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Source: United Kingdom – Executive Government & Departments

The NHS has announced a new pilot using the Garelli blood test to detect multiple different types of early stage cancer. NHS England has confirmed this project will be funded by Grail.

Dr Mangesh Thorat, Deputy Director (Clinical) of the Cancer Prevention Trials Unit at King’s College London, and Research Fellow, Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, said:

The Galleri test performs a Targeted methylation analysis of cell-free DNA (cfDNA) in blood (https://www.annalsofoncology.org/article/S0923-7534(20)36058-0/fulltext) and appears to have a reasonably good sensitivity for a select group of 12 cancers with an acceptably low false-positivity rate in a large case-control study (first type of study in clinical development pathway of a test). The test also appears to have good sensitivity in certain high mortality cancers e.g. Pancreatic and Oesophageal cancers where we do not yet have a good early detection test; this is a major strength. Another strength is that the test can also pinpoint to the location of cancer in a very high proportion of cancers, thereby guiding focussed next set of investigations. With these performance characteristics, the obvious next step would be to evaluate it in a larger cohort study representative of target population.

“The NHS pilot appears to be this next research study and one would expect that invitees are appropriately informed that they are being invited to participate in this research study. It is likely that for every testing round in this pilot population, there will be about 1000 false-positive results and the test may not be able to pinpoint the location of cancer in 3-4% of those with true positive result, necessitating a range of imaging and other investigations in these participants. Invitees will need to consider the potential harms associated with such investigations and anxiety caused by a positive test result.”

Prof Sam Janes, Respiratory Consultant at UCLH and Head of Respiratory Research Department, UCL, said:

What do we already know about the Galleri blood test and how effective it is at detecting cancers? 

“The test picks up around 6 cancers in 10 and is being improved all the time. This test has the added benefit that it tells you not only that the person has a cancer but also where the cancer is in the body.

Are there any limitations of this type of test? What are the implications of those on the pilot?

“Like most cancer blood tests it probably detects larger cancers more easily, though still works on early smaller cancers.

What are the benefits of early detection?

“Early detection of cancers is crucial. When we can detect cancers early, this means we are far more likely to be able to offer a curative treatment. It can be life saving.

Could there be any negative impacts of this test?  

“This test sometimes misses cancers so must not replace the screening tests we already are offered. It is rarely wrong though – which means people with a positive test do need investigating further.

Are there any particular types of cancer in which this could be a really important step should the pilot be successful?

“The cancers that classically present late and don’t have a current screening test could particularly benefit such as lung, ovarian and pancreatic cancer.”

Jodie Moffat, Head of Early Diagnosis at Cancer Research UK, said:

What do we already know about the Galleri blood test and how effective it is at detecting cancers?

“Galleri is a methylation-based assay to analyse cell free DNA. It looks for abnormal DNA that has been shed from cells. There have been a few different studies looking to refine and explore the use of this blood test for cancer detection, which has been developed by the company GRAIL. GRAIL has been investigating the use of AI in the interpretation of blood test findings. Results so far, from studies outside of the UK, have been promising, and the number of cancer types that it seems to be able to pick up is large. But the sample sizes, particularly for some cancer types, have been very small and so it needs to be tested in a much larger sample, and with longer follow up of patients not testing positive with the blood test to understand where it is missing cancers. Based on the evidence we have seen, the test is not currently that good at picking up stage I cancer, where it is small and hasn’t spread to other parts of the body. 

Are there any limitations of this type of test? What are the implications of those on the pilot?

“One of the challenges for this type of test comes down to being able to detect very small quantities of abnormal DNA circulating in the blood. Because the amount of circulating tumour DNA tends to increase as a cancer becomes more advanced, these types of blood tests have tended to be better at detecting later stage disease than early stage disease. This particular blood test has had some encouraging findings in this regard but there is more improvement needed if it is going to significantly shift the dial on the NHS’s Long Term Plan stage ambition by accurately detecting cancer at its earliest stages.

“The larger sample size in this proposed research study will also be important for unpicking some of the challenges raised in the detection of cancer types with known viral causation, such as cervical cancer, cancer of the anus, and head and neck cancers.

What are the benefits of early detection?

“When cancer is diagnosed at an early stage, the chances of survival are much improved.

“In England at the moment about 55% of (stageable) cancer cases are diagnosed at stage I or II – the NHS has committed to seeing this shift to 75% at stage I and II by 2028.  This is a very ambitious ambition and requires action and research on a range of fronts. This includes more quickly implementing the things we know can make a difference now, which requires significant investment in diagnostic workforce and capacity, and research to identify the innovations and, hopefully the gamechangers, of the future.

Could there be any negative impacts of this test?  

“The findings of this large scale research project will be key to understanding the negative impacts of the test. It will be important to ensure that the test is accessible to all and doesn’t add to inequalities, that the people who take part in this study are representative of our diverse population, that there is assessment of participant/patient anxiety that may be generated and that the full implications on the health service are assessed and that no other parts of the health service are compromised.

Are there any particular types of cancer in which this could be a really important step should the pilot be successful?

“There are some cancers which it can be very difficult to diagnose at an early stage, such as lung cancer and pancreatic cancer. We hope that ultimately that a test such as this could support earlier diagnosis for these and other challenging tumour types.

Any other comments?

“We welcome this research and look forward to seeing the findings. These will take a while to deliver and in the meantime its vital that the Government and NHS continues to address the challenges for cancer diagnosis in the present, and ensure that there is capacity in the system to optimise diagnosis pathways for patients with symptoms and those coming through the existing national cancer screening routes.

