Liquid Biopsy and Circulating Tumour DNA (ctDNA)

A liquid biopsy is a test that looks for signs of cancer in a blood sample, rather than in a piece of tumor tissue. The most common form looks for circulating tumor DNA, usually shortened to ctDNA, which are small fragments of genetic material that a cancer sheds into the bloodstream. By reading these fragments, a laboratory can learn about the genetic changes in a cancer from a simple blood draw. Liquid biopsy is a fast-developing area of cancer care, and you may encounter it if your doctor has ordered a blood-based test to look for treatment targets, to monitor how a cancer is responding, or to check whether a cancer has returned. This article explains, in plain language, what a liquid biopsy is, what ctDNA can and cannot tell you, how the results are used, and the important limitations to keep in mind.

What a liquid biopsy is

A liquid biopsy is a test performed on a body fluid, almost always blood, to find evidence of cancer. The name draws a deliberate contrast with a traditional tissue biopsy, where a piece of the tumor is removed with a needle or during surgery. Instead of sampling the tumor directly, a liquid biopsy captures material the cancer has released into the circulation, which can be collected with an ordinary blood draw from a vein in the arm.

Although blood is by far the most common sample, the same general principle applies to other fluids, such as urine or the fluid around the lungs, depending on the cancer. A liquid biopsy can look for several different things, including whole cancer cells circulating in the blood and abnormal RNA, but the most widely used target, and the focus of this article, is circulating tumor DNA.

What circulating tumor DNA (ctDNA) is

Circulating tumor DNA (ctDNA) is made up of small fragments of DNA that come from cancer cells and float freely in the bloodstream. When cancer cells die and break apart, as they constantly do, they release their DNA into the blood. These tumor-derived fragments carry the same genetic changes present in the cancer itself, which is what makes them so useful: reading ctDNA is a way to read the cancer’s genetic code from a blood sample.

An important detail is that ctDNA is only a small part of the DNA floating in the blood. Everyone has some DNA fragments in their bloodstream, released by normal cells as part of healthy turnover; this is called cell-free DNA (cfDNA). In a person with cancer, only a fraction of that cell-free DNA comes from the tumor. Detecting and reading the tumor’s portion against the background of normal DNA requires sensitive laboratory methods, and the amount of ctDNA present can vary widely depending on the type, size, and location of the cancer.

How a liquid biopsy is performed

A liquid biopsy for ctDNA is usually as simple as a routine blood test. A sample of blood is drawn from a vein in the arm and sent to a specialized laboratory, where the cell-free DNA is separated from the blood and analyzed for tumor-specific genetic changes. No surgery or tissue sampling is involved, which is one of the method’s main attractions.

In the laboratory, tumor DNA is analyzed using sensitive molecular methods, most often next-generation sequencing (NGS), which can assess many genes at once, or PCR, which targets specific known changes. Because ctDNA makes up such a small fraction of the total cell-free DNA, these tests are designed to detect changes present at very low levels. The same kinds of genetic changes found in a tissue sample, such as mutations and gene fusions, can often be detected in ctDNA.

What a liquid biopsy can be used for

A liquid biopsy that reads ctDNA can support several aspects of cancer care, and understanding which purpose applies helps clarify why the test was ordered. The same blood-based approach can serve very different goals.

Finding treatment targets — ctDNA can reveal genetic changes in a cancer that match a targeted therapy, such as an EGFR mutation in lung cancer. This is especially useful when a tissue sample is difficult to obtain or when there is not enough tissue left for testing, allowing treatment planning to proceed based on a blood draw.
Monitoring response to treatment — The amount of ctDNA in the blood often reflects the extent of cancer. A falling level during treatment can indicate that the cancer is responding, while a level that stops falling or begins to rise may suggest the treatment is becoming less effective.
Detecting recurrence early — After treatment, a rising ctDNA level can be an early signal that a cancer has returned, sometimes before it becomes visible on imaging. Used this way to look for tiny amounts of remaining or returning cancer, the test is sometimes described as detecting minimal residual disease.
Tracking genetic changes over time — Cancers can evolve and develop new genetic changes, including ones that cause resistance to a drug that was working. Because a blood draw is easy to repeat, ctDNA can capture these changes over time without repeated tissue biopsies, thereby guiding a switch to a different treatment.

Liquid biopsy compared with a tissue biopsy

A liquid biopsy and a traditional tissue biopsy both aim to reveal genetic changes in cancer, but they have different strengths and are often used together rather than as substitutes. Understanding the trade-offs explains why a doctor might choose one, the other, or both.

