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Where next for ctDNA liquid biopsy in the NHS?

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Circulating tumour DNA (ctDNA) testing, also known as liquid biopsy, hit the headlines in 2020 with the announcement that GRAIL’s Galleri test – a test that aims to detect cancer early – will be trialled in the NHS. The trial will evaluate whether ctDNA testing can detect more cancers earlier in patients, and whether this can improve the success of treatments. However, there are several other ways in which ctDNA testing could transform cancer management across the patient pathway, some of them closer to implementation. We recently discussed some of these at a PHG Foundation-hosted panel at the Festival of Genomics and Biodata.

What is ctDNA testing?

ctDNA testing is the process of taking a sample of body fluid (normally a blood sample) and testing it for the presence of tumour DNA, which is shed by tumour cells into the circulation. Analysis of ctDNA can provide information on the genetic alterations present in a patient’s tumour, without needing a solid biopsy sample. The presence of the ctDNA itself can also act as a biomarker, indicating that a tumour is present.

Current status of ctDNA testing in the UK

ctDNA testing was first rolled out across the UK around five years ago, to detect specific EGFR mutations in non-small cell lung cancer (NSCLC) patients. ctDNA testing is used when patients are unable to provide a solid biopsy sample, which is normally required for mutation analysis. The use of the ‘liquid biopsy’ means these patients can still access therapies that target the EGFR mutations. If the cancer continues to progress, ctDNA testing can also be used to identify if specific resistance mutations have developed. This allows the patient to access further targeted therapies without having to undergo a repeat solid tumour biopsy procedure.

Expanding molecular profiling and access to therapies

Despite the benefits of ctDNA testing in NSCLC, this is a relatively niche application. Whilst NSCLC makes up approximately 87% of lung cancers, only around 10-15% of NSCLC patients have cancer with EGFR mutations.

Many more patients with different cancer types could also benefit from ctDNA testing. Breast, prostate, and ovarian cancers, as well as NSCLCs with mutations other than EGFR, are all cancers with targeted drugs available where ctDNA testing has been trialled. Those with metastatic cancers could also benefit from ctDNA profiling. The spread of a tumour to multiple, often inaccessible locations makes it difficult to obtain a representative solid biopsy sample, which can limit therapy options. There are now ambitions to expand ctDNA testing to patients with these cancer types, to allow greater access to targeted therapies when solid biopsies are infeasible.  

Expanding ctDNA testing is likely to need changes to the technology used, for example, the use of panel tests which can detect multiple mutations across multiple genes. Could we test for all mutations present within all cancers? Whilst this may be a tempting option, for many mutations there are currently no specific therapies available. In other cases, drugs exist but are not available on the NHS. As a result, deciding which targets to include on these panel tests will require careful consideration by service providers and the wider health system.

Moving on to monitoring and prognosis

The technologies used to detect ctDNA are becoming more sensitive, able to detect and analyse ever smaller amounts of ctDNA in the blood. This means it is now possible to detect if traces of a cancer remain after treatment. For example, residual ctDNA in the system after surgery is associated with cancer recurrence, indicating the need for additional (adjuvant) treatment. Many patients currently undergo further treatment such as chemotherapy or radiotherapy ‘just in case’ they might benefit. However most post-surgery patients don’t actually need this, whilst others may have tumours that we know don’t respond to the additional treatment. Using ctDNA to guide the use of additional therapies could mean fewer patients suffer undue side effects, as well as optimised use of resources.

ctDNA testing could also be used to regularly monitor for signs of cancer recurrence, or to indicate if a treatment has stopped working, before any clinical symptoms appear. This could be trickier to put into practice; clinicians will need clear guidance on interpretation of results and consequent actions to take, for example at which time-point to start or switch a therapy. The impact of regular monitoring on improving patient outcomes is currently unclear. Trials are now taking place to assess how monitoring could be implemented, and in which scenarios it will be of most benefit.

ctDNA as a cancer screening tool

There is much excitement over ctDNA’s potential to be used as a screening tool, to detect cancers before any clinical symptoms develop. Detecting cancers earlier often means they are more treatable, with consequent improvements in patient outcomes. ctDNA could theoretically be used to screen for multiple cancers at once using a single blood sample.

Many questions remain to be answered. It is unclear whether tests will be sensitive enough to detect the earlier and more treatable cancers, which typically release less ctDNA. To be a successful screening tool, it is essential that enough cancers are detected at a treatable stage. In addition, at the earliest stages of a tumour’s development, it can be hard to distinguish between tumours which are benign and those which will lead to cancer, potentially resulting in over-diagnosis and unnecessary treatments. There are also uncertainties over whether there are sufficient NHS resources to follow up all potential positive results. A large trial of a ctDNA test to detect early cancer in people aged 50 -79 with no symptoms is being planned in the UK. This will help generate much-needed evidence to start providing answers to these questions.

ctDNA screening tests might have greater utility, and be easier to implement, if used in high-risk groups. For example, people genetically predisposed to cancers or exposed to high environmental risk such as smoking, could undergo regular ctDNA testing, to help catch cancers earlier. As these patients are more likely to develop cancer, the chance of false positive results would be lower than in the general population. 

Where do we go from here?

The technology for ctDNA testing is now at a stage where it is ready to be used in the clinic for several different applications. However, as with all new technologies, there will be challenges surrounding its implementation.

Generating real-world evidence that test results are reliable, actionable and improve patient outcomes will be key. Evidence of cost-effectiveness is often overlooked but will also be important. It is likely these sophisticated tests won’t be cheap, but may improve patient outcomes and provide longer term savings to the health system, for example by avoiding unnecessary treatments. The first step towards implementation is to identify which clinical scenarios and pathways will benefit the most from ctDNA testing, and how it will fit into these pathways. Engaging multiple stakeholders, such as researchers, clinicians, patients and policy makers, will help ensure everyone’s needs are met. 

ctDNA has the potential to transform cancer care for patients across the entire therapeutic pathway, from earlier diagnosis, to prognosis and better management of treatments. Its importance has been recognised in the recent Genome UK strategy, and can help deliver the goals of the NHS Long term Plan. Now is the time to reflect on the lessons learned from the implementation of testing for NSCLC, and apply them to areas beyond companion diagnostic testing and limited molecular profiling.

Expertise on ctDNA research, policy and genetic test implementation were provided by Prof Rachel Butler (Director, South West Genomic Laboratory Hub), Dr Anca Oniscu (Clinical Lead Molecular Pathology, Royal Infirmary of Edinburgh), Dr Nitzan Rosenfeld (Senior Group Leader, Cancer Research UK Cambridge Institute) and Dr Laura Blackburn (PHG Foundation Head of Science).

 

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