A new expert framework highlights how tissue next-generation sequencing (NGS) and liquid biopsy (ctDNA) should be used together in metastatic colorectal cancer rather than as interchangeable tests. Experts recommend ordering both at diagnosis because chemotherapy can quickly reduce ctDNA shedding, making later liquid biopsies less informative. Tissue testing captures the local tumor environment, while ctDNA reflects the dominant metastatic clone circulating in the bloodstream.
The report also shows that ctDNA accuracy depends heavily on metastatic location. Liver metastases shed DNA reliably, but lung-only, peritoneal, and soft tissue metastases often produce false-negative liquid biopsy results.
Researchers warned that liquid biopsy can overestimate biomarkers such as MSI-high and tumor mutational burden, meaning immunotherapy decisions should still require tissue confirmation. However, ctDNA may identify HER2 amplifications missed by tissue biopsies due to tumor heterogeneity.
Repeat ctDNA testing is recommended mainly at resistance to anti-EGFR, HER2-targeted, or BRAF-directed therapies, where it may help guide treatment rechallenge strategies.