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A proposal, unproven at residual disease levels: add the tumour's RNA to the tumour DNA a blood test already tracks, because a cell holds many more RNA copies of an active gene than DNA copies, and RNA could also show whether the cancer still makes the oestrogen receptor or TROP2.
Residual disease tests count tumour DNA fragments, and at a few parts per million a tube holds only a handful (see the bottleneck). A cell has two copies of each gene but between 50,000 and 300,000 messenger RNA molecules in total (Marinov 2014), and RNA carries what DNA cannot: whether ESR1 or TACSTD2 (TROP2) is switched on, splice forms such as AR-V7, and fusions. The proposal is to design both halves of the test from the tumour's own whole-genome and RNA sequencing: track the mutations in cell-free DNA as now, and in the same plasma read transcripts that the tumour expresses strongly and normal blood does not, plus the ESR1 and TACSTD2 transcripts.
What is measured supports trying it. In lung cancer, reading EGFR mutations from vesicle RNA and cell-free DNA together raised sensitivity from 26 to 74 per cent in patients whose disease sheds little (Krug 2018); RNA alone caught ALK fusions in two patients whose DNA was negative (Heeke 2025); GRAIL found 68 per cent of genes silent in normal plasma and argued that tumour content amplifies cancer signal "by orders of magnitude" over tumour fraction (Larson 2021); and the change in tumour-only small RNAs across chemotherapy tracked outcome in 192 breast cancer patients (Wang 2026).
What is measured also limits it. Free RNA is destroyed within seconds in plasma, so only packaged RNA counts and the fraction of a tumour cell's RNA that survives is unknown (Tsui 2002); about three-quarters of plasma RNA comes from blood cells (Larson 2021); detection depends on tumour fraction times expression, and in GRAIL's breast cohort the five patients with the highest tumour fraction had no detectable FABP7 (Larson 2021); for AR-V7, circulating tumour cells were more sensitive than cell-free or vesicle RNA (Nimir 2019). No study reports a cell-free RNA tumour fraction in parts per million, no study was found that reads ESR1 or TACSTD2 expression from plasma RNA in breast cancer, and no reference material for cell-free RNA assays was found, so no detection floor can yet be stated. Whether stacking helps below 10 parts per million is therefore open.
The closest published result to an RNA residual disease test in breast cancer: a burden score that tracks outcome, without a stated detection limit.
Same-draw RNA and DNA together catch fusions one alone misses.
Capturing tumour vesicles by a surface marker before reading their RNA is feasible; it was tested for detection, not residual disease.
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.
Tumour RNA can stand out in blood where a gene is silent in normal plasma, but detection depends on both how much tumour sheds and how strongly the gene is expressed, and it has not been measured below percent-level tumour fractions.
Reading a phenotype from cell-free RNA can be less sensitive than from whole tumour cells in blood.
The clearest measured case that RNA from the same blood draw adds tumour signal where DNA runs short, though in advanced disease far above residual disease levels.
Shares Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA, Read methylation and mutation on the same cell-free DNA fragment to tell what kind of cancer is left, Naming which clone or phenotype is left after treatment, Minimal / molecular residual disease (MRD).
Shares Read methylation and mutation on the same cell-free DNA fragment to tell what kind of cancer is left, Naming which clone or phenotype is left after treatment, Cell-free DNA (cfDNA), Estrogen receptor (ERα).
Shares Read methylation and mutation on the same cell-free DNA fragment to tell what kind of cancer is left, Naming which clone or phenotype is left after treatment, Cell-free DNA (cfDNA), Estrogen receptor (ERα).
Shares Analytical validation of NeXT Personal®, an ultra-sensitive personalized circulating tumor DNA assay, Whole-exome & whole-genome sequencing, Minimal / molecular residual disease (MRD), Circulating tumour DNA (ctDNA).
Shares Whole-exome & whole-genome sequencing, Minimal / molecular residual disease (MRD), Circulating tumour DNA (ctDNA), MRD / molecular residual disease testing.
Shares Read methylation and mutation on the same cell-free DNA fragment to tell what kind of cancer is left, Cell-free DNA (cfDNA), Estrogen receptor (ERα), Circulating tumour DNA (ctDNA).
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 Dormant cells and minimal residual disease, Minimal / molecular residual disease (MRD), Circulating tumour DNA (ctDNA), MRD / molecular residual disease testing.
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