Early changes in circulating tumor DNA (ctDNA) and outcome during systemic palliative treatment for metastatic colorectal cancer: A systematic review and meta-analysis — An initiative under the ctDNA RECIST program

BackgroundIn metastatic colorectal cancer (mCRC), decisions during systemic palliative treatment are primarily based on the imagine-based Response Evaluation Criteria in Solid Tumors (RECIST). However, RECIST is known to be a suboptimal surrogate marker for survival. Hence, there is an urgent need for better surrogate markers. This systematic review aims to evaluate the current knowledge on the prognostic value of early changes in ctDNA during systemic palliative treatment of mCRC.MethodsThe systematic review by Callesen et al (PROSPERO: CRD42019125630) was updated focusing on studies reporting a prognostic value of early changes in ctDNA during systemic palliative treatment for mCRC. PubMed was searched on 08/04/2024. We performed separate random-effects meta-analyses to investigate if early changes in ctDNA levels during treatment were associated with survival. Studies reporting a hazard ratio (HR) based on univariate analysis, corresponding 95% confidence interval (95%CI), and the number of patients (n) included in the analysis were included in the meta-analysis.ResultsA total of 52 studies were included with around 7.000 patients. The inter-study heterogeneity was significant not allowing evaluation of the optimal time for blood sampling, ctDNA marker, cut-off, or analytical methods. Despite interstudy heterogeneity, the tendency across studies was uniform; a decrease in ctDNA during systemic palliative treatment was associated with treatment response and prolonged survival. Twenty studies were included in meta-analyses. An early decrease in ctDNA levels during treatment was associated with longer PFS (HR=2.8;95%CI 2.3-3.4;n=848) and OS (HR=2.5;95%CI 2.1-3.1;n=877).ConclusionsIn conclusion, early ctDNA dynamic during systemic palliative treatment is a strong prognostic marker with the opportunity to assist or even replace radiological evaluations. However, there is an urgent need for prospective clinical trials with a standardized methodology to evaluate the added clinical value for the patients. This is the focus of the ctDNA RECIST program.Legal entity responsible for the studyThe authors.FundingLC was supported by DCCC ctDNA Research Center—The Danish Research Center for Circulating Tumor DNA Guided Cancer Management, Danish Cancer Society (grant no. R257-A14700) and Danish Comprehensive Cancer Centers. KLS was supported by Health Research Foundation of Central Denmark Region (grant no. A1602). Funding has been provided by Danish Cancer Society, Health Research Foundation of Central Denmark Region.DisclosureAll authors have declared no conflicts of interest.