Clinical Applications of Minimal Residual Disease Assessments by Tumor-Informed and Tumor-Uninformed Circulating Tumor DNA in Colorectal Cancer

Simple Summary Circulating tumor DNA, or ctDNA, are fragments of tumor DNA that can be detected in the blood of patients with colorectal cancer. Measuring ctDNA levels in the blood has shown the potential to provide important information that can be helpful in the clinical care of patients with colorectal cancer. For example, in patients with colon cancer that has been removed by surgery, measuring ctDNA in the blood can predict the likelihood of cancer recurrence, while in those with metastatic colorectal cancer, measuring ctDNA can inform the clinician whether chemotherapy is effective at earlier timepoints than currently available tests. In this review, we discuss the results from ongoing studies describing the utility of ctDNA measurements across all stages of colorectal cancer. We also discuss the various clinical scenarios that ctDNA may have the most immediate impact in colorectal cancer management. Emerging data suggest that circulating tumor DNA (ctDNA) can detect colorectal cancer (CRC)-specific signals across both non-metastatic and metastatic settings. With the development of multiple platforms, including tumor-informed and tumor-agnostic ctDNA assays and demonstration of their provocative analytic performance to detect minimal residual disease, there are now ongoing, phase III randomized clinical trials to evaluate their role in the management paradigm of CRC. In this review, we highlight landmark studies that have formed the basis for ongoing studies on the clinically applicability of plasma ctDNA assays in resected, stage I-III CRC and metastatic CRC. We discuss clinical settings by which ctDNA may have the most immediate impact in routine clinical practice. These include the potential for ctDNA to (1) guide surveillance and intensification or de-intensification strategies of adjuvant therapy in resected, stage I-III CRC, (2) predict treatment response to neoadjuvant therapy in locally advanced rectal cancer inclusive of total neoadjuvant therapy (TNT), and (3) predict response to systemic and surgical therapies in metastatic disease. We end by considering clinical variables that can influence our ability to reliably interpret ctDNA dynamics in the clinic.