Preoperative positive ctDNA analysis is associated with the tumor microenvironment, and the risk of recurrence in non-metastatic colorectal cancer

Recurrence after curative-intent surgery for colorectal cancer is a major cause of cancer-related death. Circulating cell-free tumor DNA (ctDNA) is increasingly used in the perioperative setting to detect residual disease. However, the association between preoperative ctDNA, the tumor microenvironment, including tumor-infiltrating lymphocytes, and recurrence is unknown. We explored the association between ctDNA and the tumor microenvironment in patients with non-metastatic CRC undergoing curative-intent surgery. ctDNA was assessed using a tumor-agnostic hypermethylated cfDNA test. Among 140 patients, ctDNA tested positive in 102 (72.9%) before surgery, with 38 (27.1%) tumors classified as immune infiltration high. ctDNA was associated with expression of cancer-metastasis pathways, while immune active phenotypes were associated with immune infiltration high tumors. ctDNA status could identify deficient mismatch repair tumors with an active immune phenotype. The results suggest that a positive ctDNA analysis before surgery is associated with a metastatic tumor microenvironment.