A prospective study of methylated ctDNA in patients undergoing treatment for liver metastases from colorectal cancer

Background: Decision regarding local treatment of colorectal liver metastases (CRLM) is a multidisciplinary assessment, and liver intervention should be performed when the metastases are deemed resectable. There is no standard biomarker to aid neither this decision nor the postoperative treatment decisions. The present prospective, observational study aimed to investigate the potential clinical utility of a combined tumor-specific and organ-specific methylated circulating DNA assay in the perioperative setting of CRLM. Material and methods: The study included 56 cases with CRLM. Blood samples were drawn preoperatively and postoperatively. Multiplex methylation analysis of the markers NPY, KANK1, and GAL3ST3 (meth-ctDNA) was performed using droplet digital PCR. Results: The assay detected preoperative and postoperative meth-ctDNA in 37 % and 46 % of patients, respectively. Patients with negative preoperative meth-ctDNA had a longer median PFS compared to those with positive preoperative meth-ctDNA (HR = 2.2, 95 % CI 1.2-3.9, p G 0.01). In a multivariate analysis, preoperative negative meth-ctDNA was identified as a strong independent predictor of PFS (HR = 3.3, 95 % CI 1.5-7.2, p G 0.01). Similarly, patients with negative postoperative meth-ctDNA had longer median PFS (HR = 3.0, 95 % CI = 1.6-5.6, p G 0.001) and OS (HR = 4.1, 95 % CI 1.9-9.1, p G 0.001) compared to those with positive postoperative meth-ctDNA. Conclusion: Preoperative meth-ctDNA may serve as an important biomarker to inform the multidisciplinary assessment and treatment planning of CRLM. Negative meth-ctDNA may indicate the optimal timing for liver intervention, whereas positive meth-ctDNA may indicate initiation or re-orientation of chemotherapy, or immediate local intervention. Our results confirm postoperative negative meth-ctDNA as a strong prognostic marker of survival.