Liquid Biopsy

Plasma-based testing analyses circulating tumour DNA when tissue is limited, inaccessible or no longer representative of current disease. It complements, rather than replaces, tissue-based analysis.

When plasma testing is informative

Circulating tumour DNA (ctDNA) is tumour-derived cell-free DNA (cfDNA) shed into the bloodstream. Analysing it allows a genomic question to be asked from a peripheral blood sample rather than from tissue. This matters in three recurring clinical situations: when a biopsy is not safely accessible, when the available tissue block is exhausted or of insufficient quality, and when disease has evolved since the archival specimen was taken and that specimen no longer reflects the tumour being treated.

Plasma analysis is complementary to tissue analysis rather than a substitute for it. A variant detected in plasma is informative; the absence of a variant is harder to interpret, because shedding varies with tumour burden, site and biology. A negative plasma result therefore does not exclude an alteration, and tissue testing remains appropriate where the clinical question requires it.

Interpreting plasma findings

Plasma results are read together with the tissue result, the treatment history and the clinical course. Two considerations recur. Clonal haematopoiesis of indeterminate potential can place variants into plasma that arise from the haematopoietic compartment rather than from the tumour, and it becomes more common with age. Variant allele fractions in plasma are typically low, so assay sensitivity, input quantity and pre-analytical handling all bear on how a result should be read.

Where a plasma finding would change management, orthogonal confirmation is considered in the context of the wider result set.

ESR1 and endocrine-resistant disease

ESR1 mutations are an acquired mechanism of resistance to endocrine therapy in hormone-receptor-positive breast cancer, and they emerge under treatment pressure. Because they appear during therapy rather than at diagnosis, plasma is a natural sampling compartment. The department performs ESR1 mutation testing by droplet digital PCR, an approach suited to detecting a defined alteration at low allele fraction, and participates in QuIP external quality assessment for this assay — see Quality Assurance.

Relationship to the wider service

Plasma work sits alongside tissue-based Solid Tumor Genomics and germline Hereditary Cancer Genomics; a complete picture often draws on more than one of them. Methodological development in cell-free DNA is described under the Cancer Genetics & Genomics research programme.