Clinical Implications of Ultrasensitive MRD Detection With Next-Gen ctDNA Assays

Advances in ctDNA testing have dramatically improved sensitivity, moving well beyond traditional imaging and earlier detection methods. Current technology can detect 1 cancer DNA molecule per million fragments of cell-free DNA, an enormous leap from the hundred per million detection limit of earlier generations. This increased sensitivity offers the potential to identify residual disease years before conventional methods would detect recurrence, providing a larger window for intervention. Patients can thus be informed that their test can pick up tiny traces of cancer well before it becomes visible on scans, helping guide earlier, potentially more effective treatment decisions.

This evolution in ctDNA testing also holds promise for improving the negative predictive value of the tests. Although the positive predictive value is already high—meaning a positive result reliably indicates recurrence—the negative predictive value is still limited. Currently, a negative test does not guarantee the absence of disease because residual cancer might still be present below the detection threshold. However, as tests become ultrasensitive, there is hope that truly negative results can safely support therapy de-escalation, sparing patients from unnecessary treatment and its adverse effects, with the ability to reintroduce therapy if ctDNA becomes detectable again.

Clinicians explain to patients that despite the high sensitivity, ctDNA results are ultimately binary (positive or negative) and that positive tests signify viable cancer requiring action. Negative results are reassuring but do not completely rule out dormant disease. Ongoing improvements in assay technology promise to enhance patient care by enabling more personalized, timely, and adaptive treatment strategies that could extend survival and quality of life. The field is advancing rapidly, bringing new hope to patients and providers alike.