Minimally invasive, maximum potential: liquid biopsy is redefining diagnosis

Many of us will know someone who has undergone a biopsy during a medical diagnosis: we may even have had one ourselves. Traditional biopsies extract a small sample of tissue or cells for analysis and are used to help diagnose a spectrum of diseases, although they are probably associated most with detecting cancerous cells and tumours.

Tissue biopsy relies heavily on a clinician being able to identify and access the tissue in question. Obtaining tissue samples can be painful, invasive and difficult to repeat, possibly even involving serious surgical procedures. In some cases a traditional biopsy may not be possible at all. A single tissue biopsy also provides a static snapshot in time of the disease or tissue, giving no indication of how a disease may be developing or changing.

Fortunately for patients and medical practitioners alike, liquid biopsy (aka fluid biopsy or fluid phase biopsy) promises to become a key part of routine healthcare. In essence, liquid biopsy involves diagnosing diseases by collecting and analysing molecules found in bodily fluids.

So, what are we looking for and in which “liquids” might it be found?

Are all liquids created equal?

Liquid biopsy emerged in oncology thanks to advances in precision medicine and personalised healthcare. The term was coined initially to describe measuring tumour cells or cancer-related nucleic acids circulating in the blood (including in blood components such as plasma and serum).

As liquid biopsy technologies have grown in popularity, efficacy and sensitivity, the term has expanded to cover detecting molecules in other biofluids like urine, saliva, lymph, cerebrospinal fluid, amniotic fluid and even breast milk. The field has extended more generally beyond oncology too and can encompass the detection of non-cancerous molecules.

What might be lurking in our liquids?

A variety of different biomarkers can be detected via a liquid biopsy and these can be useful for diagnosing many different diseases.

Circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA)

CTCs and ctDNA are rarely found in healthy people so their presence in the blood indicates that a cancer may be present or spreading (metastatic cancer).

There are several FDA-approved platforms available that can be used to detect CTC and ctDNA biomarkers. These include the CELLSEARCH® CTC Kit for diagnosing metastatic breast, prostate or colorectal cancer, and the cobas® EGFR Mutation Test v2 (Roche) for detecting ctDNA mutations involved in non-small cell lung cancer.

CTCs and ctDNA can be useful in companion diagnostics to select the right treatment according to a patient’s specific healthcare needs.

Cell-free DNA (cfDNA)

Cell-free DNA is a general term for DNA that is freely circulating in the bloodstream: it does not have to be associated with a cancer or tumour and it can be detected in healthy people as well as in patients with disease. Whilst ctDNA above is a type of cfDNA, cfDNA refers to circulating DNA more broadly.

Prenatal testing of foetal cfDNA is a clinical success story. An expectant mother has cell-free DNA from the foetus circulating in her blood and a simple blood test allows us to determine the sex and the paternity of the foetus, as well as pick up any genetic abnormalities.


Proteins are also found in bodily fluids such as blood and urine, and their presence or amount can help diagnose disease.

The traditional PSA (prostate specific antigen) test for prostate cancer has been followed by the 4Kscore Test which measures four PSA protein biomarkers in the blood and is able to identify the risk of a patient developing aggressive prostate cancer. Detection of a different protein, PCA3, in urine can also signal that prostate cancer is present and is proving to be more accurate than the traditional PSA blood test.

Thrive’s CancerSEEK assay is being developed as an early detection test for multiple cancer types (ovary, liver, stomach, pancreas, esophagus, colorectal, lung, and breast) and assesses both ctDNA mutations and a panel of eight circulating protein markers in the blood, giving a holistic view of a developing cancer.

SomaLogic’s SomaSignalTM test can measure thousands of proteins at a time and uncover patterns in protein changes to help understand varying clinical situations, including cardiovascular risk, percentage body fat and glucose tolerance. A “liquid liver biopsy” test is also being developed for non-alcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD), which can detect the same components as a traditional liver biopsy but without the invasive tissue collection.


Exosomes are extracellular vesicles (i.e. particles with a lipid membrane that are produced by cells) that measure about 40-200 nm in diameter. They contain ‘cargos’ such as proteins, DNA and RNA which can reflect the molecular profile of their parent cell. They are very stable and can be found in almost every body fluid, meaning that they could be used to detect and diagnose a huge range of diseases.

Exosomal liquid biopsy is not as advanced as the CTC/ctDNA techniques but exosomes are easier to detect and analyse so they possess real potential in the liquid biopsy field.

Why is liquid biopsy becoming so popular?

Liquid biopsy has many advantages over traditional tissue biopsy:

  • It allows for earlier detection e.g. before a tumour even exists or before a cancer has spread
  • It allows for frequent, repeated sampling and monitoring progression of a disease or treatment in real time
  • It is minimally invasive, less painful and does not require access to the tissue
  • It can provide a more complete picture of a disease via genomic or tumour profiling
  • Its use in companion diagnostics can guide treatment decisions that are tailored to the particular patient.

As further biomarkers are identified and the technology improves in sensitivity and breadth, we can expect to see liquid biopsy used more and more routinely in general healthcare to inform diagnosis and effective treatment.