New blood10 May 2021
The almost total shutdown in invasive cancer diagnostics during the first wave of Covid-19 focused attention on the need for alternatives. Now, all eyes are turning to liquid biopsies. Tim Gunn talks to Naureen Starling, consultant medical oncologist at The Royal Marsden NHS Trust in London and a clinical senior lecturer at the Institute for Cancer Research, about how simple blood tests could save lives.
For many patients, the distinctive thing about an endoscopy is the one-eyed tube it sends worming into their torso through their mouth or anus. Laxatives might be required to clear bowels beforehand, but the fibre-optic spelunker that goes in tends to cause more anxiety than whatever airborne particles it might push or suck out – particularly as they are usually too small and light to be detected, passing easily around and through surgical masks, and sitting in the air long after the patient responsible for them has left.
Those tiny particles became hugely significant in 2020. As the first wave of the Covid-19 pandemic swept across the planet, the spray-releasing procedures that allow doctors to see what’s happening inside their patients had to be curtailed to limit the spread of the virus. Oncology is yet to recover.
“Invasive diagnostics are what we call aerosolgenerating procedures, and can create a spray in the room that carries Covid,” explains Dr Naureen Starling, consultant medical oncologist at The Royal Marsden NHS Trust in London and a clinical senior lecturer at the Institute for Cancer Research. “That aerosol can infect the staff, infect the room and, therefore, infect other patients going through that room. Suddenly our diagnostics were switched off, and we had patients highly likely to have cancer who had no way of progressing to the next step of starting treatment.”
By the end of March, UK endoscopic activity had collapsed to 5% of pre-pandemic levels, only crawling back up to 20% by the end of May. Over that period, endoscopic cancer detection fell by 58% overall, and by 72% for colorectal cancer. The backlog of procedures has been climbing ever since, reaching an estimated 476,000 in January 2021, according to figures in a Lancet Gastroenterology and Hepatology paper. The meaning of those numbers will become palpable in many families over the years to come. A recent modelling study in Annals of Oncology indicated that a surgical delay of three months across all solid tumours in the UK would lead to 4,755 excess deaths, escalating to 10,760 after six months. The earlier a cancer is caught, the easier it is to stop. Those that aren’t stopped kill.
With that in mind, the Royal Marsden Trust looked at its options. Together with its academic partner, the Institute of Cancer Research, it has established itself as a leading centre for research into the use of noninvasive fluid samples, or liquid biopsies, for monitoring cancers through the circulating tumour cells (CTCs) and scraps of cell-free circulating tumour DNA (ctDNA) they leak into the bloodstream. Staff have even developed a number of their own clinicallyvalidated liquid biopsy assays for everything from monitoring how breast cancers respond to treatment to investigating what ctDNA can tell us about the likelihood that bowel cancer might return after surgery.
“We put our heads together and said, ‘What can we do to support the cancer effort in this exceptional situation, where our diagnostics are switched off?’” recalls Starling. In record time, they devised and launched the PREVAIL-ctDNA study to explore the possibility of replacing invasive tissue biopsies for patients presenting with symptoms of pancreatic, lung, bladder, colorectal and gastrointestinal cancers. Preliminary results are encouraging, and Starling, a gut cancer specialist as well as the coordinating investigator for the protocol, is particularly excited by the potential she sees for liquid biopsies to shorten diagnostic pathways for conditions like pancreatic and bile duct cancer, which are hard to detect with endoscopes and other existing diagnostic tools. “One in four patients has a difficult, protracted diagnostic pathway, with even invasive diagnostics not quite clinching the diagnosis and having to be repeated, and seeing various specialists on and off,” she explains. “That can take a few months – but we’ve made a diagnosis with liquid biopsies much sooner for a number of patients.”
For the lung cancer cohort, there’s a dual benefit. As well as simplifying the diagnostic process for a cancer that’s often difficult to reach and identify with a bronchoscopy, liquid biopsies also provide the molecular information needed to guide precision therapeutics. “It’s two for the price of one,” says Starling – and at a cost patients are far more willing to pay, given the alternative is inhaling several feet of electrical cable.
The next step for the PREVAIL-ctDNA study is a larger-scale protocol across more diagnostic units. “This was very much a feasibility programme, to deploy the test in a setting that we thought was very important because of the pandemic,” continues Starling, “but actually it just makes sense in the future in terms of supporting the diagnostic pathway, and to really to put a stop to the more protracted, difficult diagnostic cases, and potentially to even reduce the burden on these pressurised resources in endoscopy.”
Given the international endoscopy backlog – and the capacity limits caused by greater cleaning and PPE requirements, not to mention the lingering possibility of another surge in the virus – those resources will be stretched for a long time to come. It’s revealing that invisible particles should have brought us to this point. Cancer is defined as much by its ability to escape and spread imperceptibly through the bloodstream as the fact it agglomerates into the solid tumours we seek out and sample with endoscopes. The future of cancer diagnosis will be defined by tools that reflect that.
Late last year, the NHS announced a 165,000- patient pilot of a test capable of detecting and pinpointing more than 50 types of cancer through a single blood draw. The Galleri multi-cancer early detection (MCED) blood test, as it’s called, combines liquid biopsy technology with sophisticated machine learning capabilities to both identify the presence of ctDNA in a blood sample, and determine its tissue of origin through methylation analysis.
The UK’s mid-pandemic endoscopic activity low compared with pre-pandemic. It only climbed back up to 20% by the end of May last year.
