Prognostic value of perioperative circulating tumor DNA levels estimated by cell-free DNA methylation in patients with resectable colorectal liver metastases

Half of the patients with colorectal liver metastases (CRLM) undergoing local treatment with curative intent experience recurrence within one year. New biomarkers are needed to stratify patients before and/or after surgery to minimize both overtreatment and undertreatment with perioperative chemotherapy. In a cohort study at 4 centers in The Netherlands,120 patients with CRLM not treated with (neo-)adjuvant chemotherapy were profiled using a combined assay for genome-wide cell-free DNA methylation and copy number both pre-operatively and three weeks after local treatment for CRLMs. The ctDNA estimates based on both DNA methylation and copy numbers were significantly correlated with mutation-based ctDNA fractions and captured tumor-derived information, such a tumor size. The continuous ctDNA established using methylation was an independent pre-operative prognostic marker for both recurrence-free survival (p=0.019) and overall survival (p=0.002) after accounting for age, sex, Fong risk score, primary tumor location, and metastasis timing. Elevated ctDNA levels post-operatively were significantly associated with shorter RFS (p=0.03), but not OS (p=0.16).The authors conclude that these results demonstrate the prognostic value of pre-operative and post-operative ctDNA in a homogeneous, chemotherapy-naïve cohort of patients with CRLM as well as its potential to guide decisions of administering peri-operative chemotherapy.