Loading
Blood carries fragments of tumour DNA. This roadmap follows the tests that read them, from the first sighting in 1948 to blood tests that now choose a drug, spare chemotherapy, or screen for many cancers at once, and it lists the readouts to watch next.
Circulating tumour DNA (ctDNA) testing has three jobs, and each is at a different stage. Genotyping from blood is settled: the cobas EGFR plasma test became the first FDA-approved liquid biopsy in June 2016, and Guardant360 CDx and FoundationOne Liquid CDx followed in August 2020 as broad companion diagnostics. Residual disease testing after surgery has crossed from prognosis to action: DYNAMIC showed in 2022 that a ctDNA-guided approach halves chemotherapy in stage II colon cancer without harm, and in May 2026 the FDA approved adjuvant atezolizumab for ctDNA-positive muscle-invasive bladder cancer on IMvigor011, the first drug approval that depends on a ctDNA residual disease result. Escalation for a positive test is not yet proven: ALTAIR missed its endpoint and the MERMAID lung trials closed small.
Multi-cancer early detection is the least settled. Shield won FDA approval for colorectal screening in July 2024 on a single-cancer claim. Galleri has one randomised trial behind it: NHS-Galleri did not reduce stage III and IV cancers combined, its primary endpoint, while reporting fewer stage IV diagnoses, and the FDA's advisory panel considers the test on 23 September 2026. The NCI's Vanguard study is the first randomised US test of the approach and runs to 2029.
The steps below are grouped by what the evidence allowed at the time. The 'What to watch' list carries registry completion dates and meeting dates as their sources state them. Tumour-informed assays (built from the patient's own tumour sequence) and tumour-naive assays (fixed panels, often methylation-based) compete on sensitivity, turnaround and cost; the roadmap treats that split as a running theme rather than an era.
Mandel and Metais reported nucleic acids in human blood plasma in 1948, and in 1977 Leon and colleagues found that people with cancer carried more free DNA in their serum and that levels fell when treatment worked. Nobody could yet say which fragments came from the tumour, so for four decades this stayed an observation rather than a test.
Digital PCR and deep sequencing made it possible to count tumour-specific mutations in plasma: Diehl and colleagues showed mutant DNA rising and falling with disease in 2008, Dawson and colleagues tracked metastatic breast cancer with it in 2013, and Bettegowda and colleagues detected ctDNA across early- and late-stage cancers in 2014. Tie and colleagues then showed in 2016 that ctDNA found after surgery for stage II colon cancer predicted recurrence, the observation the residual disease trials were built on.
On 1 June 2016 the FDA approved the cobas EGFR Mutation Test v2 for plasma, the first liquid biopsy companion diagnostic, letting lung cancer patients start erlotinib on a blood result when tissue was unavailable. Two broad panels followed in August 2020: Guardant360 CDx on 7 August and FoundationOne Liquid CDx on 26 August, each a companion diagnostic for several drugs, with a negative blood result sent back to tissue testing.
Signatera sequences each patient's tumour, picks 16 mutations, and looks for them in plasma after surgery; in the GALAXY registry a positive test four weeks after colorectal surgery carried a tenfold higher recurrence risk. Medicare's MolDX programme finalised coverage for serial Signatera testing in stage II and III colorectal cancer on 3 September 2020, and its coverage article for residual disease tests now lists several tests and cancers, which is how tumour-informed testing became routine before any randomised trial had finished.
DYNAMIC, published in June 2022, randomised 455 people with stage II colon cancer and cut adjuvant chemotherapy from 28 percent to 15 percent with two-year recurrence-free survival of 93.5 against 92.4 percent; the five-year update in 2025 held at 88 against 87 percent. Escalation has been harder to prove: ALTAIR, which gave trifluridine/tipiracil to ctDNA-positive patients after colorectal surgery, did not meet its disease-free survival endpoint, the MERMAID lung trials closed with 89 and 30 participants, and TRACC, BESPOKE and CIRCULATE-Japan's VEGA de-escalation trial are still running.
IMvigor011 tested 761 people after cystectomy for muscle-invasive bladder cancer and randomised the 250 whose blood turned ctDNA-positive to atezolizumab or placebo: disease-free survival hazard ratio 0.64 and overall survival hazard ratio 0.59, published in NEJM in December 2025. On 15 May 2026 the FDA approved adjuvant atezolizumab for patients with ctDNA molecular residual disease after cystectomy, with Signatera CDx as the companion diagnostic, so a residual disease blood test now sits inside a drug label.
PATHFINDER, published in 2023, was the first prospective test of a multi-cancer blood test in 6,621 adults without symptoms: 1.4 percent had a signal, 38 percent of those had cancer, and resolving a positive took a median of 79 days. Shield became the first FDA-approved blood test for colorectal cancer screening on 26 July 2024, for average-risk adults aged 45 and over with colonoscopy after a positive. NHS-Galleri, the randomised trial of Galleri in 142,250 people in England, reported on 30 May 2026 that stage III and IV cancers combined were not reduced (the primary endpoint) while stage IV diagnoses fell by 14 percent; PATHFINDER 2 reported a positive predictive value of 60.3 percent in 35,878 people the next day, and GRAIL's premarket application, filed on 29 January 2026, goes to an FDA advisory panel on 23 September 2026. The trial's peer-reviewed test-performance paper appeared in Nature Medicine on 22 September 2026: positive results in 1.03, 0.80 and 0.90 percent of intervention-arm participants across three annual rounds, positive predictive values of 58.0, 50.4 and 45.8 percent, specificity of 99.50 to 99.60 percent and episode sensitivity of 26.7 to 37.2 percent for all cancers; it states the primary endpoint was not met and is reported elsewhere.
