ctDNA and Adjuvant Therapy for Colorectal Cancer: Time to Re-Invent Our Treatment Paradigm

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. While there have been significant developments in the treatments for patients with metastatic CRC in recent years, improving outcomes in the adjuvant setting has been more challenging. Recent technological advances in circulating tumour DNA (ctDNA) assay with the ability to detect minimal residual disease (MRD) after curative intent surgery will fundamentally change how we assess recurrence risk and conduct adjuvant trials. Studies in non-metastatic CRC have now demonstrated the prognostic impact of ctDNA analysis after curative intent surgery over and above current standard of care clinicopathological criteria. This ability of ctDNA analysis to stratify patients into low- and very-high-risk groups provides a window of opportunity to personalise adjuvant treatment where escalation/de-escalation of adjuvant systemic therapy could potentially increase cure rates and also reduce treatment-related physical and financial toxicity. Emerging data suggest that conversion of ctDNA from detectable to undetectable after adjuvant chemotherapy may reflect treatment efficacy. This real-time assessment of treatment benefit could be used as a surrogate endpoint for adjuvant novel drug development. Several ctDNA-based randomized adjuvant trials are ongoing internationally to confirm the clinical utility of ctDNA in colorectal cancer.