Liquid biopsy (circulating tumor DNA / ctDNA): the revolution in modern oncology explained in a way that everyone can understand

Have you heard that cancer can be “tracked” through a simple blood test, without a painful biopsy? It’s not science fiction, but the reality of 2026. It’s called liquid biopsy and it represents one of the most important innovations in the history of oncology. This guide explains, in a way that everyone can understand, what circulating tumor DNA (ctDNA) is, how it helps in early detection, choosing treatment, and detecting relapses — often months before classic imaging.

1. What exactly is liquid biopsy?

Liquid biopsy is the analysis of non-invasive biological samples (usually blood) to obtain diagnostic, prognostic, and therapeutic information. Unlike a classic biopsy — which involves extracting a piece of tumor with a needle or through surgery — a liquid biopsy requires only a routine blood draw.

The central idea is simple: tumors “shed” small fragments of their DNA into the blood. These are called circulating tumor DNA (ctDNA) and are part of a larger category called circulating free DNA (cfDNA).

Why is it so valuable? Because it overcomes a major limitation of classic biopsy: tumor heterogeneity . A needle biopsy samples only a small region of the tumor and can “miss” areas responsible for resistance or metastasis. Blood, on the other hand, provides an overview of the entire disease, including metastatic lesions.

2. How do we “read” tumor DNA in the blood?

The technical challenge is huge: ctDNA often represents only a tiny fraction of all free DNA in the blood (the majority comes from healthy cells). To detect it, laboratories use ultrasensitive technologies:

• Next-generation sequencing (NGS) – analyzes dozens of mutations simultaneously.
• Droplet digital PCR (ddPCR) – counts rare mutant molecules in a massive pool of normal DNA with extraordinary accuracy.

A fascinating discovery from 2024 are so-called “priming agents” — liposomes and protective antibodies that temporarily increase the level of ctDNA in the blood, making it easier to detect. In mice, a single injection produced massive increases in free DNA in blood collected immediately afterward. This is important because ctDNA is cleared from the circulation sometimes in as little as 30 minutes.

3. Application 1: Early cancer detection (MCED tests)

The most spectacular use of liquid biopsy is early detection , through tests that look for multiple types of cancer in a single blood sample (MCED tests – Multi-Cancer Early Detection).

Benchmark results from 2026:

• PATHFINDER 2 study (Galleri test), the largest of its kind in the US, enrolled 35,878 participants and demonstrated that adding the test to standard screening resulted in a more than seven-fold increase in the number of cancers detected in one year.
• About three-quarters of the cancers Galleri discovered have no recommended screening test today.
• The test predicted the origin of the cancerous signal with 92% accuracy , and resolving the diagnosis took an average of 46 days.

⚠ Note: sensitivity for stage I cancers remains limited (only 15.4% for some tests), meaning that most very small tumors may still be missed. Therefore, these tests complement, not replace, classic screening.

4. Application 2: Choosing personalized treatment (genotyping)

This is where liquid biopsy is already showing its value in everyday practice. By analyzing ctDNA, the doctor can identify “actionable” mutations in the tumor — that is, those genetic defects for which there is a specific targeted drug.

Concrete examples:

• In lung cancer , detection of the EGFR mutation in the blood allows the choice of a targeted therapy (EGFR inhibitor) without the need for an invasive lung biopsy.
• The US FDA has already approved several non-invasive genotyping tests for advanced cancers.

A major advantage: if the tumor develops resistance to treatment (for example, the appearance of the T790M mutation in EGFR), this can be detected in the blood, allowing for early change of therapy.

5. Application 3: Treatment monitoring and residual disease (MRD)

By taking repeated samples, doctors can track in real time how the tumor is responding to treatment. A rapid and massive drop in ctDNA (for example, a 100-fold reduction after a cycle of chemotherapy) is an excellent sign of response.

But the most promising application is the detection of Minimal Residual Disease (MRD) — that is, the microscopic fragments of tumor remaining after an apparently successful surgery.

Results from recent studies (2024–2026):

Study / Cancer	Key result
GALAXY (colorectal)	MRD-positive patients who did NOT achieve ctDNA clearance had an 11-fold higher risk of relapse
DYNAMIC-III (colorectal)	ctDNA-guided chemotherapy increased relapse-free survival from 6.7 to 18.7 months in ctDNA+ patients
Ovarian cancer (2026)	100% MRD positivity rate before treatment, by exome sequencing

Basically, MRD allows us to identify patients at real risk of relapse (who need additional chemotherapy) and, equally importantly, to spare patients without residual disease from unnecessary and toxic treatments.

