Liquid biopsy vs. tissue NGS: choosing the right specimen for solid tumour profiling

Solid tumour molecular profiling can be performed on two specimen types: tissue (typically formalin-fixed paraffin-embedded, FFPE, blocks or fresh frozen tumour) and liquid biopsy (circulating cell-free DNA, cfDNA, extracted from peripheral blood). The two approaches are complementary rather than interchangeable. Choosing the right specimen depends on the clinical question, the material available, and the degree of sensitivity required.

Tissue-based NGS remains the standard of care for initial tumour profiling in most solid tumours. FFPE material from a biopsy or resection specimen allows direct assessment of tumour cells, typically yields higher tumour content, and produces comprehensive mutational profiles across large gene panels. When adequate tissue is available from a recent, representative biopsy, tissue-based NGS should generally be the first choice for treatment selection — particularly in the newly diagnosed setting.

Liquid biopsy has distinct advantages in several clinical scenarios. When adequate tumour tissue is unavailable — because of biopsy inaccessibility, insufficient material on prior sampling, or exhaustion of the tumour block — cfDNA testing provides an alternative route to molecular profiling. Liquid biopsy is also the preferred approach for monitoring treatment response and detecting acquired resistance: because blood can be sampled serially, it enables real-time tracking of the mutational landscape without repeat invasive biopsies. In addition, cfDNA testing can capture tumour heterogeneity across metastatic sites that a single-site biopsy may miss.

The key limitation of liquid biopsy is sensitivity. Detection depends on the amount of circulating tumour DNA shed into the bloodstream, which varies by tumour type, burden, and anatomical location. Tumours with low shedding — including many CNS tumours, early-stage disease, and some gastrointestinal primaries — may yield false-negative results. A negative cfDNA result does not exclude targetable alterations, and in these settings tissue testing should be prioritised. Most cfDNA platforms have a lower limit of detection that may miss low-frequency subclonal variants or alterations present in only a small fraction of circulating DNA.

When ordering, start with the clinical question. Is this initial profiling for treatment selection in a newly diagnosed patient with accessible tissue? Choose tissue NGS. Is this a patient with disease progression on targeted therapy, or one where repeat biopsy carries unacceptable risk? Liquid biopsy is appropriate. In some cases — particularly advanced disease with high tumour burden — both can be complementary: tissue to establish the baseline profile, cfDNA to track resistance evolution. Contact Advanced Consensus with the clinical context and specimen available; we can help identify the most appropriate assay and laboratory pathway.