Cell-Free Circulating (Tumor) DNA before Surgery as a Prognostic Factor in Non-Metastatic Colorectal Cancer: A Systematic Review

SIMPLE SUMMARY: Patients with colorectal cancer without distant metastases are often cured by surgical tumor resection. Follow-up is needed because of the risk of disease recurrence. Patients at risk of disease recurrence may benefit from additional chemotherapy. Detection of cell-free circulating tumor DNA (ctDNA) after surgery reflects the presence of remaining cancer cells and is associated with a very high risk of recurrence. Therefore, postsurgery detection of ctDNA is a promising approach to accurately identifying high-risk patients. However, postsurgery ctDNA analysis is challenging. Moreover, in some patients, chemotherapy before surgery might be more beneficial than chemotherapy after surgery. In this review, we provide an overview of current knowledge regarding the association between ctDNA detection before surgery and the risk of recurrence and conclude that the current literature is insufficient to determine this association. Dedicated studies that primarily focus on ctDNA before surgery in colorectal cancer patients are needed. ABSTRACT: Identification of non-metastatic colorectal cancer (CRC) patients with a high risk of recurrence after tumor resection is important to select patients who might benefit from adjuvant treatment. Cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) analyses after surgery are promising biomarkers to predict recurrence in these patients. However, these analyses face several challenges and do not allow guidance of neoadjuvant treatment, which might become a novel standard option in colon cancer treatment. The prognostic value of cfDNA/ctDNA before surgery is unclear. This systematic review aims to provide an overview of publications in which the prognostic value of presurgery cfDNA/ctDNA in non-metastatic CRC patients was studied and is performed according to PRISMA guidelines. A total of 29 out of 1233 articles were included and categorized into three groups that reflect the type of approach: measurement of cfDNA, ctDNA somatic alterations, and ctDNA methylation. Overall, a clear association between presurgery cfDNA/ctDNA and the outcome was not observed, but large studies that primarily focus on the prognostic value of presurgery cfDNA/ctDNA are lacking. Designing and performing studies that focus on the value of presurgery cfDNA/ctDNA is needed, in addition to standardization in the reporting of cfDNA/ctDNA results according to existing guidelines to improve comparability and interpretation among studies.