What Is a Liquid Biopsy—and How Does It Work?

For decades, biopsy has been closely associated with tissue: identify a suspicious area, obtain a sample, and examine it for evidence of disease. Today, advances in molecular diagnostics are expanding what a "biopsy" can look like.

Liquid biopsy uses a sample of body fluid, most commonly blood, to look for tumor-associated biomarkers. In oncology, many liquid biopsy approaches analyze circulating cell-free DNA (cfDNA), including the smaller fraction that originates from tumor cells, known as circulating tumor DNA (ctDNA). The FDA describes ctDNA as tumor-derived DNA found within cfDNA shed into the bloodstream.

For clinicians, that creates another potential source of molecular information without requiring a traditional tissue collection procedure.

What a Liquid Biopsy Is and What It Is Not

"Liquid biopsy" is an umbrella term rather than a single test or technology. Depending on the assay and its intended use, testing may evaluate ctDNA or other circulating biomarkers for molecular characteristics associated with cancer.

It is also important to distinguish liquid biopsy from a conventional tissue biopsy. A blood draw does not produce the tissue architecture available to a pathologist from a tissue specimen, and liquid biopsy should not automatically be viewed as a replacement for tissue testing or established screening and diagnostic pathways.

Instead, its value depends on the specific assay, patient population, clinical question, and evidence supporting that use.

That distinction matters because liquid biopsy technologies now span several areas of oncology from tumor genomic profiling to treatment selection and investigation of molecular residual disease (MRD).

How Does Liquid Biopsy Work?

Although individual assays differ, a ctDNA-based liquid biopsy generally begins with peripheral blood. Plasma is separated and cfDNA is isolated. The sample is then analyzed for molecular signals of interest, often using technologies such as next-generation sequencing (NGS), polymerase chain reaction (PCR), or other specialized molecular methods.

The analytical challenge is significant: tumor-derived DNA may represent only a small fraction of the total cfDNA circulating in the bloodstream. The amount of ctDNA can also vary based on factors including tumor type, location, stage, tumor burden, and response to treatment.

Some assays use predefined panels to search for specific genomic alterations. Others are tumor-informed, first sequencing a patient's tumor and then developing an individualized approach to look for those tumor-associated variants in plasma. The FDA is actively studying these approaches in early-stage cancers, including their potential application to MRD.

Where Are Clinicians Already Seeing Liquid Biopsy?

Liquid biopsy has moved beyond being simply an investigational concept.

One established application is tumor molecular profiling in patients with diagnosed cancer. FDA classifications include NGS-based tests that analyze circulating cell-free nucleic acids from plasma to identify mutations that can aid the management of previously diagnosed cancers.

Liquid biopsy is also used as a companion diagnostic in selected settings. For example, FDA-authorized plasma-based tests include Guardant360® Liquid CDx for specific biomarkers and therapies across several malignancies. Current FDA listings include plasma-based ESR1 testing associated with therapies for breast cancer, along with genomic targets in lung and colorectal cancers.

A newer milestone is the use of ctDNA for molecular residual disease. In May 2026, the FDA approved Signatera™ CDx, a personalized, tumor-informed ctDNA assay, to identify MRD-positive patients with muscle-invasive bladder cancer who may benefit from specified therapy.

These examples illustrate an important point: liquid biopsy isn't one clinical use case. It is a technological category that can support different questions at different points in cancer care.

Benefits of Liquid Biopsy

Liquid biopsy offers several practical and scientific advantages, although the benefit depends on the specific assay and its validated clinical use.

Less invasive sampling. Many liquid biopsy tests require only a peripheral blood draw, providing an alternative source of molecular information when obtaining adequate tumor tissue is difficult or when repeated tissue sampling is impractical.

Potential for repeat testing. Because blood samples can be collected at multiple time points, liquid biopsy may allow clinicians to assess molecular changes over the course of disease and treatment. The National Cancer Institute notes that serial liquid biopsy samples may help clinicians understand genetic or molecular changes occurring in a tumor.¹

Access to tumor-associated molecular information. Depending on the assay, liquid biopsy can identify genomic alterations that may help guide treatment decisions. FDA-authorized plasma-based companion diagnostics already support biomarker-directed treatment decisions in several cancers.²

A growing role across the cancer continuum. Liquid biopsy applications extend beyond genomic profiling. Researchers and clinicians are evaluating or using blood-based biomarkers for treatment selection, monitoring, molecular residual disease and early detection. In 2026, for example, the FDA authorized a plasma-based ctDNA molecular residual disease companion diagnostic for muscle-invasive bladder cancer.²

Limitations of Liquid Biopsy

The accessibility of liquid biopsy does not eliminate important biological and analytical limitations.

Not every tumor releases the same amount of detectable material. The amount of tumor-derived DNA circulating in blood can vary, which can affect whether an assay detects a molecular alteration.

