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Liquid Biopsies for Cancer Moving Towards 'Holy Grail'

The 'holy grail' of cancer detection – being able to spot the disease at the very earliest stage – is moving closer to realisation thanks to a raft of trials currently ongoing using ‘liquid biopsies’ (i.e., minimally invasive blood tests) to detect circulating cancer markers. As well as potential use in screening, the technique could also play a role in monitoring patients after treatment, aiming to spot recurrence potentially long before it would be detected with traditional methods.

The latest phase of one such trial, TRACC ('Tracking mutations in cell free DNA to predict Relapse in eArly Colorectal Cancer'), will evaluate the use of circulating tumour DNA (ctDNA) to guide chemotherapy treatment decisions after curative surgery in patients with early stage colorectal cancer. 

Patients Could be Spared Unnecessary Chemotherapy

TRACC is a multi-centre, prospective, randomised study sponsored by the Royal Marsden (RM) NHS Foundation Trust and recruiting across approximately 40 sites around the UK, with a planned inclusion of 1621 patients over 4 years. It uses a ctDNA test, Guardant Reveal™, created by Californian company Guardant Health, to determine whether patients can be spared unnecessary chemotherapy and the associated side effects if they test negative for ctDNA. 

Professor Stan Kaye, consultant medical oncologist at the RM, is director of research for an alliance of RM partners, which includes 10 acute NHS trusts, two sustainability and transformation partnerships, and 14 clinical commissioning groups, plus specialised commissioning groups, community services, hospices, and third-sector and voluntary organisations across London. 

He said: "With TRACC, we’re investigating whether the persistence or reappearance of tumour DNA in the bloodstream following surgery can predict colorectal cancer relapse earlier and more accurately than standard methods of CT scanning, and early enough for a cure to still be possible."

'Not Clear' Which Patients Benefit From Chemotherapy

Although surgery is curative in around half of patients with stage 3 colorectal cancer , between 30-50% relapse due to microscopic minimal residual disease. Because of this, chemotherapy is generally recommended post-surgery to reduce the risk of future recurrence, although it is not clear which patients are likely to benefit. 

"Patients with high-risk colorectal cancer are often over-treated and can suffer long-term neurotoxicity from chemotherapy," said Professor David Cunningham, director of clinical research at the RM and chief investigator for the TRACC study. "This study will generate evidence and insights to help us understand when we can avoid unnecessary chemotherapy for our patients who have no disease detected following surgery. This information can help us tailor treatment decisions to benefit patients and potentially realize significant cost savings for the healthcare system."

Several global studies have shown that a negative ctDNA result after surgery can accurately predict those patients in whom the cancer is very unlikely to return. Monitoring ctDNA to reveal microscopic traces of cancer in the bloodstream that would be invisible on a scan may mean that trial volunteers are able to avoid potentially unnecessary chemotherapy. TRACC will compare 3-year survival rates for patients whose treatment was guided by ctDNA liquid biopsy with those who went on to standard-of-care intravenous chemotherapy after surgery. The RM said that the trial "could revolutionise treatment for operable bowel cancer within 5-8 years".

Dr Naureen Starling, principal TRACC investigator, said: "Half of patients with stage 3 bowel cancer are cured by surgery alone, so we are over-treating a large proportion of patients.” The outcome of the trial could affect the way thousands of bowel cancer patients are treated every year. Avoiding unnecessary chemotherapy is “good for the patient, it’s good for the health service, it’s good for cost savings within the NHS. That would be a win-win”, she said.

Trials are also under way in the UK to monitor patients with lung and breast cancer in the same way, with early trials elsewhere showing that breast cancer recurrence could be picked up at least 4 years earlier than it would be detectable by a scan.

'Immense' Potential Includes Early Diagnosis

In addition, Dr Starling said, the potential for this new technology across cancer care was "immense", not only for detecting residual disease after surgery but also for early diagnosis. 

Prof Kaye said: "This may translate into early diagnosis for the general population, where a simple blood test or liquid biopsy can detect cancers up to 8 months before they become symptomatic."

RM Partners is also piloting a lung cancer screening programme, which will invite smokers and ex-smokers over a certain age to attend a health check and possibly a CT scan so that any cancers are picked up as early as possible. Alongside this, they are working with Imperial College London to develop a blood test that can detect increased risk of lung cancer.

Liquid biopsies are also under test in the NHS-Galleri trial, which is looking at the potential of a test developed by another Californian company, GRAIL, as a screening test that might detect potentially more than 50 types of tumour at the pre-symptomatic phase. It could help to detect cancers that are typically difficult to identify early – such as head and neck, bowel, lung and pancreatic cancers.

Galleri has enrolled around 140,000 volunteers aged 50-77 and interim results are due early next year. A subsequent phase planned could include 25,000 people aged 40 and above with suspicious signs or symptoms of cancer. Successful trial results could lead to the test being rolled out across the NHS.

Prof Kaye said: "The direction of travel for the next 5-10 years is to identify people with an increased risk of developing certain cancers, or relapsing after treatment for primary cancer, and do non-invasive screening. In particular, there is potential to improve early detection of lung and colorectal cancers."

Liquid biopsy tests are already available privately.

TRACC is funded by the National Institute for Health & Care Research (NIHR).