Circulating tumor cells and tumor DNA in patients with resectable colorectal liver metastases: The MIRACLE.

3011 Background: Recurrence risk after curative surgery for colorectal liver metastases (CRLM) remains high, underlining the need for prognostic markers to detect minimal residual disease after local treatment. The aim of this study was to determine the association between recurrence-free survival (RFS) and detection of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) before and after surgical treatment of resectable CRLM. Methods: The MIRACLE isa prospective, observational biomarker study in patients with isolated, resectable CRLM without (neo)adjuvant chemotherapy, recruited between October 2015 and December 2021. The study was powered to detect at least a 20% difference in one-year recurrence rate between detectable and undetectable circulating tumor load after surgery. Blood samples were collected one day before surgery (T0) and three weeks (T3) after surgery. CTCs were enumerated using the FDA-approved CellSearch system. ctDNA before surgery was measured by next generation sequencing (NGS) using a targeted panel (Oncomine Colon cfDNA assay) and postoperatively by digital PCR (dPCR). Results: CTC enumeration resulted in positivity for 43 out of 192 patients (22%) at baseline and 14 out of 161 patients (9%) at T3. ctDNA was detected in 125 out of 191 patients (65%) at baseline, of which 25 (20%) still had detectable ctDNA at T3. Patients with postoperative undetectable CTC had a significantly improved RFS (1-year RFS: 15% vs. 51%, log-rank test p=0.009). Also, patients with postoperative undetectable ctDNA had a significantly improved RFS (1-year RFS: 20% vs. 54%, log-rank test p<0.001). In multivariable analysis, at baseline no association was found between RFS and CTCs (HR 1.01; p=0.97) or ctDNA (HR 1.29; p=0.29). In contrast, after surgery a significantly shorter RFS was observed in patients with detectable CTCs (HR 3.09; p=0.002) and ctDNA (HR 3.53; p<0.001). Postoperative ctDNA status was a stronger predictor of recurrence compared to known clinical risk factors. Conclusions: This is the first study conducted in patients with resectable CRLM without (neo)adjuvant chemotherapy, which demonstrates the impact of detectable circulating tumor load after surgery on RFS. Postoperative ctDNA and CTC detection are a strong predictor for a shorter RFS after local treatment, as opposed to preoperative ctDNA or CTC detection. Table: see text