Cambridge Conversations – Circulating Tumour DNA

John Chevers

1 June 2018

A diverse group of stakeholders learn about this exciting liquid biopsy technique and discuss its future applications.

Earlier in the year, PHG Foundation led a round-table event with representatives from the research, clinical, biotech/diagnostics, investment and insurance sectors to hear their feedback on recent developments and anticipated applications of these important technologies.

What is ctDNA?

Circulating tumour (ct) DNA testing, also known as liquid biopsy, is a technique which analyses blood samples for small quantities of cell-free DNA that came from a patient's tumour.

Liquid biopsy is a less invasive medical procedure than a solid tumour biopsy, which has a risk of side-effects such as bleeding or tissue/organ damage. As with oher blood tests, liquid biopsy can be carried out more frequently throughout treatment, for example to monitor treatment response, or to detect the emergence of resistance to therapy. 

What did delegates learn?

Three speakers provided different perspectives to the current status of ctDNA technologies

From a research perspective…

The focus is to stratify patients to inform the most suitable care for their individual clinical needs. ctDNA allows the measurement of very specific genetic markers which are unique to the tumour concerned. However the real challenge affecting the use of liquid biopsies is the scarcity of ctDNA in the blood, which can constitute 10% of plasma cell-free DNA in advanced cancer patients, but significantly less in those with early-stage disease.

A significant application is to use ctDNA to monitor the status of patients, particularly as an indicator of relapse post-surgery and to direct additional treatment.

Early-stage diagnostics (for example for prostate cancer) have the potential to precede conventional biopsy techniques and may be integrated in the clinical pathway alongside imaging and pathology. However, a recent study shows only a 40% detection rate for early stage cancer detection, so we must be cautious to avoid over-stating current capabilities.

From an innovation perspective…

The challenge is taking the results of research and developing a clinically useful test based on ctDNA. Any test must inform clinical decision-making along the patient pathway – key applications are to inform:

  • Risk of disease
  • Earlier detection of cancer
  • Prognosis of existing patients
  • Monitoring of treatment response
  • Evidence of relapse

However, progress is needed on improving and standardising technologies and decisions on how best to target testing are necessary. Significant investment will be required to fund this development and set up the studies necessary to test with patients.

From the NHS perspective…

ctDNA testing is already in use on a small-scale in the NHS, to test patients with non-small cell lung cancer who have failed solid tumour biopsy, to determine if they have mutations in a gene called EGFR. If so, the patient can receive a targeted drug. However not all eligible patients receive a test, so there is a challenge to be met in terms of supporting implementation of ctDNA testing and ensuring that it is available equitably. Key areas where action could be taken are:

  • Formal consideration of test provision by commissioners
  • Engagement with the health system about testing, via the multidisciplinary team
  • Development of clinical guidelines
  • Support for strategies that deliver drugs and the tests needed to prescribe them in parallel

Sector priorities

Investment

The UK has a significant business advantage in the development of ctDNA technologies – given the right investment opportunities this may prove a vehicle to make a significant contribution to the British life science sector

Clinical

Essential to their adoption is the education of clinicians to raise awareness of existing tests as well as guidance  for the clinical application of these technologies - momentun is needed to establish guidelines.Health economic data is needed to prove the benefit of tests, even if they are yet be optimised.

Diagnostics

Whilst drugs are approved for cancer treatment, companion diagnostics to help specify and target the treatment are missing. Also crucial will be a regulatory environment that keeps pace with the continuing development for ctDNA tests.

Insurance

  • In some world regions tests are being specified without regard to their effectiveness – clinicians and insurance companies need evidence and advice on the value of testing and its impact on long-term outcomes
  • The definition of ‘Critical Illness’ specified in many policies may need revision in the light of diagnosis by ctDNA testing detecting cancer earlier and with greater sensitivity
  • As tests are easily commissioned privately, this may become a source of information asymmetry between insurance companies and their clients

Implications

The implications of ctDNA testing are widespread and are having an impact beyond the healthcare and pharmaceutical sectors. Variability between different countries in how testing is used and regulated will have an impact on patients according to the rules of that country - there is a danger that some patients will receive suboptimal testing that hasn't been clinically proven.

Given an aging population, and the availability of improving technologies to detect cancer earlier, we will have to consider how to categorise cancer as a disease given that a) cancer is primarily a disease of aging and b) in some cases it can be treated for years as a chronic disease. This will have implications for the insurance sector in terms of how it defines disease, but more broadly these tests have the potential to make a significant contribution to cancer care, in terms of prescribing targeted drugs and monitoring patients during their treatment journey.