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Blood tests can now find a few parts per million of tumour DNA after treatment, but at those levels there are too few molecules to say which branch of the tumour is left, or whether it still carries the oestrogen receptor or TROP2.
Ultrasensitive residual disease tests reach a few parts per million by adding up evidence across hundreds to about 1,800 tracked mutations: NeXT Personal reports a 95 per cent limit of detection of 3.45 parts per million (Northcott 2024). Saying which subclone the tumour DNA came from cannot pool that way, because it may use only the mutations private to that subclone. The published tool built for the job, ECLIPSE from TRACERx, states its operating point at 0.1 per cent clonal ctDNA (1,000 parts per million) with at least 10 ng of DNA, for a subclone present in 20 per cent of cancer cells and tracked by four mutations (Abbosh 2023). That is about a hundred to three hundred times above where detection now works.
Breast cancer makes the gap wider. Patients in one early breast cancer study had a median of 57 trackable mutations (range 2 to 346) (Parsons 2020), against TRACERx's median of 200 in lung cancer, and commercial panels are deliberately built from clonal, trunk mutations. The phenotype question is harder still: TROP2 expression is set mainly by DNA methylation rather than by mutation (Notini 2026), TROP2 PET uptake changes with treatment (Liu 2026), and the methods that read oestrogen receptor activity from blood (Griffin, METER, cfChIP-seq) were validated at 3 to 5 per cent tumour fraction, four orders of magnitude above residual disease. The one published case tying a resistant subclone to a TROP2 change, TACSTD2 T256R on one branch and TOP1 E418K on another under sacituzumab govitecan, was read from tissue at progression (Coates 2021). No commercial residual disease report reviewed on 4 November 2026 names the clone that remains.
TROP2 is not a fixed property of a breast cancer; treatment can move it. A test of TROP2 taken at diagnosis may not describe what is left later.
At these levels the honest unit is a count of molecules, not an allele fraction, which is the counting limit behind attributing residual disease to a clone.
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.
Surveillance blood tests in hormone-receptor-positive breast cancer find relapse, but often too late to act on it before scans show it. The randomised question, whether treating at molecular relapse helps, has not yet reported.
Subclonal variants are seen less often in residual disease than clonal ones, which is what limits attributing what is left to a subclone.
Personalised whole-genome designs can detect tumour DNA at a few parts per million. The panel favours variants present at high fraction in the tumour, so it is built to detect the trunk, not to tell branches apart.
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.
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 Utility of circulating tumor DNA in cancer diagnostics with emphasis on early detection, Genome-wide ctDNA mutation integration (MRDetect, MRD-EDGE), Plasma epigenomic profiling (cfChIP-seq), EPIC-seq (expression inference from cell-free DNA).
Shares Analytical validation of NeXT Personal®, an ultra-sensitive personalized circulating tumor DNA assay, ctDNA MRD positivity (molecular residual disease after curative treatment), ctDNA tests roadmap: from a curiosity in plasma to blood tests that decide treatment, MRD / molecular residual disease testing.
Shares Highly Accurate Detection of Circulating Tumor DNA for Monitoring Minimal Residual Disease in Solid Tumors: Analytical and Clinical Validation of the Haystack MRD Assay, Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer, Analytical validation of NeXT Personal®, an ultra-sensitive personalized circulating tumor DNA assay, Personalized and Tumor Informed Circulating Tumor DNA Assay for Molecular Residual Disease Monitoring of Solid Malignancies.
Shares ctDNA MRD positivity (molecular residual disease after curative treatment), ctDNA tests roadmap: from a curiosity in plasma to blood tests that decide treatment, MRD / molecular residual disease testing, Liquid biopsy (ctDNA).
Shares METER (methylome-based ctDNA detection and subtyping), Read methylation and mutation on the same cell-free DNA fragment to tell what kind of cancer is left, Estrogen receptor (ERα), HR-positive / HER2-negative breast cancer.
Shares Genome-wide ctDNA mutation integration (MRDetect, MRD-EDGE), ctDNA MRD positivity (molecular residual disease after curative treatment), ctDNA tests roadmap: from a curiosity in plasma to blood tests that decide treatment, MRD / molecular residual disease testing.
Shares Utility of circulating tumor DNA in cancer diagnostics with emphasis on early detection, Genome-wide ctDNA mutation integration (MRDetect, MRD-EDGE), Plasma epigenomic profiling (cfChIP-seq), Highly Accurate Detection of Circulating Tumor DNA for Monitoring Minimal Residual Disease in Solid Tumors: Analytical and Clinical Validation of the Haystack MRD Assay.
Shares Griffin (nucleosome profiling of cell-free DNA), Read methylation and mutation on the same cell-free DNA fragment to tell what kind of cancer is left, Estrogen receptor (ERα), HR-positive / HER2-negative breast cancer.
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