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

Abstract

Background: Loco-regional treatment strategies of colorectal cancer (CRC) metastases are evolving, but biological markers that can benefit patients and assist physicians in clinical decisions are lacking. The primary objective of this systematic review and meta-analysis is to investigate the current knowledge on circulating DNA and its clinical utility in predicting outcomes in patients undergoing loco-regional treatment of CRC metastases.

Methods: A systematic search of PubMed, Embase, and Cochrane Central Register of Controlled Trials was conducted on March 22, 2022. We included studies on patients undergoing loco-regional treatment of CRC metastases reporting the predictive or prognostic value of circulating DNA in the blood. Hazard ratios (HR) were pooled in separate random-effects meta-analyses to investigate if pre- or post-ablation measurements of circulating DNA were associated with survival. The risk of bias was assessed according to the Quality in Prognosis Studies tool.

Results: Twenty-eight studies with 2868 patients were included, of which 16 studies were eligible for meta-analyses. As expected in this new research field, a majority of included studies (n = 21/28) had a high risk of bias in at least one domain. Circulating DNA above the cutoff in a plasma sample taken before loco-regional treatment was associated with a short recurrence-free survival [pooled HR = 2.8, 95% confidence interval (CI) 1.4-5.7, n = 162] and overall survival (pooled HR = 4.7, 95% CI 1.1-20.6, n = 105). Circulating DNA above the cutoff in a plasma sample taken after loco-regional treatment was associated with a short recurrence-free survival (pooled HR = 4.5, 95% CI 3.4-6.1, n = 569) and overall survival (pooled HR = 7.5, 95% CI 2.0-27.3, n = 161). There was limited data on the association between dynamics in circulating DNA and outcome.

Conclusions: Measurements of circulating DNA can be valuable when selecting and monitoring patients undergoing loco-regional treatment of CRC metastases. Studies designed to investigate the true clinical utility of circulating DNA in the context of various ablation modalities are warranted.The review has been registered at PROSPERO (ID: CRD42022320032).

Keywords: biomarker; cell-free DNA; circulating free DNA; circulating tumor DNA; loco-regional treatment; metastatic colorectal cancer.

Figure 1.

Schematic overview of clinical applications of liquid biopsies in patients undergoing loco-regional treatment of colorectal cancer metastases. RFS, recurrence-free survival; OS, overall survival.

Figure 2.

PRISMA diagram and eligible studies by year of publication. (a) PRISMA flow diagram of the study selection process and (b) number of included studies by year of publication.

Figure 3.

Assessment of risk of bias using Quality in Prognosis Studies tool. The authors’ judgments regarding each risk-of-bias domain presented as percentages across all included studies.

Figure 4.

Forest plots of the association between circulating DNA and survival. Forest plots of the association between circulating DNA above the cutoff in a pre-ablation sample and RFS (a) and OS (b); between circulating DNA above the cutoff in a post-ablation sample and RFS (c) and OS (d); all under the random-effects model. Studies ordered according to publication date. CI, confidence interval; HR, hazard ratio; n, number of patients included in the analysis; OS, overall survival; RFS, recurrence-free survival. *More than one result with complete data due to test of different circulating DNA markers. Results from the analysis with circulating tumor DNA detectability as marker are included in the meta-analysis. **Same research group.