Prognostic value of peri-operative circulating tumour DNA levels estimated by cell-free DNA methylation in patients with resectable colorectal liver metastases

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BACKGROUND: Half of the patients with colorectal liver metastases (CRLM) that undergo local treatment with curative intent experience recurrence within one year. New biomarkers are needed to stratify patients before and/or after surgery to minimise both over- and under-treatment with peri-operative chemotherapy. METHODS: We profiled 120 patients with CRLM not treated with (neo-)adjuvant chemotherapy using a combined assay for genome-wide cell-free DNA methylation and copy number profiling both pre-operatively and three weeks after local treatment of CRLMs. These data were used to estimate the proportion of circulating tumour DNA (ctDNA) in these patients using data from healthy controls and CRLM tissues for reference. The prognostic value of pre-operative and post-operative ctDNA load was assessed on Recurrence-Free Survival (RFS) and Overall Survival (OS) using Cox proportional hazards models. FINDINGS: The ctDNA estimates based on both DNA methylation and copy numbers were significantly correlated with mutation-based ctDNA fractions and captured tumour-derived information, such as tumour size. The continuous ctDNA amount estimated using methylation was an independent, pre-operative prognostic marker for both RFS (HR = 1.20, 95% CI = [1.03, 1.39], p-value = 0.019) and OS (HR = 1.31, 95% CI = [1.10, 1.55], p-value = 0.002) after accounting for age, sex, Fong risk score, primary tumour location and metastasis timing. Elevated ctDNA levels post-operatively were significantly associated with shorter RFS (p-value = 0.03), but not OS (p-value = 0.16). INTERPRETATION: This study demonstrated 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 on administering peri-operative chemotherapy. FUNDING: Dutch Cancer Society, Dutch Digestive Health Fund.

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