Navigating the Landscape of Liquid Biopsy in Colorectal Cancer: Current Insights and Future Directions

Abstract

Liquid biopsy has emerged as a valuable tool for the detection and monitoring of colorectal cancer (CRC), providing minimally invasive insights into tumor biology through circulating biomarkers such as circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Additional biomarkers, including tumor-educated platelets (TEPs) and exosomal RNAs, offer further potential for early detection and prognostic role, although ongoing clinical validation is still needed. This review summarizes the current evidence on the diagnostic, prognostic, and predictive capabilities of liquid biopsy in both metastatic and non-metastatic CRC. In the non-metastatic setting, liquid biopsy is gaining traction in early detection through screening and in identifying minimal residual disease (MRD), potentially guiding adjuvant treatment and reducing overtreatment. In contrast, liquid biopsy is more established in metastatic CRC for monitoring treatment responses, clonal evolution, and mechanisms of resistance. The integration of ctDNA-guided treatment algorithms into clinical practice could optimize therapeutic strategies and minimize unnecessary interventions. Despite promising advances, challenges remain in assay standardization, early-stage sensitivity, and the integration of multi-omic data for comprehensive tumor profiling. Future efforts should focus on enhancing the sensitivity of liquid biopsy platforms, validating emerging biomarkers, and expanding multi-omic approaches to support more targeted and personalized treatment strategies across CRC stages.

Keywords: adjuvant therapy guidance; colorectal cancer; liquid biopsy; minimal residual disease; resistance mechanisms.

Figure 1

Clinical applications of liquid biopsy in colorectal cancer. The figure illustrates the sources, analytes, and clinical applications of liquid biopsy in CRC. On the left, different body fluids (blood, urine, saliva, and bronchoalveolar lavage fluid) are depicted as collection matrices. The central circle highlights the key analytes, including circulating tumor DNA (ctDNA), cell-free DNA (cfDNA), microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), proteins, tumor-educated platelets (TEPs), and exosomes. The outer ring summarizes the major clinical applications across the CRC continuum: screening, minimal residual disease (MRD) detection, prognosis, rechallenge and treatment selection, and monitoring. This schematic figure underscores the multidimensional utility of liquid biopsy by integrating diverse analytes and specimen types at various decision-making points throughout CRC management.

Figure 2

Proposed stage-specific algorithm for integrating liquid biopsy in CRC management. (a) Screening: liquid biopsy used for early detection; a positive ctDNA result leads to colonoscopy and potential early diagnosis, while a negative test prompts follow-up or repeat testing. (b) Localized CRC: post-surgical ctDNA assessment to guide adjuvant chemotherapy decisions. (c) mCRC: liquid biopsy enables molecular profiling to support treatment selection and monitoring response. CRC = colorectal cancer; ctDNA = circulating tumor DNA; MRD = minimal residual disease; CHT = chemotherapy; adj = adjuvant; EGFR = epidermal growth factor receptor.