In patients under surveillance for colorectal cancer, the median time from a positive ctDNA test to radiographic recurrence is extremely short—only 3 to 5 months. This narrow window underscores the high-risk nature of this state and the critical urgency required to enroll these patients into clinical trials immediately upon ctDNA detection.

Circulating tumor DNA (ctDNA) testing is described as unequivocally the most prognostic tool available for colorectal cancer. Patients who remain serially negative have a minimal recurrence risk, while a positive result almost universally predicts a future clinical recurrence by 6-8 months.

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.

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.

Clinical trial data provides a clear directive for using MRD testing. The DYNAMIC study showed that for stage 2 colon cancer, a ctDNA-guided approach halved chemotherapy use with identical outcomes. In contrast, the DYNAMIC-3 study found that de-escalating chemo for high-risk stage 3 patients based on a negative ctDNA result led to worse outcomes.

Despite the excellent prognosis associated with a negative post-operative MRD test, oncologists are not yet comfortable omitting adjuvant chemotherapy for younger, high-risk stage II colon cancer patients. The current data is not considered sufficient to justify de-escalation based on a negative ctDNA result alone outside of a clinical trial setting.

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.

When a patient becomes ctDNA positive during surveillance after completing adjuvant therapy, the optimal next step is not immediate systemic chemotherapy. Clinicians should instead initiate intensive imaging (e.g., CT, PET) to identify a potential radiographic recurrence, which may be isolated and resectable.