At least two multi-cancer detection (MCD) blood tests – one blood test that can detect 50 cancers or more before symptoms appear – are already on the market, with more coming, yet scientists say there are still several unanswered questions.
The tests are designed to detect circulating tumour cells, cell-free tumour DNA, proteins, and other biomarkers that suggest cancer might be present.
However, what the results mean and how they should be used is not yet clear, JAMA reports
Although cancer is the leading cause of death worldwide, only five types – colorectal, lung, breast, cervical, and prostate – have recommended screening methods, at least for some populations.
There is now growing interest in a multi-cancer screening test that could detect many of the around 200 other types of malignancies.
“It’s exciting,” said gastroenterologist Anne Marie Lennon, MD, PhD, who recently became chair of medicine at the University of Pittsburgh Medical Centre. Lennon previously was on the faculty at Johns Hopkins, where she co-developed an MCD test not yet on the market.
The assays are meant to complement available screening for common cancers, not replace it. The don’t diagnose cancer.
As with conventional cancer screening methods, a positive MCD test identifies individuals who need further evaluation to determine whether they have cancer, while a negative test doesn’t necessarily mean cancer isn’t lurking somewhere.
Yet while drawing a tube of blood may be easy, what comes after that is not.
“The technology is not well enough developed to be marketed,” Ruth Etzioni, PhD, a biostatistician at the Fred Hutchinson Cancer Centres Public Health Sciences Division told JAMA.
In fact, the two tests that have been commercialised in the US have not yet been approved by the Food and Drug Administration (FDA), being marketed as laboratory developed tests (LDTs), a category over which the FDA has exercised enforcement discretion for 50 years.
The agency hasn’t enforced applicable regulatory requirements, specifically the demonstration of safety and effectiveness, for the majority of LDTs. Most labs that offer LDTs follow only the regulatory requirements of the Clinical Laboratory Improvement Amendments – which regulate operations, not tests.
The Galleri MCD assay has not yet been approved by the FDA, but more than 150 000 tests have been sold since launch two years ago, says Grail, the Californian company that developed it.
Grail has also partnered with HCA Healthcare, which provides the test to physician practices, and has established a network of more than 9 000 prescribers in private practice.
But there is still much uncertainty about the harms and benefits of MCD tests. Do they lead to improved cancer prognoses, and uncover tumours better left undetected? Do they cause unnecessary anxiety or provide false reassurance?
Setting the stage
At least three MCD tests have a head start toward FDA approval or clearance.
The agency has designated the Grail test and the MCD tests developed by Geneseeq, a Canadian company, and Burning Rock, in California, as breakthrough devices, which “provide for more effective treatments or diagnosis of life-threatening or irreversibly debilitating diseases or conditions”, justifying priority review.
The Maryland company, 20/20 GeneSystems, that makes OneTest, the other MCD test available in the US, will not seek FDA approval until it collects real-world data about its accuracy in detecting cancer from a statistically significant number of people.
Last November, the FDA convened a meeting of the Molecular and Clinical Genetics Panel of its Medical Devices Advisory Committee to make recommendations on the design of MCD tests, including what end points could help assess probable risks and benefits.
And MCD tests are a major focus of the new Cancer Screening Research Network launched by the National Cancer Institute (NCI) in January, “geared towards studying various technologies for cancer screening”, said oncologist Lori Minasian, MD, deputy director of the NCI’s Division of Cancer Prevention. “Not every cancer sheds into the blood. Some are detected better in urine or sputum or breathalysers.”
One of their first projects is the Vanguard study, enrolling 24 000 people aged 45 to 70 to test two MCD assays and lay the groundwork for a larger randomised trial.
Vanguard will not be comparing the tests with each other, Minasian noted. “We’re not expecting a winner…but a better understanding of how to use these assays.”
Minasian couldn’t discuss which MCD assays will be tested in Vanguard.
GeneSystems CEO Jonathan Cohen hopes that its test will be selected for Vanguard, while Grail President Joshua Ofman said his company isn’t interested in participating. “We have so much more data already.”
The 20/20 GeneSystems MCD test was developed using data from Taiwan, chief science officer Michael Lebowitz, PhD, said.
Physicians there have been offering tumour marker testing as part of annual physical examinations for a few years, and his company has access to a database of information about the testing in 27 000 individuals.
Real-world data might not be enough, though. At November’s FDA advisory committee meeting, panellists concluded that real-world data and evidence should be used to support clinical validation of MCD tests only in select situations, like post-market settings. They advised that randomised trials be conducted to validate MCD tests.
Currently, the Grail test, which claims to detect more than 50 cancers, cost $949. The standard 20/20 GeneSystems test, which claims to detect more than 20 cancers, costs $189; a premium version, which tests for additional biomarkers, is $269.
