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

SIMPLE SUMMARY: There is currently a lack of useful tests to detect microscopic residual disease in patients who have undergone surgery to remove their bowel cancer. This inability to identify patients with microscopic cancer could lead to over- and under-treatment with chemotherapy. Circulating tumour DNA (ctDNA) has shown significant promise to fill this gap to potentially personalize treatment after curative intent surgery allowing de-intensifying and intensifying of adjuvant therapies to reduce unnecessary toxicity of systemic therapy and also to hopefully cure more patients with ‘high risk of relapse’. This review article focuses on the current clinical use and future direction of ctDNA for early-stage bowel cancer. ABSTRACT: 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.