The Promise of Circulating Tumor DNA (ctDNA) in the Management of Early-Stage Colon Cancer: A Critical Review

SIMPLE SUMMARY: Currently, the treatment for localized colon cancer consists of surgery and, if the presence of residual cancer cells is suspected, chemotherapy following the surgery. However, the current standard tools to determine the presence of residual cancer after the surgery are imprecise, which results in under- or overtreatment in a significant number of patients. Emerging research indicates that circulating tumor DNA (ctDNA) can reveal the presence of residual cancer after surgery with much higher precision than the presently available tools, and can help with the treatment decision regarding a need for chemotherapy after the surgery. Furthermore, ctDNA can potentially help determine the effectiveness of chemotherapy and detect cancer recurrence much earlier than the current standard tools. In this review, we have critically evaluated available data to provide the readers with an overview of how ctDNA can potentially transform the treatment of localized colon cancer in the near future. ABSTRACT: The current standard treatment for patients with early-stage colon cancer consists of surgical resection, followed by adjuvant therapy in a select group of patients deemed at risk of cancer recurrence. The decision to administer adjuvant therapy, intended to eradicate the clinically inapparent minimal residual disease (MRD) to achieve a cure, is guided by clinicopathologic characteristics of the tumor. However, the risk stratification based on clinicopathologic characteristics is imprecise and results in under or overtreatment in a substantial number of patients. Emerging research indicates that the circulating tumor DNA (ctDNA), a fraction of cell-free DNA (cfDNA) in the bloodstream that originates from the neoplastic cells and carry tumor-specific genomic alterations, is a promising surrogate marker of MRD. Several recent studies suggest that ctDNA-guided risk stratification for adjuvant therapy outperforms existing clinicopathologic prognostic indicators. Preliminary data also indicate that, aside from being a prognostic indicator, ctDNA can inform on the efficacy of adjuvant therapy, which is the underlying scientific rationale for several ongoing clinical trials evaluating ctDNA-guided therapy escalation or de-escalation. Furthermore, serial monitoring of ctDNA after completion of definitive therapy can potentially detect cancer recurrence much earlier than conventional surveillance methods that may provide a critical window of opportunity for additional curative-intent therapeutic interventions. This article presents a critical overview of published studies that evaluated the clinical utility of ctDNA in the management of patients with early-stage colon cancer, and the potential of ctDNA to transform the adjuvant therapy strategies.