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.

In follicular lymphoma, the treatment goal is durable remission with manageable toxicity, not necessarily a cure. Therefore, clinicians frequently prefer using a bispecific antibody first, reserving the more complex and toxic CAR-T cell therapy for transformed disease or after a bispecific fails.

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.

The InVigor11 study was the first to show that detecting recurrence via a ctDNA test before it's visible on scans is not just a prognostic sign, but an actionable clinical state. Intervening with therapy at this early stage was proven to improve patient outcomes, establishing a new paradigm for cancer surveillance.

After immunotherapy, many colorectal cancer patients have residual nodules on scans that appear to be partial responses. However, ctDNA testing can confirm these are often just scar tissue, not active disease. This provides the confidence to stop therapy at the two-year mark and avoid unnecessary surgeries for what are effectively complete responses.

The main barrier to widespread ctDNA use is not its proven ability to predict who will recur (prognostic value). The challenge is the emerging, but not yet definitive, data on its ability to predict a patient's response to a specific therapy (predictive value).

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.

Before initiating a CD20-targeting bispecific antibody in patients who have failed CAR-T therapy, a new biopsy is mandatory. Up to 30% of these patients experience CD20 antigen loss, which would render the bispecific therapy ineffective and necessitates choosing a drug with a different target.