Meanwhile, Grail announced in November that it is teaming with the Centres for Medicare & Medicaid Services to conduct a real-world study of the clinical impact of its test in 50 000 Medicare beneficiaries.
Shifting the stage
Research has shown recommended population cancer screening tests reduce mortality. But none has been conducted to determine whether MCD tests lower cancer deaths.
Developers say clinical trials with a mortality end point would be impractical, requiring 15 to 20 years and 1m participants to answer that question.
Philip Castle, PhD, MPH, director of the NCI’s Division of Cancer Prevention and a member of the FDA’s Medical Devices Advisory Committee, said the reason to screen is to reduce cancer incidence or mortality. “Mortality must be the end point – cancer-specific mortality. And for many cancers, there is not a proven surrogate end point that has been shown to correlate with mortality benefit.”
Ofman and others say demonstrating MCD tests lead to earlier-stage cancer diagnoses is a reasonable surrogate for mortality.
Earlier diagnosis alone benefits patients because it affords a better quality of life and less toxic therapies, Ofman said.
Grail is funding a trial with the UK’s National Health Service (NHS) to determine whether its test leads to earlier cancer diagnoses. In 10 months, in 2021 and 2022, the trial reached its goal of enrolling more than 140 000 people aged 50 to 77. Those randomised to screening will receive the Grail test annually for three years.
Results won’t be known for several more years, at which point Grail will make its final submission to the FDA to support its application for approval. The NHS is committed to buying around 1m Grail tests if initial results are promising.
Positive or negative – now what?
In a pilot study of around 6 700 people over 50, the Grail test identified a cancer signal in 1.4% of participants, and 0.5%, or one in every 200 tested was found to have cancer. The test’s first or second cancer signal origin prediction was accurate 97% of the time.
However, 52% of the cancers detected were stage 4 or stage 4, not the early-stage tumours MCD tests aim to find.
The 20/20 GeneSystems test looks for a handful of older cancer biomarkers, including the prostate-specific antigen (PSA) and cancer antigen 125 (CA-125), not currently recommended for population screening. For $80, the test’s premium version adds five more biomarkers, including C-reactive protein, typically used to monitor inflammation in conditions like infections, asthma, and autoimmune diseases, and CA 15-3, most commonly used to monitor metastatic breast cancer during therapy.
And the tests alone can’t precisely pinpoint where in the produce section a cancer might be, or if it’s even present – one reason Etzioni worries that a positive test result could lead to “a diagnostic odyssey”. “If we’re going to take on these tests, we must also understand imaging better than we do.”
CancerSEEK, an MCD test developed by Lennon and Johns Hopkins colleagues and acquired in 2021 by Exact Sciences Corporation, uses full-body positron emission tomography–computed tomography (PET-CT) scans to follow up on positive test results. “You really need to know where the cancers are,” Lennon said.
In 2020, she and her collaborators published the results of what they said was the first large prospective interventional clinical trial to evaluate an MCD test. They incorporated an early version of their MCD test into the routine clinical care of 10 000 women with no cancer history.
In 26 of them, nine types of cancer were first detected by the MCD test. Fifteen underwent PET-CT imaging; the other 11 developed signs or symptoms leading to other types of imaging. Seventeen of the 26 had localised or regional disease.
The researchers extracted information from electronic medical records until November 2022 for an observational study of the longer-term health status of the 26 participants with cancer first detected by the test. After treatment, half remained cancer free for more than four years; nine patients, all diagnosed at stage III or stage IV, died.
Let sleeping tumours lie?
One concern is that MCD tests might detect slow-growing tumours that people would die with, not of, leading to unnecessary treatment and anxiety.
Neurosurgeon Daniel Orringer, of the New York University Grossman School of Medicine, compared the MCD tests with whole-body MRI scans, which can detect incidental cancers that never would have harmed a patient. Orringer co-authored a “discovery study” last year about an MCD test that uses spectroscopy and machine learning algorithms to detect cancer.
“Those whole-body MRI scans detect all kinds of lesions that are subclinical and asymptomatic,” he said.
Physicians should approach MCD test findings the way they approach whole-body MRI findings, he added. “We treat the patient, not the scan. We’re going to treat the patient, and we’re not going to treat the result from a mail-away test.”
He said it was a misconception that MCD tests may pick up tumours that never would have caused harm. “Slow-growing tumours that are unlikely to kill people are the same tumours not shedding into the blood.”
MCD tests are “tuned” to be highly specific to reduce the risk of false-positive results, but these still occur.
The tests’ high specificity comes at a cost of sensitivity. “They are not informative if they’re negative,” Etzioni said, “because they haven’t been designed to rule out cancer. They’ve only been designed to rule in cancer.”
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Potential lifesaving blood test spots multiple cancer types early – Pathfinder study
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