Looking to the future, we see that blood tests such as this could be an important part of the suite of interventions for early detection and diagnosis, but it is important that we don’t take our eye off the other key developments and innovations that will be needed to deliver on this ambitious agenda and give more patients a better chance of surviving their cancer.”

 

Prof David Cunningham, Consultant Medical Oncologist and Director of Clinical Research at The Royal Marsden NHS Foundation Trust, said:

“This exciting programme could quite literally be a gamechanger for detecting cancer at an earlier stage – where treatment is less invasive and more likely to be successful – and it would be wonderful to see this technology being taken into general practice in England and eventually the rest of the UK as a result.

“Where this study is targeting the general population, we’re currently researching similar technologies at The Royal Marsden to find residual evidence of disease with patients who have had a cancer diagnosis, and our results have been very promising so far.

“We know that some cancers, particularly those at an advanced stage, present more DNA in the blood, so we will need to see whether there are limits of detection with this new technology.”

Prof Paul Pharoah, Professor of Cancer Epidemiology, University of Cambridge, said:

“The Galleri blood test is a test that might be able to detect cancer in the blood in individuals with early cancer, though the evidence that it does this effectively is weak. 

“It is extremely difficult to determine, from this press release, the scientific basis for this so-called pilot study.  There is no published evidence that this test is an effective test for screening for cancer, so one has to question the aims of the pilot.

“There are several issues that are immediately apparent.

1) A pilot study is a study designed to evaluate the feasibility of a process – the implementation in the NHS as described is not a pilot.  It is not necessary to use the test 165,000 times in order to pilot the feasibility.  This suggests that the aim of the ‘pilot’ is to address a scientific question or questions.  However, those questions are not described.  Furthermore, it is not the role of the NHS to roll out clinical services before the important scientific questions have been appropriately addressed.

2) Will patients be informed that this test is experimental and the benefits and harms are unknown?

3) The test is going to be applied in 140,000 individuals without symptoms.  As such it is being applied as a screening test.  The only valid way to evaluate the performance of a screening test is by randomised controlled trial and the NHS should not be investing in such a test until it has been formally evaluated in such trials and then subject to the scrutiny of the National Screening Committee.

4) The only published paper I could find reporting on the validity this test for detecting 50 cancers included just 654 cancers of which only 185 were the very early stage cancers that an early detection test needs to detect in order to be effective.  In these early stage cancers the sensitivity of the test was less than 25% – this is the proportion of these cancers that were detected by the test.  In the more advanced stage 2 cancers the sensitivity was less than 50%.   This level of performance is completely inadequate for a screening test.

5) Who is going to bear the cost of the test?

6) Who is going to bear the cost of the investigation of individuals with a positive test many of whom will not have a detectable cancer?

“In short the NHS should not be investing in such a test before it has been adequately evaluated in well-conducted, large-scale clinical trials.”

 

Prof Justin Stebbing, NIHR Research Professor of Cancer Medicine and Medical Oncology, Imperial College London, said:

“Detecting cancers including common and rare ones at an earlier stage should increase the cure rate. Blood tests, especially those that look at cancer DNA in the blood, that are touted to detect cancer are being increasingly studied, but their real world applicability, for example in the NHS, is still unproven. Investigating this with the possibility of potentially helping millions of people, and integrating this into the NHS would be very worthwhile.”

Prof Lawrence Young, Professor of Molecular Oncology and Director of the Warwick Cancer Research Centre, Warwick Medical School, University of Warwick, said:

“The Galleri test is one of a number of novel blood tests being developed to detect cancer at a very early stage where treatment options are more effective. The test identifies distinct methylation patterns that are associated with specific cancers to detect a number of those cancers early and to provide information about the organ of origin. There are a number of trials evaluating this approach and a publication from the Circulating Cell-free Genome Atlas (CCGA) consortium examining the Galleri test in 6689 participants has generated very encouraging results in more than 50 different cancers at different stages of development.

“The pilot study by the NHS announced today will provide further validation of usefulness of the Galleri blood test in detecting cancer in individuals who have no symptoms. Other trials of the Galleri test along with the evaluation of different cancer blood tests bode well for the development of effective, minimally invasive and simple screening methods for the early detection of multiple cancers. Excitingly these include cancers that are currently not detected early because of a lack of effective screening tests e.g. cancers of the lung, liver, ovary and pancreas.”

Michelle Mitchell, Cancer Research UK’s chief executive, said:

“Earlier detection of cancer offers arguably the single biggest opportunity to save lives from the disease, and tests like GRAIL’s have great transformative potential. Large research studies of these tests are essential for determining if they’re effective, and a vital step in getting them to patients, if proven to work.

“All too often, people are diagnosed with cancer at a late stage, when their disease is more difficult to treat. This is a human tragedy, not just in terms of lives lost, but it also means more expensive treatments, hospital stays and monitoring. If we can turn this on its head and find cancer at its earliest stages when it’s easier to treat, not only will we be able to save lives on a vast scale, but we may be able to save our NHS millions of pounds.

“Cancer Research UK’s Early Detection and Diagnosis of Cancer Roadmap highlights the challenges facing the entire early diagnosis ecosystem, from the development of new tests, through to boosting capacity in diagnosis. The announcements from the Government in the spending review yesterday were a step in the right direction, but we will need further long term investment in both cancer services and research and development to make early detection of cancer a reality for every patient.”

 

The NHS is planning a pilot using the Galleri blood test to detect early stage cancers

 

 

Declared interests

Prof Sam Janes: “is the chief investigator on the SUMMIT study, another study examining the GRAIL test and providing CT screening to 25,000 people in London.”

Prof David Cunningham: “No declarations of interest.”

Prof Paul Pharoah: “I have no conflicts of interest to declare.”

None others received.

MIL OSI United Kingdom