Circulating tumor DNA as prognostic marker in patients with metastatic colorectal cancer undergoing systemic therapy: A systematic review and meta-analysis

Abstract

Background: The response to systemic therapy against metastatic colorectal cancer (mCRC) is currently assessed by radiologic imaging. However, an increasing number of studies have shown that circulating tumor DNA (ctDNA) as liquid biopsy can be used as an alternative method to assess therapy efficacy. We conducted a systematic review with subsequent meta-analysis of primary studies to assess the prognostic value of sequential liquid biopsies in patients with metastatic colorectal cancer treated with systemic therapy.

Methods: Randomized, non-randomized, and prospective observational studies, reporting on the change in ctDNA concentration in total cell-free DNA over the course of systemic therapy of patients treated for metastatic colorectal cancer to predict treatment response according to RECIST criteria were included.

Results: Fifty-six studies involving 3735 evaluable patients with metastatic colorectal cancer were included in the meta-analysis. ctDNA increase during systemic therapy as compared to baseline was strongly associated with progression-free survival (HR: 2.44, 95% CI: 2.02-2.95) and overall survival (HR: 2.53, 95% CI: 2.01-3.18), which were reported in 39 and 33 studies, respectively.

Conclusion: Our analyses underscore the strong prognostic value of longitudinal plasma-based ctDNA analysis through liquid biopsy in mCRC patients. Subsequent research should evaluate the role of ctDNA in guiding therapy decisions, particularly in identifying patients likely to benefit from continuation or change of systemic therapy. While further standardization of ctDNA testing remains necessary, current evidence supports integrating serial ctDNA monitoring into upcoming clinical mCRC intervention trials, to lay the groundwork for its inclusion into future RECIST versions.

Protocol registration: The protocol for this review was registered on PROSPERO (CRD42023420012).

Keywords: Circulating tumor DNA; Colorectal cancer; Liquid biopsy; Meta-analysis; Metastasis; Systematic review; Systemic therapy.