The Role of ctDNA in the Management of mCRC

Circulating tumor DNA (ctDNA) testing represents the most significant advancement in prognostic technology for colorectal cancer, offering superior sensitivity compared to traditional markers like CEA for detecting recurrence during surveillance. Multiple companies now offer ctDNA assays with varying claims about sensitivity and specificity, though clinical utility remains an evolving area. The most established application involves minimal residual disease (MRD) detection in stage II patients who are clinically low risk but ctDNA positive, as these patients have over 80% recurrence risk without treatment.

Current clinical applications focus on informing adjuvant therapy decisions, particularly in stage II disease where treatment benefits are marginal. ctDNA-positive patients in otherwise low-risk clinical situations warrant consideration for doublet adjuvant therapy with oxaliplatin-based regimens or extended capecitabine treatment. However, surveillance applications remain controversial, as earlier detection of recurrence through ctDNA monitoring may not translate to improved outcomes due to lead-time bias. The question remains whether detecting recurrence 3 to 6 months earlier through ctDNA changes ultimate patient outcomes.

Emerging data reveals concerning patterns in MRD monitoring, where patients who clear ctDNA with adjuvant therapy still experience recurrence at high rates, just delayed by approximately 2 years compared to persistently positive patients. This suggests that tumor biology may be predetermined and that adjuvant therapy serves as a temporary intervention rather than curative treatment. These findings highlight the need for novel therapeutic approaches in ctDNA-positive patients and may accelerate drug development by providing earlier end points for clinical trials compared with traditional adjuvant studies.