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A proposal, untested: when a blood test finds a tumour fragment after treatment, also read the chemical marks on that same piece of DNA, which might show whether the cell it came from was making the oestrogen receptor or TROP2.
This is a proposal with no evidence yet that it works. Ultrasensitive residual disease tests find a handful of tumour-derived molecules by their mutations, and then discard everything else those molecules carry. The same fragment also carries its methylation, and TROP2 expression is controlled mainly by methylation of its gene rather than by mutation (Notini 2026). Reading a tracked tumour mutation and the methylation of nearby CpG sites on one molecule would tie each rare tumour fragment to an epigenetic state, so that even a few molecules could carry phenotype information that tumour-naive methods (Griffin, METER, cfChIP-seq) only recover at 3 to 5 per cent tumour fraction. Duplex strand reading such as SaferSeqS shows single rare molecules can be read accurately; whether their methylation can be read at the same time, and whether a few fragments near a mutation say anything about ESR1 or TACSTD2 regulation elsewhere in the genome, is unknown.
If TROP2 levels are set by methylation rather than by mutation, a blood test that tracks a tumour's mutations carries almost no information about whether the cells left behind make TROP2. A test that reads methylation might.
Methylation in blood can say whether advanced breast cancer still carries the oestrogen receptor. Subtyping still needs percent-level tumour content.
One negative blood test after surgery misses about half of the people who will relapse, even with a very broad tumour-informed panel; repeated testing catches more. The test's sensitivity is limited by how much DNA the tumour sheds, not only by the assay.
The phenotype of advanced breast cancer, not only its mutations, can be read from blood. The method needs percent-level tumour DNA, so it does not yet reach residual disease after surgery.
Error is no longer what stops a blood test reading one rare molecule; how many molecules there are is.
Resistance can come from different subclones in the same person, each with its own mechanism, and one of them changed the TROP2 protein itself. It is the clearest published link between a residual clone and a TROP2 phenotype, made from tissue at progression rather than from blood.
Shares ECLIPSE (subclone tracking from ctDNA), Naming which clone or phenotype is left after treatment, Tumour heterogeneity and clonal evolution, Dormant cells and minimal residual disease.
Shares Griffin (nucleosome profiling of cell-free DNA), Naming which clone or phenotype is left after treatment, Cell-free DNA (cfDNA), DNA methylation profiling.
Shares Naming which clone or phenotype is left after treatment, Minimal / molecular residual disease (MRD), Circulating tumour DNA (ctDNA), MRD / molecular residual disease testing.
Shares ctDNA tests roadmap: from a curiosity in plasma to blood tests that decide treatment, Minimal / molecular residual disease (MRD), Circulating tumour DNA (ctDNA), MRD / molecular residual disease testing.
Shares Griffin (nucleosome profiling of cell-free DNA), Naming which clone or phenotype is left after treatment, Cell-free DNA (cfDNA), Circulating tumour DNA (ctDNA).
Shares DNA methylation profiling, Dormant cells and minimal residual disease, ctDNA tests roadmap: from a curiosity in plasma to blood tests that decide treatment, Minimal / molecular residual disease (MRD).
Shares Naming which clone or phenotype is left after treatment, Estrogen receptor (ERα), Minimal / molecular residual disease (MRD), Circulating tumour DNA (ctDNA).
Shares DNA methylation profiling, ctDNA tests roadmap: from a curiosity in plasma to blood tests that decide treatment, Minimal / molecular residual disease (MRD), Circulating tumour DNA (ctDNA).
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