The open questions each have a trial with a date on the registry. For screening, the NCI's Vanguard study randomises 24,000 people to multi-cancer detection tests or usual care, with primary completion listed for 31 January 2029, and NHS-Galleri's follow-up continues. For residual disease, CIRCULATE-US randomises stage III colon cancer patients by Signatera result to more or less chemotherapy (primary completion 10 March 2029), TRACC follows 1,000 people to 2029, and VEGA asks whether ctDNA-negative patients can skip chemotherapy altogether. If escalation trials keep missing, the field's case will rest on de-escalation and on ctDNA as a surrogate endpoint.
Two technical routes are competing to make the tests more sensitive without a tumour sample: methylation, which reads chemical marks that also point to the tissue of origin, and fragmentomics, which reads the sizes and positions of the fragments themselves. Whole-genome approaches and repeated sampling aim to catch relapse earlier than a three-monthly draw. The gating question for all of them is utility rather than sensitivity: finding disease earlier has to change an outcome, and the clonal haematopoiesis of normal blood cells is the main source of false positives.
In the United States, Medicare pays for residual disease tests through a MolDX coverage article that names tests and cancers one at a time (revision effective 1 January 2026); screening tests need their own coverage route, and most health systems outside the United States pay for none of this yet. Laboratories run different assays with no shared reference material, so a positive in one is not a positive in another, and a screening positive still needs a fast, agreed diagnostic pathway. Coverage with evidence, reference plasma standards and a national positive-result pathway are the proposals on the table.
Every era's records, trial outcomes and papers, and every watch item, as JSON.
Readouts, decisions and registry completion dates ahead. Each date is quoted from its source, not inferred; a missing date means no source states one.
Loading this step…
Loading this step…
Loading this step…
Loading this step…
Loading this step…
Loading this step…
Loading this step…
Loading this step…
Loading this step…
Loading this step…
For someone offered the test, these are the numbers that describe what a result means in an NHS population: about 1 in 100 tests came back positive each year, between 46 and 58 in 100 positives were cancer, and a negative result left about 1 in 100 with an undetected cancer within the year. The test found between a quarter and a third of all cancers diagnosed in a screening round, and about half to two thirds of the 12 cancer types it was designed to find. Whether finding them this way reduces late-stage diagnoses is the primary question, and this paper says only that the answer was no; the primary-endpoint paper had not appeared on Europe PMC by 23 September 2026.
After bladder removal, a blood test can now tell who needs immunotherapy and who can safely be spared it. This is the model for MRD-guided adjuvant therapy across cancers: treat the blood-positive, watch the blood-negative.
The first prospective test of acting on ctDNA in triple-negative disease, and a negative one: with a quarterly, single-mutation assay the window between detectable DNA and visible metastasis was too short to intervene. Later designs use tumour-informed assays, earlier sampling and drugs with more single-agent activity.
The blood test stratifies risk far better than stage or pathology. It supports treating ctDNA-positive patients and suggests ctDNA-negative patients gain little from chemotherapy, but because treatment was not randomised the de-escalation claim needs the randomised trials that are now under way.
A multi-cancer blood test can be run in ordinary clinics, and most positive results can be resolved with imaging. But six in ten positives are false alarms that take months to resolve, and the test misses most cancers. Whether it reduces late-stage cancer or deaths is unknown; that requires randomised trials.
For stage II colon cancer, where most patients are cured by surgery alone, a blood test can identify the minority who benefit from chemotherapy and spare everyone else its side effects. It does not yet prove that treating ctDNA-positive patients improves survival compared with not treating them.
NHS-Galleri is the trial that will decide whether a blood test for many cancers at once should be offered by a health system. Its endpoint is a reduction in late-stage cancer rather than deaths, so even a positive result leaves the mortality question to be settled by longer follow-up.
The proof that a blood test can split residual-disease patients into those likely to relapse and those likely cured, the premise of the ctDNA-guided adjuvant idea; no completed trial has yet acted on the result.
Shares MRD / molecular residual disease testing, Liquid biopsy (ctDNA) and the tags ctdna, mrd.
Shares RaDaR, Guardant Reveal, Association of Circulating Tumor DNA and Circulating Tumor Cells After Neoadjuvant Chemotherapy With Disease Recurrence in Patients With Triple-Negative Breast Cancer: Preplanned Secondary Analysis of the BRE12-158 Randomized Clinical Trial, Results of the c-TRAK TN trial: a clinical trial utilising ctDNA mutation tracking to detect molecular residual disease and trigger intervention in patients with moderate- and high-risk early-stage triple-negative breast cancer and the tag ctdna.
Shares PATHFINDER 2, PATHFINDER: the first prospective test of a multi-cancer blood test in people without symptoms, Galleri, NHS-Galleri and the tag mced.
Shares Liquid biopsy (ctDNA) and the tag liquid-biopsy.
Shares BESPOKE CRC, TRACC, CIRCULATE-US, CIRCULATE-Japan (GALAXY / VEGA / ALTAIR).
Shares BESPOKE CRC, TRACC, CIRCULATE-US, CIRCULATE-Japan (GALAXY / VEGA / ALTAIR).
Shares MRD / molecular residual disease testing and the tag mrd.
Shares MRD / molecular residual disease testing and the tag mrd.