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.

Achieving a pathologic complete response (path CR) in the bladder after neoadjuvant therapy is a marker of drug efficacy, not a signal to stop treatment. Because patients die from metastatic, not local, disease, a path CR should be seen as a reason to "double down" on the effective systemic therapy to eradicate micrometastases.

Menin inhibitors achieve high rates of MRD-negative remissions. However, the median duration is very short (4-6 months), suggesting current MRD assays may not adequately capture residual disease and that "MRD negativity" is not a reliable predictor of long-term benefit for this drug class.

The North Star study shows local therapy like radiation or surgery improves survival in stage IV patients on osimertinib, but only if every site of residual disease is treated. Treating some but not all spots provides no additional benefit over standard TKI therapy.

Minimal Residual Disease (MRD) negativity is now recognized by regulators as a surrogate endpoint in oncology. Because it is considered 'reasonably likely to predict progression-free survival,' this shift allows drug developers to use MRD data to support accelerated approval pathways, expediting the availability of new therapies.

Emerging data from major trials shows that ctDNA clearance during neoadjuvant therapy and negative post-surgical MRD status are strong predictors of improved survival. MRD positivity, in contrast, is associated with worse biology and rapid progression.

Both experts advocate shifting immune cell engager use from late-stage, high-burden cancer to a minimal residual disease (MRD) setting. Treating a low tumor load maximizes the effector-to-target ratio, enhances efficacy, and significantly reduces side effects, potentially moving these therapies to first-line combinations.

Data from the ADAURA trial suggests that EGFR-mutated lung cancer patients with detectable ctDNA before starting adjuvant osimertinib are at very high risk of recurrence. This finding supports considering indefinite, lifelong osimertinib for this subgroup, deviating from the standard three-year duration.

The ADAURA trial's MRD analysis reveals that a negative ctDNA test after surgery is not a reliable indicator of being cured. Patients still require adjuvant therapy, as recurrence remains a significant risk, especially within 12 months after stopping treatment.