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The emergence of liquid biopsy

The applications of liquid biopsy are becoming increasingly apparent – but where did it all begin? Here we explore the beginnings and future of liquid biopsies.

Not a single disease

In the UK, 1 in 2 people will be diagnosed with cancer in their lifetime. For most of us, the effects of cancer have ripped through our families, leaving voids impossible to fill.

People often ask “Why isn’t there a cure for cancer already?” However, cancer is not a single disease. It encompasses hundreds of illnesses sharing common features, each with their own characteristics, risks factors, causes and treatments. But that’s not all. Cancer is also complex at an individual level. Intra- and even inter-tumour heterogeneity within a single individual introduces significant challenges in designing effective treatment strategies.

Towards precision medicine

The dawn of the Human Genome Project has led to a change in paradigm from ‘one size fits all’ to the concept of ‘precision medicine’, with the aim of tailoring therapies for each patient. As a result, the limitations of current sampling and profiling methods have become apparent. Traditional biopsies and surgical procedures are often invasive, not repeatable and sometimes not possible to perform when the tumour is inaccessible or when clinical conditions have worsened. In addition, genetic profiling of biopsy tissues only reflects a single point in time for a specific region of the tumour. Therefore, it does not represent the true genetic heterogeneity of the tumour. The genomic landscape of tumours and metastases dynamically evolve over time, particularly in response to different selective pressures. The limitations of current methods are particularly evident in the presence of resistance to therapies and in monitoring disease during follow up.

As a result, in recent years, attention has turned to the use of cancer-derived components that circulate in the bloodstream. During cancer cell apoptosis or necrosis, circulating cell-free DNA fragments – circulating tumour DNA (ctDNA) – are released into the blood stream. Circulating tumour cells (CTCs) from primary tumours can also shed and enter the bloodstream. These CTCs can subsequently become seeds for metastases in distant organs. Isolation of these tumour-derived components from the peripheral blood and their assessment represents a new diagnostic tool known as liquid biopsy.

Origins of liquid biopsy

In 1869, Thomas Ashworth described the microscopic observation of CTCs in the blood of a man with metastases. He suggested that these tumour cells were shed into the bloodstream, leading to the metastatic cancer. The first publication of cell-free DNA (cfDNA) was in 1948. It was not until the 1980s that cfDNA was first discovered in oncology patients. However, at this time researchers were not able to distinguish between tumour and healthy cfDNA.

Fast forward to today and researchers have developed numerous tests based on circulating nucleic acids and undertaken various research to determine the value of this technique. There are several types of liquid biopsy methods including:

  • In cancer studies, CTCs, ctDNA, exosomes and microRNAs can be collected
  • In prenatal diagnosis, cell-free fetal DNA (cffDNA) is extracted from maternal blood. Researchers can also extract and analyse amniotic fluid
  • In heart attack diagnosis, circulating endothelial cells (CECs) are sampled

Benefits and limitations of liquid biopsy


  • Unlike traditional methods liquid biopsy is less invasive
  • Tests results are typically rapid
  • Overcomes tumour heterogeneity
  • Less expensive and can easily repeat the tests
  • Allows for patient stratification and real-time monitoring of therapies
  • Can estimate risk for metastatic relapse or progression
  • Can perform follow-up examinations


  • Circulating tumour molecules are typically rarer than non-cancer-related fragments in the blood. Therefore, they are often difficult to detect
  • Molecular protocols are not yet standardised
  • Test variability and sensitivity
  • Risk of false-positive and false-negative results
  • Large-scale cohort studies required to determine their effectiveness and sensitivity

Current and Future Applications

Liquid biopsy shows great promise for the detection, prognosis and prediction of response to cancer treatment. Among the sources, ctDNA currently leads applications for diagnostic purposes.

Retrospective studies have shown that ctDNA analysis is able to accurately genotype mutations found in tumours. However, as there have been few large prospective studies, there has been uncertainty about the validity of ctDNA testing in routine practice. To address this, a recent large-scale prospective study – plasmaMATCH – showed that liquid biopsy can offer accurate, rapid genotyping for adoption into routine clinical cancer care.

Researchers have already shown through observational studies that CTCs and ctDNA are clinically relevant for different cancer types. However, researchers must conduct intervention clinical trials to further prove ctDNA utility. Due to lack of standardisation, only a few interventional clinicals trials are ongoing. For example, the STIC CTC METABREAST study recently explored the clinical utility of CTCs in assigning people with metastatic breast cancer either chemotherapy or hormonal therapy. They found that CTC count, in most people, confirmed that an appropriate clinical choice had been made.

Researchers have attempted to combine data to obtain a precise tumour profile, which could help guide treatment plans. For example, the European project PROLIPSY is combining analysis of CTCs, cfDNA and exosomes in people with high serum levels of the protein prostate-specific antigen. The aim is to first identify people with prostate cancer and then differentiate between aggressive and non-aggressive disease.

Liquid biopsy is not currently a routine clinical test, yet its potential applications are rapidly growing. The FDA recently approved two liquid biopsy tests – Guardant360 CDx test and FoundationOne Liquid CDx test for use. Guardant360 CDx uses NGS technology to identify patients with specific EGFR mutations in metastatic non-small cell lung cancer. Whereas, FoundationOne Liquid CDx looks for mutations within 324 genes (including EGFR) that are implicated in cancer. Although liquid biopsy is unlikely to fully replace surgical biopsies soon, it is likely that this technique will complement traditional methods within the next few years.

‘Liquid Biopsy Online’

Don’t forget to register for our ‘Liquid Biopsy Online’ webinar series starting on Thursday (1st October 2020). This four-part webinar series will provide you with all you need to know about the liquid biopsy technologies that are about to transform cancer care. The confirmed speakers for our 1st interactive discussion on Thursday about the future of liquid biopsy include:

  • Klaus Pantel, Chairman of the Institute of Tumour Biology, The University Medical Centre Hamburg-Eppendorf
  • Lauren Leiman, Executive Director, BloodPac
  • Valerie Taly, Group Leader, INSERM
  • Catherine Alix-Panabieres, Director of Laboratory of Rare Human Circulating Cells, The University of Montpellier
  • Jonathan Beer, Director of Disruptive technologies, Novartis

Image credit: By kjpargeter –

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Cancer / Cancer Research / Liquid Biopsy