Diagnostics 99%
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
12
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.
Practical Patient Care /
www.practical-patient-care.com
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