Postoperative circulating tumour DNA is associated with pathologic response and recurrence-free survival after resection of colorectal cancer liver metastases

Abstract

Background Recurrence rates after resection of colorectal cancer liver metastases (CRLM) are high and correlate with worse survival. Postoperative circulating tumour DNA (ctDNA) is a promising prognostic biomarker. Focusing on patients with resected CRLM, this study aimed to evaluate the association between the detection of postoperative ctDNA, pathologic response and recurrence-free survival (RFS). Methods Twenty-three patients were selected from an ongoing phase-3 trial who underwent resection of RAS -mutant CRLM after induction systemic treatment. CtDNA analysis was performed by droplet digital PCR using blood samples collected at baseline, before and after resection. Pathologic response of CRLM was determined via the Tumour Regression Grading system. Findings With a median follow-up of 19.6 months, the median RFS for patients with detectable ( N = 6, [26%]) and undetectable ( N = 17, [74%]) postoperative ctDNA was 4.8 versus 12.1 months, respectively. Among 21 patients with available tumour tissue, pathologic response in patients with detectable compared to undetectable postoperative ctDNA was found in one of six (17%) and 15 of 15 (100%) patients, respectively ( p < 0.001). In univariable Cox regression analyses both postoperative detectable ctDNA (HR = 3.3, 95%CI = 1.1–9.6, p = 0.03) and pathologic non-response (HR = 4.6, 95%CI = 1.4–15, p = 0.01) were associated with poorer RFS and were strongly correlated ( r = 0.88, p < 0.001). After adjusting for clinical characteristics in pairwise multivariable analyses, postoperative ctDNA status remained associated with RFS. Interpretation The detection of postoperative ctDNA after secondary resection of CRLM is a promising prognostic factor for RFS and appeared to be highly correlated with pathologic response.

Comparing single‐target and multitarget approaches for postoperative circulating tumour DNA detection in stage II–III colorectal cancer patients

“…As the MT strategies were the same, the difference to our results likely reflects the rigor with which our ST‐ddPCR analyses were conducted. In contrast to the Loupakis study, and several other studies using ddPCR for ctDNA detection [ 28 , 36 , 37 , 38 ], our targets were carefully selected from WES data after a thorough clonality assessment. While the addition of WES prior to ST analysis increases costs, including it minimizes the risk of tracking a subclonal and noninformative variant.…”

Circulating DNA in patients undergoing loco-regional treatment of colorectal cancer metastases: a systematic review and meta-analysis

“…18 Meta-analysis of the association between postablation circulating DNA and RFS included 10 eligible studies. 2,23,25,[27][28][29]31,34,35,36 Circulating DNA above the cutoff in a post-ablation sample was associated with a shorter RFS (pooled HR = 4.5, 95% CI 3.4-6.1, n = 569) (Figure 4(c)), and the funnel plots indicated no major publication bias (Supplemental Figure 2). Minimal heterogeneity was observed (χ 2 = 10.5, df = 10, p = 0.31, I 2 = 28.5%).…”

“…27 The analytical methods used included polymerase chain reaction (PCR) based methods (e.g., BEAMing, ddPCR) (n = 13/28), 2,12,14,19,20,[28][29][30][31][32]35,37,39 targeted sequencing (n = 11/28), 17,18,[21][22][23][24][25][26][27]33,36 direct fluorescent assay (DFA) (n = 2/28), 38,15 mass spectrometry (n = 1/28), 40 or combined PCR and targeted sequencing (n = 1/28). 34 The majority of studies chose a tumor-agnostic marker of ctDNA, that is, assays covering mutations in RAS/BRAF (n = 6/28), 2,12,20,30,35,40 large gene panels covering various numbers of genes (n = 6/28), 21,22,25,26,33,36 or epigenetic markers (n = 2/28). 29,27 Less frequently a tumor-informed approach was applied (n = 7/28) 14,23,24,…”

The Impact of Molecular Biology in the Seeding, Treatment Choices and Follow-Up of Colorectal Cancer Liver Metastases—A Narrative Review

“…Kobayashi et al showed that patients with resectable CRCLM who had preoperative detectable ctDNA in their plasma had statistically lower DFS and a tendency to have lower OS [ 71 ]. Achieving undetectable levels of ctDNA after CRCLM resection seems also to be associated with better DFS and a good pathological response to neoadjuvant chemotherapy [ 63 , 72 , 73 ]. Tie at al observed a 40-fold decrease in mutated ctDNA levels after neoadjuvant chemotherapy.…”