Estimated excess cancer deaths in the UK if all solid tumour surgeries were delayed by six months.
Annals of Oncology
“We’ve made a diagnosis with liquid biopsies much sooner [than a few months] for a number of patients.”
As Dr Joshua Ofman, chief medical officer and head of external affairs for GRAIL, the company behind the Galleri, points out, there are currently only five guideline-recommended screening tests in the US, each of which only screens for a single cancer at a time. Meanwhile, cancers responsible for 71% of all cancer deaths have no available early detection screening. “The most pressing unmet need in early cancer detection,” he stresses, “is to identify cancers for which there are no existing recommended screening tests.”
Level of specificity at which GRAIL’s Galleri test can detect cancers across all stages.
Annals of Oncology
Helpfully, then, the circulating cell-free genome atlas (CCGA) study on which GRAIL’s work is founded demonstrated that an earlier version of the Galleri test can detect cancers across all stages (at a stage I–III sensitivity of 43.9%, and a stage I–IV sensitivity of 54.9%, rising to 67.3% and 76.4% in a pre-specified group of 12 high-signal cancers) at a specificity of more than 99%. The targeted methylation approach was also shown to identify the tissue of origin with over 90% accuracy. It’s encouraging, but there’s a lot still to prove. Despite the ‘early’ in MCED, ctDNA has tended to be a better indicator of later-stage cancers, which release more material into the bloodstream. As such, in the CCGA study, the Galleri’s sensitivity was only 18% across all stage I cancers.
Nevertheless, a modelling analysis since published in Cancer Epidemiology, Biomarkers & Prevention indicates that adding MCED tests to current guideline-recommended screening could reduce late-stage cancer diagnoses by nearly 70%, resulting in a 39% reduction of five-year cancer deaths, with only 8% more false positives. As such, the NHS hopes that implementing GRAIL’s test will help it meet one of the headline – and, on account of Covid-19, now more distant – goals of its 2019 long-term plan: diagnosing 75% of all cancers in stage I or II of their progression by 2028, up from 55% pre-pandemic.
In contrast to more limited liquid biopsies like those being trialled as part of the PREVAIL-ctDNA protocol at the Royal Marsden, however, MCED tests need to be validated in tens to hundreds of thousands of participants, and the algorithms for filtering out what Ofman calls the “background noise” in blood samples need to be trained and proved on broad and diverse population-scale data sets before they’re applied at scale in raucous real-world settings.
For the NHS partnership, that means recruiting approximately 140,000 participants over the age of 50 and without any suspicion of cancer, and a further 25,000 aged 40 and above with signs or symptoms. Based on data from the programme, access to the test could be expanded to around a million people in the UK across 2024 and 2025, before being rolled out to a larger population thereafter. Ofman characterises it all as an opportunity to keep improving the Galleri, bringing to mind Starling’s ‘two for the price of one’ analogy. “As more and more people use the test, the data we get will improve our ability to interpret the test for the next people,” he explains. “That’s the beauty of machine learning.”
There are numerous other important efficiencies. Whereas the false positive rates of different single-cancer tests stack when they are used in combination, the Galleri has a single, low false positive rate (approximately seven per thousand patients, which Ofman contrasts to mammography’s rate of one in ten) across all cancers, which could further reduce the need for invasive follow up procedures while reducing testing cost and patient anxiety.
No golden means
That said, not every step on the cancer pathway needs what Starling calls an “all-singing, all-dancing, genomic-plus-methylation test”. Much of liquid biopsy technology’s value comes from its flexibility – its ability to offer breadth or depth of information depending on the needs of the doctor and the patient. Cheaper liquid biopsies could be repeated to dynamically inform treatment decisions by first identifying the appropriate precision medicines for a particular patient, and then monitoring the development of any resistance mechanisms. In areas with fewer precision medicines, it’s also possible that ctDNA could be used to track how and whether resistance mechanisms decline after drug regimens are ceased, potentially enabling doctors to rechallenge cancers where previously they had no other options. “Before, we just didn’t know that,” says Starling. “You’d say, ‘That’s that drug – we can’t go back to it.’ And, actually, when there are limited treatment options for patients, every treatment option is incredibly precious.”
The current ‘one-size-fits-all’ approach to chemotherapy after surgery is another area Starling believes could be improved through the use of liquid biopsies. Around half of all patients with high-risk stage II or III bowel cancer are cured with surgery alone, but all of them are offered post-operative chemotherapy. Now, however, the Royal Marsden’s TRACC study is investigating whether the presence of ctDNA in the blood after surgery can be used to identify patients who don’t need chemotherapy. “Until recently, we haven’t had a sophisticated way to have that discussion with a patient in the clinic,” she explains. “We’ve said to everyone, ‘We don’t know [whether you’re cured], so we’re going to offer you chemo.’ And people are so terrified of the cancer coming back that they’ll have the chemotherapy, with its potentially unpleasant consequences.”
Veering from under-diagnosis to overtreatment, the current cancer pathway can be dizzyingly unpleasant. It won’t be fixed by the introduction of a single superior test, no matter how adaptable. Endoscopies during Covid are an extreme example, but there’s a reason patients fixate on the endoscope itself. Every diagnostic tool has the potential to get in the way of its use. Liquid biopsies will save lives, but their very flexibility creates issues around standardisation. Solving those, says Starling, will take a highly coordinated and iterative global process. It will be uncomfortable, but we have all the motivation we need.