How Close Are We to Detecting Multiple Cancers Early with a Single Blood Sample?

Multi-cancer early detection (MCED= Multi Cancer Early Detection) tests promise a major advance in cancer research. Using a single blood sample, these tests can identify biomarkers for many different cancers before symptoms appear. This may make it possible to detect disease at an early stage, before patients receive a cancer diagnosis. It could be a revolutionary medical development, but some experts argue that we are not there yet and point to the challenges of wider use. Do these tests really live up to the excitement?

Galleri Has Sparked Debate

Several MCED tests have received permission for direct-to-consumer marketing and are being tested in both the United States and the United Kingdom's NHS. Grail's Galleri test, the most advanced of these, looks for altered DNA methylation patterns in the blood.

The results of the University of Oxford-led SYMPLIFY study were published in July 2023. The study evaluated the performance of this cancer screening test. Among 5461 symptomatic cases, it detected a cancer signal in 323, of whom 244 were diagnosed with cancer. The findings showed impressive rates: a 75.5% positive predictive value, 97.6% negative predictive value, 66.3% sensitivity and 98.4% specificity.

• Positive Predictive Value (75.5%): The proportion of positive test results that correctly predict the actual presence of cancer. Here, a positive result was correct 75.5% of the time.
• Negative Predictive Value (97.6%): The proportion of negative test results that correctly predict the absence of cancer. This means that a negative result was reliable 97.6% of the time.
• Sensitivity (66.3%): The test's ability to correctly identify people with cancer. This rate indicates that the test correctly identified 66.3% of people who had cancer.
• Specificity (98.4%): The test's ability to correctly identify people without cancer as negative. In this case, 98.4% of people without cancer were correctly identified as negative.

Sensitivity increased with age and cancer stage, from 24.2% (stage I) to 95.3% (stage IV).

Among people with confirmed cancer, the predicted organ of origin was correct in 85.2% of cases.

Galleri is currently in an NHS pilot trial involving 140 thousand volunteers without any signs or symptoms. Results are expected at the end of this year.

Both the test and the trial were discussed earlier this month in The Lancet, in an article raising concerns about

• low detection rates for early-stage cancers,
• high false-positive rates,
• uncertain analysis of the cancer's origin,
• the need for follow-up investigations or scans,
• high costs and
• unproven reductions in mortality,
• as well as possible political influence on the NHS's preference for this test over others. These concerns have fueled debate.

Galleri claims to detect more than 50 cancer types. The hope is to identify tumors that are difficult to detect early, such as head and neck, bowel, lung and pancreatic cancers, and prevent situations that lead to costly treatment by addressing cancers usually diagnosed late and associated with a poor prognosis (disease outlook).

Tests May Make the "Worried Well" Even More Worried

MCED tests do not appear to detect early-stage disease very well. Although they are good at detecting advanced cancer, their results can be quite nonspecific and include false positives. The real problem with all MCED tests is that they may make the worried well even more worried!

Pilot trial results may therefore be disappointing.

Research to date suggests that these tests are not very effective at detecting early-stage cancers, namely stage I or II disease. It is also reported that identifying where in the body the cancer originates is often not possible. What should a general practitioner, for example, do with someone who has a positive test but no signs or symptoms? As an oncologist, what should I do when they are referred to me?

Who Will Fund Further Research?

There is a real dilemma when manufacturers only need to demonstrate that a test can detect cancer without having to establish its health economic value.

If screening capacity is limited and a choice must be made, it generally makes more sense to prioritize a patient with clear signs and symptoms, such as vomiting blood. These may indicate a serious health problem requiring urgent intervention. Someone who appears entirely healthy but has a positive test may need additional tests and assessment; however, when there is no emergency, symptomatic patients should take priority.

Current clinical trials of MCED tests are extensive and promising, but it is too early to introduce them widely as a public health tool, which is what Galleri is trying to do. Nevertheless, a multi-cancer early detection test that receives approval could meaningfully improve cancer mortality statistics.

That, of course, is the politics behind it. Health authorities want to show that they support MCED tests because these are seen as the solution. Yet the problem will not be solved quickly. Unless conventional diagnostic capacity is increased, more people will die because of late-stage diagnosis.

The potential for MCED tests to provide early diagnosis also brings hope of reducing cancer treatment costs. Cancer drugs are not always curative, patients need multiple lines of treatment, and many drugs have side effects that impair quality of life, often creating problems that require still more medication. Early-stage cancer is easier and less expensive to treat. If MCED tests substantially reduce the number of people diagnosed with advanced cancer, this should directly improve survival rates. At a population level, even a 15-20% reduction in cancer deaths would be a major achievement.

MCED tests offer a screening method for cancers without effective conventional screening tests (accounting for 70-75% of all cancer deaths) and for those too rare for population-wide screening. This cancer screening with a single blood sample is cost-effective only for breast, lung, colorectal and cervical cancers. A modeling study by Hackshaw, reported in the British Journal of Cancer in 2021, suggested that the ratio of true positives to false positives fell from 1:18 to 1:1.6 with an earlier version of Galleri compared with existing screening tests. In addition, the cost of diagnostic investigations per cancer detected among people with positive screens fell from £10,452 to £2175 with the MCED test.

MCED tests are expected to be cost-effective. Although more research is needed, they appear capable of saving health authorities in many countries substantial amounts of money.