The advantages of a liquid biopsy come from its simplicity. It requires only a blood draw, so it is less invasive, carries little risk of bleeding or infection, and is easy to repeat over time. It can also sample DNA shed from cancer throughout the body at once, capturing differences between separate tumor sites that a single tissue biopsy, taken from one spot, might miss. A tissue biopsy, in turn, provides a larger and richer sample, allows the pathologist to examine the cancer cells directly under the microscope, and remains the standard for making the initial diagnosis. Because each approach sees something the other may not, the two are frequently complementary.

Limitations of liquid biopsy and ctDNA testing

While a liquid biopsy is a valuable tool, it has real limitations, and knowing them helps put a result in context. A ctDNA test reads tumor DNA in the blood, and several factors affect how reliable that reading is.

Sensitivity — The most important limitation is that a liquid biopsy can miss cancer that is truly present. Some cancers shed little ctDNA into the blood, particularly early-stage cancers or certain tumor types, so a negative result does not rule out cancer or a treatable genetic change. When a liquid biopsy is negative but a specific change is still suspected, testing tumor tissue may be recommended to be sure.
False signals from normal blood cells — As people age, the blood-forming cells in the bone marrow can acquire harmless genetic changes, a common phenomenon called clonal hematopoiesis. These changes can appear in a blood sample and be mistaken for cancer-derived DNA, which is one reason ctDNA results are interpreted carefully rather than taken at face value.
A result that needs clinical context — A ctDNA result is not interpreted in isolation. Its meaning depends on the type of cancer, the stage, prior treatments, and the imaging and clinical picture. A liquid biopsy result is one piece of information the care team weighs alongside the rest.

Liquid biopsy for cancer screening in healthy people

A separate use of blood-based testing has received a great deal of attention: using a liquid biopsy to screen for cancer in people who have no symptoms and no known cancer. These tests, often called multi-cancer early detection (MCED) tests, are different from the ctDNA testing described in the rest of this article, which is used in people who already have a cancer diagnosis to guide and monitor treatment.

Multi-cancer early detection tests aim to find signs of several cancers from a single blood sample before any symptoms appear. This is a promising and rapidly developing area, but it is still being studied, and these tests are not a replacement for established screening such as mammograms or colonoscopy. A result from this kind of test, whether positive or negative, has to be interpreted with caution and confirmed with standard tests. If you are considering or have taken one of these tests, the result should be discussed carefully with a doctor.

Practical questions patients often have about liquid biopsy

Is a liquid biopsy as accurate as a tissue biopsy?

It depends on what is being asked. For detecting a specific genetic change to guide treatment, a positive liquid biopsy result is generally reliable. The main concern is a negative result, because a liquid biopsy can miss a change that a tissue test would find, especially when a cancer sheds little ctDNA. For this reason, a negative liquid biopsy is often followed by tissue testing when a treatable change is still suspected.

Will a liquid biopsy replace my tissue biopsy?

Usually not entirely. A tissue biopsy is still the standard way to make an initial cancer diagnosis and lets the pathologist examine the cancer directly. A liquid biopsy is most often used alongside tissue testing, or in situations where obtaining tissue is difficult, rather than as a complete replacement.

Why might my doctor repeat a liquid biopsy?

Because it only needs a blood draw, a liquid biopsy is easy to repeat, and repeating it over time is often the point. Serial testing can track whether a cancer is responding to treatment, detect an early return of cancer, or reveal new genetic changes that affect which treatment is likely to work next.

Does a negative liquid biopsy mean I am cancer-free?

No. A negative ctDNA result means no tumor DNA was detected in that sample, not necessarily that no cancer is present. Some cancers shed very little ctDNA, so the test can be negative even when cancer remains. A negative result is interpreted together with imaging, examination, and the overall clinical picture.

Questions to ask your doctor

Why are you recommending a liquid biopsy, and what specifically will it look for?
Is this test being used to find a treatment target, to monitor my cancer, or to check for recurrence?
Should I also have a tissue biopsy, or is the liquid biopsy enough on its own?
If the liquid biopsy is negative, what are the next steps?
How should I understand a rising or falling ctDNA level over time?
Could a result reflect a harmless change in my blood cells rather than my cancer?
How will the liquid biopsy result be combined with my imaging and other tests?
How often might this test be repeated during my care?
Did the test read many genes or only specific ones, and could a change have been missed?
How long will the results take, and can treatment decisions wait for them?