A negative result does not always rule out relevant tumor findings. FDA labeling for plasma-based companion diagnostics explicitly cautions that a negative plasma result does not assure that the patient's tumor is negative for genomic findings. For certain biomarkers, FDA labeling recommends tissue testing following a negative plasma result when feasible.

Liquid biopsy does not provide tissue architecture. Unlike a conventional biopsy, a blood-based assay does not give a pathologist a tissue specimen for histopathologic examination. The two approaches can therefore provide different and sometimes complementary types of information.

Clinical utility is test- and indication-specific. "Liquid biopsy" describes a broad category of technologies, not a single interchangeable test. Providers should consider what an individual assay measures, the population in which it has been validated, its intended use, and how its results should influence care.

These limitations reinforce an important principle: the clinical value of a liquid biopsy should be evaluated based on the evidence supporting the specific test and intended use - not the technology category alone.

Frequently Asked Questions About Liquid Biopsy

1. Can a liquid biopsy detect cancer before symptoms appear?

Potentially—but this requires an important distinction between what the technology may be capable of detecting and what has been clinically validated for screening.

Some blood-based approaches are being studied to identify cancer-associated signals before symptoms develop. NCI describes detection of tumor-derived DNA and other circulating biomarkers as an active area of cancer screening and early detection research.³

However, performance varies by test and cancer type, and detection alone does not establish that a test improves clinical outcomes. For providers, the appropriate question is whether a specific assay has been validated for early detection in the intended patient population and clinical setting.

2. Can a liquid biopsy replace a tissue biopsy?

Not universally. Liquid and tissue biopsies provide different types of information.

A liquid biopsy can provide molecular information from tumor-associated material circulating in blood and may be particularly useful when tissue is difficult to obtain or serial molecular assessment is desired. Tissue biopsy, however, provides cellular and architectural information needed for many diagnostic and pathological assessments.

The appropriate role depends on the clinical question and the individual assay. FDA labeling for some plasma-based companion diagnostics specifically recommends tissue testing after certain negative plasma results when tissue is available.

3. What does a negative liquid biopsy result mean?

It depends on the test.

A negative result means that the biomarker or molecular signal targeted by that particular assay was not detected according to the test's criteria. It does not necessarily mean that cancer is absent or that the tumor lacks a particular genomic alteration.

For example, current FDA labeling for Guardant360 Liquid CDx states that a negative plasma result does not assure that the patient's tumor is negative for genomic findings and recommends tissue testing for specified biomarkers when feasible.⁴

That makes test-specific performance characteristics, including sensitivity, intended use and the clinical meaning of a negative result, essential when interpreting any liquid biopsy.

Why Is Liquid Biopsy Generating So Much Interest?

The appeal starts with accessibility. A peripheral blood draw can provide molecular information without the procedural requirements of obtaining another tissue specimen.

But convenience alone isn't what makes the field clinically important.

Because circulating biomarkers can potentially be measured repeatedly, liquid biopsy also creates opportunities for longitudinal molecular assessment. Depending on the validated application, clinicians and researchers are studying or using these technologies to identify actionable alterations, characterize tumor genomics, assess treatment response, and detect evidence of residual disease.

The FDA's November 2024 guidance on ctDNA in early-stage solid-tumor drug development underscores the growing scientific significance of this biomarker, while also emphasizing the need for assay standardization, harmonization, and appropriate clinical validation.⁵

In other words, the promise of liquid biopsy does not eliminate the need for rigorous evidence. It makes that evidence increasingly important.

What Should Providers Consider?

As liquid biopsy options expand, the clinically useful question isn't simply, "Should I use liquid biopsy?"

It is: What does this particular test measure, in which patient population, for what clinical purpose and what evidence supports acting on its result?

Consider the assay's intended use, analytical and clinical validation, sensitivity and specificity within the relevant population, regulatory status, and how a result is intended to inform the existing care pathway. A negative plasma result, for example, does not universally exclude the presence of a tumor-associated alteration; limitations depend on the assay and clinical setting.

That test-specific approach helps distinguish meaningful clinical utility from enthusiasm about the technology itself.

Another Layer of Insight

Liquid biopsy represents a broader evolution in precision medicine: increasingly sophisticated biological information can be obtained from an accessible blood sample.

For HCPs, understanding both the benefits and limitations of these technologies is becoming increasingly relevant as blood-based testing expands into more areas of oncology. The opportunity isn't to replace proven standards indiscriminately. It is to understand where a validated liquid biopsy can provide another layer of insight—and where imaging, tissue or other established approaches remain necessary.

As the science advances, the defining question will be less about what can be measured in blood and increasingly about how that information can responsibly support better-informed care.

Interested in how blood-based testing may complement your breast health program? Connect with our team to review the clinical evidence, explore the science behind Certitude, and learn how it may fit into your practice.

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