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Clinical Studies

Circulating tumour DNA and its clinical utility in predicting treatment response or survival in patients with metastatic colorectal cancer: a systematic review and meta-analysis

Abstract

Background

We investigate the current knowledge on circulating tumour DNA (ctDNA) and its clinical utility in predicting outcomes in patients with metastatic colorectal cancer (mCRC).

Methods

PubMed, Embase, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials were searched. Last search 16/12/2020. We included studies on patients with mCRC reporting the predictive or prognostic value of ctDNA. We performed separate random-effects meta-analyses to investigate if baseline ctDNA and early changes in ctDNA levels during treatment were associated with survival. The risk of bias was assessed according to the Quality in Prognosis Studies tool.

Results

Seventy-one studies were included with 6930 patients. Twenty-four studies were included in meta-analyses. High baseline ctDNA level was associated with short progression-free survival (PFS) (HR = 2.2; 95% CI 1.8–2.8; n = 509) and overall survival (OS) (HR = 2.4; 95% CI 1.9–3.1; n = 1336). A small or no early decrease in ctDNA levels during treatment was associated with short PFS (HR = 3.0; 95% CI 2.2–4.2; n = 479) and OS (HR = 2.8; 95% CI 2.1–3.9; n = 583). Results on clonal evolution and lead-time were inconsistent. A majority of included studies (n = 50/71) had high risk of bias in at least one domain.

Conclusions

Plasma ctDNA is a strong prognostic biomarker in mCRC. However, true clinical utility is lacking.

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Fig. 1: Schematic overview of clinical applications of liquid biopsies in patients with metastatic colorectal cancer during systemic anti-cancer treatment.
Fig. 2: PRISMA diagram and eligible studies by year of publication.
Fig. 3: Assessment of risk of bias using QUIPS (Quality in Prognosis Studies) tool.
Fig. 4: Forest plots of the association between ctDNA levels and survival.

Data availability

The full text of all included studies were retrieved from the online databases PubMed, Embase, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials. The data of this systematic review and meta-analyses are all public and available from PubMed, Embase, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials. Template data collection forms, data extracted from included studies, data used for analyses and analytic code used and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We would like to thank Marie Susanna Isachsen, Senior Librarian, University of Oslo for help in developing the search string. Additionally, we would like to thank Lene Kristine Juvet, Scientific Director, Norwegian Institute of Public Health and Kjell M. Tveit, Professor Emeritus, University of Oslo for valuable scientific discussions.

Funding

LC 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. Registered PROSPERO(CRD42019125630). The remaining authors received no specific funding for this work.

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Study concept and design: JH, AB, KLS, LC, data collection and collation: JH, AB, LC, statistical analysis: JH, LC, writing—original draft: JH, LC, writing—review and editing: JH, AB, NP, TKG, EHK, KLS, LC, Interpretation of the data, critical revision of the paper for important intellectual content and approval of the final paper for submission: JH, AB, NP, TKG, EHK, KLS, LC. The corresponding author proves that all listed authors meet the authorship criteria, and that no other eligible authors have been omitted.

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Correspondence to Louise B. Callesen.

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Callesen, L.B., Hamfjord, J., Boysen, A.K. et al. Circulating tumour DNA and its clinical utility in predicting treatment response or survival in patients with metastatic colorectal cancer: a systematic review and meta-analysis. Br J Cancer 127, 500–513 (2022). https://doi.org/10.1038/s41416-022-01816-4

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