What's new in cancer?: Cell-free DNA and liquid biopsies

For decades, making a diagnosis of cancer and choosing treatment has relied on a biopsy – a procedure that removes a piece of the tumour for microscopic examination by pathologists. However, collecting samples of tumour tissue can be difficult, dangerous and uncomfortable for patients.

Samuel Shem’s 1978 satire ‘The House of God’, set amongst young American doctors, coined the quote: ‘There is no body cavity that cannot be reached with a 14 gauge needle and a good strong arm’. While it’s true that modern imaging techniques allow interventional radiologists to guide needles further and more safely in pursuit of biopsies, it would be better if the procedures could be avoided altogether. Liquid biopsies offer a future alternative.

As cancers grow, cells will die and release small fragments of DNA – referred to as cell-free DNA (cfDNA). A liquid biopsy uses any body fluid that may contain cfDNA as a source of the information needed for treatment. Usually, the liquid in question is the patient’s blood but in some circumstances could be urine, cerebro-spinal fluid or fluid that builds up around the lungs (pleural effusion) or in the abdomen (ascites) in some cancer types. CfDNA was first identified in blood as early as 1948 and by the 1980s it was possible to find the cfDNA from cancer cells in blood.

Over subsequent decades, techniques have been refined to be incredibly sensitive. If we look at cfDNA as a needle in a haystack, then new liquid biopsies are a very helpful giant magnet. CfDNA can now potentially be used at all stages of a cancer treatment:

Aside from prevention, the best way to reduce harm from cancer is early diagnosis, when curative treatments are more likely to succeed. Liquid biopsies may detect cancer cfDNA in a person with no symptoms at all, long before the cancer is large enough to become easily noticeable or obvious on scans.

The most commercially advanced use of diagnostic cfDNA tests is the Galleri test, which claims to be able to find early evidence of up to 50 different cancers. There are problems with such a test including false positives (leading a person to think they have a cancer when they do not), overdiagnosis (finding cancers that wouldn’t become important in the person’s lifetime) and the investigations required to follow up on a positive test. Questions about the test’s utility will hopefully be answered by the large GRAIL study. GRAIL aims to recruit over 140,000 over 50s and is currently running in several Cancer Alliances in England.

New cancer treatments are often designed to target very specific molecular alterations. Obtaining biopsies in order to identify these specific targets for treatment has become an important part of many treatment pathways. In lung cancer, there are now several genomic mutations that determine optimal treatment strategies (such as EGFR and ROS-1). However collecting tumour tissue samples can risk lung collapse in people who are the least likely to be able to tolerate such a risk.

Liquid biopsies allow lung cancer clinical teams to advise people without these dangerous interventions. A UK trial (the plasmaMATCH study) has shown the utility of using cfDNA to plan treatments for women with advanced breast cancer. Although not routinely universally funded within the NHS, liquid biopsies are available in some centres and access is increasing as costs fall.

As liquid biopsy testing techniques grow in sensitivity, it is hoped that in the future tests may be able to prove the absence of cancer. Being able to tell a person that there is no molecular evidence of their cancer after treatment would represent a huge advance.

Tens of thousands of cancer patients receive adjuvant therapies which are given ‘just in case’ any microscopic disease has been left behind after surgery or radiotherapy. If a liquid biopsy could prove a cancer was gone, and gone for good, it would spare a huge amount of toxicity.

Monitoring levels of cfDNA may also help teams determine the optimum duration and intensity of treatment for people based on very individualised data. A current trial running in the UK (the ZEST study) is hoping to identify a cfDNA early warning system in people treated for triple negative breast cancer. The trial is testing whether the earliest recognition of cfDNA will allow newer treatments to eradicate the cells before they become a problem for patients.

These potential applications mean that cfDNA and liquid biopsy are arguably the most disruptive emerging cancer technologies. Market competition, increased trials and increased automation should also hopefully see costs reduce and availability increase so that access is widened. There is UK Government commitment to harnessing what genomic analysis of tumours can do to improve healthcare outcomes, and liquid biopsies should be a key part of that.

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