Liquid Biopsy Advances Precision Medicine for Colorectal Cancer Management

Liquid biopsy, as a source of circulating tumour DNA (ctDNA), has been utilized to characterize tumour molecular heterogeneity, facilitating the identification of actionable targets for precision medicine-guided therapies and the detection of emerging genomic drivers of drug resistance in patients with metastatic colorectal cancer. In addition, liquid biopsy-based analysis of ctDNA has been validated as a tool for detecting minimal residual disease (MRD) following locoregional treatment in patients with localized colon or rectal cancer, offering improved prognostic stratification and supporting the tailoring of adjuvant systemic therapy.

Methodological evolution from PCR analysis of a few known mutations in one gene or a small panel of genes to the assessment of hundreds of genes and pathogenic variants by next-generation sequencing has enabled comprehensive genomic profiling (CGP), thereby improving knowledge of cancer molecular complexity at the individual patient level. Liquid biopsy-based CGP is an easily repeatable and minimally invasive approach that can provide a dynamic portrait of colorectal cancer molecular heterogeneity to guide personalized and adaptive treatment based on biomarkers of response and resistance.

In metastatic colorectal cancer, plasma ctDNA sequencing was initially used to test for 'hotspot' point mutations in single genes (KRAS, NRAS and BRAF) to guide anti-EGFR antibody therapy in patients without tumour tissue available for analysis. Subsequently, next-generation sequencing has extended the potential clinical use of liquid biopsy-based ctDNA testing, enabling more comprehensive genomic profiling to detect a wider range of potentially actionable gene alterations, as well as to identify molecular mechanisms of cancer cell resistance to therapy.

Liquid biopsy enables real-time, longitudinal monitoring of disease and might facilitate precision oncology by capturing patient-specific tumour molecular alterations throughout the disease course, thereby informing individualized treatment decisions. Liquid biopsy enables non-invasive analysis of circulating tumour DNA in patients with metastatic colorectal cancer and facilitates the detection of minimal residual disease following definitive locoregional therapy in patients with early-stage colorectal cancer.

In patients with early-stage colorectal cancer, MRD after initial locoregional treatment is highly predictive of disease recurrence; therefore, escalation or de-escalation of adjuvant therapy based on the presence or absence of detectable ctDNA, respectively, is under ongoing evaluation in several trials, as are opportunities for non-operative management in some patients.

The implementation of liquid biopsy analysis in colorectal cancer poses several challenges, including limited sensitivity in the context of metastatic tumour sites associated with low levels of ctDNA shedding, the need to define optimal strategies for MRD detection following curative-intent treatment of locoregional disease, and the requirement to broaden accessibility at a reasonable cost.