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.

Despite emerging trial data, clinicians are not yet ready to change therapy based on ctDNA positivity alone. Key concerns cited include the absence of a proven survival benefit from early intervention, the potential to use future treatment lines prematurely, and overall feasibility. The consensus is that while promising, the technology is not yet ready for routine clinical decision-making.

For resected EGFR-mutated lung cancer, ctDNA status after surgery could personalize adjuvant osimertinib duration. A patient with initially positive ctDNA that clears on therapy is considered very high-risk for recurrence. This prompts discussion of continuing osimertinib indefinitely, beyond the standard three years.

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.

In early-stage non-small cell lung cancer, the presence of circulating tumor DNA before surgery is not a statistically significant predictor of survival. However, detecting ctDNA after curative-intent surgery is a strong negative prognostic indicator, highlighting the critical value of post-operative testing.

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.

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.

While adjuvant immunotherapy benefits ctDNA-positive patients, it may not be the optimal strategy. Given their near-certainty of relapse (95%), using a single-agent immunotherapy when a more potent combination like EV-Pembro exists for metastatic disease raises the critical question of whether these high-risk patients are being undertreated.

Many deaths from colon cancer occur in patients with Stage II disease not offered adjuvant therapy due to a lack of traditional risk factors. Post-surgical ctDNA testing can identify a ~10% subset with minimal residual disease who are at high risk of recurrence and would benefit from chemotherapy.