The emergence of liquid biopsies as companion diagnostics

The development of liquid biopsies

The term liquid biopsy refers to the use of different body fluids such as blood, urine and saliva for analysis of the health of patient, with blood samples being most commonly used. Amongst the many components of blood, circulating tumour DNA (ctDNA) is of particular clinical interest as these fragments of DNA are released into the bloodstream by tumour cells and can be used as an effective biomarker for the diagnosis of cancers.

An important advantage of performing a liquid biopsy is the minimally-invasive nature of this technique. Compared to tissue biopsies, taking a blood sample is quicker, has a lower risk of complications and can be repeated many times to monitor disease progression as well as response to treatments. Furthermore, the heterogeneous nature of tumours means that genetic differences often exist between different regions of the same tumour. A tissue sample taken from one location often is not representative of the entire tumour. In contrast, liquid biopsies are not tied to specific locations and have much more potential for accurately capturing the genetic heterogeneity of tumours, therefore providing clinicians with a more complete picture of the cancer genome.    

One of the main challenges associated with the analysis of liquid biopsies is the difficulty in detecting the low concentrations of ctDNAs in blood. Different types of DNA circulate in the bloodstream and often, ctDNA represents only a small proportion of the total cell-free DNA (cfDNA) found in the blood. Healthy, non-cancerous tissues also release cfDNA into the bloodstream, which must be distinguished from ctDNA. This is particularly challenging when detecting early-stage cancer, where the fraction of ctDNA in total cfDNA can be as low as 0.1%.

Despite this challenge, over the past decades assays have been developed which use ctDNA as a biomarker for the accurate detection of a range of cancers. To enhance detection sensitivity, methods have been developed to separate the tumour-derived ctDNA from other cfDNA based on differences in size as well as by targeting known mutations in certain cancers. Recent studies have shown that the analysis of both genetic and epigenetic variations in ctDNA holds potential for diagnosing a range of cancer types as well as for determining the tissue of origin, which can be useful when the location of tumours is unclear. A multicancer test is also in development which uses a single blood test to screen for multiple types of cancer. Results from a clinical study indicate that the test has potential for diagnosing cancers across 10 organs at a stage where patients are asymptomatic, suggesting that this approach could revolutionise the diagnosis of very early-stage cancers.

Personalising cancer treatment

In recent years there has been growing interest in the clinical utility of liquid biopsies as diagnostic tools for selecting between treatments in cancer. A number of liquid biopsy-based companion diagnostics have been co-developed alongside cancer drugs to assess the safety and efficacy of the specific drugs on individual patients.

The first liquid biopsy test to receive approval by the US Food and Drug Administration (FDA) was the cobas® EGFR Mutation Test v2. This blood test is currently used as a companion diagnostic to assess the efficacy of three drugs against non-small cell lung cancer; erlotinib, osimertinib and gefitinib. These three drugs fall in a class of kinase inhibitors which have proven efficacy in treating NSCLC patients that have a mutation in the EGFR gene. Traditionally, EGFR mutation testing is carried out on a tumour sample obtained by tissue biopsy and the results are used to predict whether an individual will respond to treatment or if drug resistance is likely. However, particularly for advanced cases of non-small cell lung cancer, patients may be too unwell to undergo a biopsy by surgical means. A liquid biopsy provides an alternative diagnostic method for patients that are ineligible for tissue biopsy. Furthermore, test results are must faster and can be provided within 1-2 days, compared to an average turnaround of 3 weeks for a tissue biopsy.

Another recently-launched liquid biopsy-based companion diagnostic is the PIK3CA Mutation CDx, which is used to determine whether breast cancer patients are suitable candidates for therapy with alpelisib. Up to 40% of patients with certain types of breast cancer have a mutation in the PIK3CA gene. Alpelisib shows good anticancer activity in this subpopulation of patients and therefore the mutational status of the PIK3CA gene in an individual can be used as a biomarker to predict the efficacy of alpelisib. Two separate assays have been developed by Neogenomics to assess the mutational status of PIK3CA, with one performed on solid tumour samples and the other on blood plasma obtained by a liquid biopsy. Results from a clinical trial suggest that a liquid biopsy-based assessment of PIK3CA mutational status represents a better indicator of progression-free survival compared with assessment using a tissue biopsy. Together with the advantage of being less invasive, these results show that the PIK3CA liquid biopsy test is a promising development in the management of breast cancer.

There is also growing interest in expanding the scope of liquid biopsy-based diagnostics beyond the analysis of single genes. For example, the launch of the InVisionFirst®-lung liquid biopsy was recently announced, which uses next-generation sequencing to test a panel of 37 genes relevant to the care of advanced non-small cell lung cancer. By testing a larger panel of actionable genes, the results from this test offer a more comprehensive genetic profiling of patients to aid in the delivery of highly personalised treatments.


In the era of precision medicine, companion diagnostics are critical tools for tailoring treatments to individual patients. Whilst tissue biopsies have been the gold standard for genetic testing in cancer over the past decades, liquid biopsies hold great promise in the field of precision medicine and are emerging as a convenient and accurate alternative to conventional tissue biopsies.