6. Application 4: Fragmentomics — the frontier of 2026

A new and extremely promising direction is fragmentomics — the study of how DNA fragments “break”. It seems that tumor DNA has a different “pattern” of fragmentation than healthy DNA (shorter fragments, specific ends).

Impressive results:

• For kidney cancer (which does not have an effective screening test), a fragmentomics-based test achieved an accuracy (AUC) of 0.966 , working even at a very low sequencing depth.
• Fragmentomics is also used for early detection of ovarian cancer , combined with protein biomarkers.

7. Not just in oncology: transplant and pregnancy

Liquid biopsy has also revolutionized other areas:

• Organ transplantation: Donor-derived free DNA ( dd-cfDNA ) increases sharply when the transplanted organ is “rejected”. A randomized trial from 2024–2026 showed that dd-cfDNA monitoring reduced the time to diagnosis of rejection from 14.5 months to just 2.8 months , allowing many invasive biopsies to be avoided.
• Prenatal medicine (NIPT test): analysis of fetal DNA from the mother’s blood allows the detection of Down syndrome (trisomy 21) with an accuracy of up to 99.8% , without the risks of amniocentesis. ACOG and SMFM guidelines now recommend this test for all pregnant women.

8. Current limits and challenges

Like any technology, liquid biopsy has limitations that you need to be aware of:

• Clonal hematopoiesis (CHIP): with advancing age, blood cells can accumulate mutations that “mimic” tumor mutations, generating false-positive results. Up to 10% of mutations in cfDNA in healthy adults may have this origin.
• Sensitivity in early stages: In early cancers, the amount of ctDNA may be too small to be detected.
• Lack of standardization: different laboratories and platforms report different values, making it difficult to establish common thresholds.

The 4 applications of liquid biopsy (ctDNA) in oncology

🔬 Application	🎯 What is it after?	🧪 Method / Marker	📊 Key results (2024–2026)
1. Early detection (MCED tests)	Finding cancer before symptoms, from a single blood sample	ctDNA mutations + methylation + fragmentomics (Galleri test)	7x increase in detection; 92% accuracy for signal origin
2. Genotyping (what is ctDNA)	Identifying “actionable” mutations for targeted therapy	NGS / ddPCR on circulating tumor DNA	Detection of EGFR/T790M in blood, without invasive lung biopsy
3. Treatment monitoring	Real-time verification of response to therapy	Serial ctDNA measurements (2-log decrease)	100× reduction in ctDNA after 1 cycle = excellent response; early detection of resistance
4. Minimal residual disease (MRD)	Finding microscopic tumor after surgery	Personalized analyses (tumor-specific mutations)	11× higher risk of relapse ; DYNAMIC-III: RFS from 6.7 to 18.7 months

💡 Future direction – Fragmentomics: the study of how DNA fragments “break” has achieved an accuracy (AUC) of 0.966 for kidney cancer, working even at a very low sequencing depth (1×) and a tumor fraction of only 0.1%.

⚠ Note (2026 limits): MCED sensitivity for stage I cancers remains limited (~15.4%), and clonal hematopoiesis (CHIP) may generate false-positive results in elderly patients. Therefore, liquid biopsy complements, not replaces, classical screening and imaging.

How Artificial Intelligence helps you leverage liquid biopsy

As you have seen, liquid biopsy generates a huge amount of genomic data — mutations, fragmentation patterns, ctDNA levels — and their interpretation requires correlation with thousands of studies and guidelines that are updated from month to month.

Oncoexpertai platform comes in . Unlike a simple reading of the results, our advanced Artificial Intelligence algorithms instantly scan the molecular profile obtained through liquid biopsy and correlate it with thousands of clinical studies and international oncology guidelines updated in real time (NCCN / ESMO). The technology does not replace the doctor, but gives him the certainty that the chosen targeted therapy perfectly matches the genetic profile of your tumor.

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Disclaimer: The information in this article is for informational and educational purposes only. It is not a substitute for the consultation, diagnosis, or treatment provided by a qualified medical professional. For any decision regarding your health, always consult a medical professional. .

Bibliography

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Dr. Onisim Florin Senior Medical Oncologist | Founder of OncoExpertAI