapy and then surgery is associated with a dramatically increasing hazard ratio for death, signaling profound treatment failure.

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.

The type of treatment inducing ctDNA clearance matters. Clearance from immunotherapy appears to be more permanent and strongly prognostic than clearance from chemotherapy, which can be transient. This suggests immunotherapy may achieve a more profound and lasting elimination of cancer cells versus cytotoxic agents.

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.

In neoadjuvant therapy, a patient's long-term outcome is better predicted by stopping tumor DNA shedding (ctDNA clearance) than by achieving pathologic complete response (pCR), the traditional gold standard. This redefines what constitutes a successful treatment response before surgery.

In adjuvant bladder cancer trials, ctDNA status is both prognostic and predictive. Patients with positive ctDNA after surgery are at high risk of relapse but benefit from immune checkpoint inhibitors. Conversely, ctDNA-negative patients have a lower risk and derive no benefit, making ctDNA a critical tool to avoid unnecessary, toxic therapy.

In neoadjuvant breast cancer treatment, patients with residual cancer post-therapy remain at high risk of recurrence (10-20%) even if their ctDNA tests are negative. This finding suggests that the physical presence of residual disease is a critical factor, and ctDNA status alone cannot justify forgoing additional adjuvant therapy in this cohort.

Observational data from the BESPOKE study showed that the survival benefit from adjuvant chemotherapy was only seen in patients who tested positive for ctDNA post-surgery. In contrast, ctDNA-negative patients had overlapping survival curves whether they received chemotherapy or not, questioning its utility for that group.

The interpretation of ctDNA is context-dependent. Unlike in the adjuvant setting, in the neoadjuvant setting, remaining ctDNA positive post-treatment signifies that the current therapy has failed. These high-risk patients need a different therapeutic approach, not an extension of the ineffective one.