ulticancer early detection (MCED) tests aim to identify cancer in people without any signs or symptoms by detecting cancer biomarkers circulating through the bloodstream. Unfortunately, there is no evidence that MCED tests save lives or improve health. Instead, MCED tests may inadvertently cause harm through complications from follow-up procedures (such as biopsies) for false positives and incidental findings. The increased use of health services for follow-up care may also overburden healthcare systems.

Despite these concerns, hundreds of thousands of MCED tests have been sold commercially in the US, and the tests are available through some private clinics and insurers in Canada, Hong Kong, Singapore, the Philippines, and the UK. The first MCED test is also currently under review for regulatory authorization in the US despite its negative clinical trial. Before regulatory authorization and widespread adoption, high-quality trials with meaningful clinical endpoints are needed to evaluate whether MCED tests are effective and safe screening tools that save lives.

MCED test evaluations must address two challenges: 1) determining whether MCED tests save lives without causing excessive harm and 2) accounting for system-wide impacts from additional diagnostic tests and treatment for patients receiving positive MCED test results.

Challenge #1: Determining Whether MCED Tests Save Lives Without Causing Undue Harm

Early Detection Does Not Necessarily Mean Improved Outcomes
Finding cancers early sounds promising: earlier detection could lead to earlier diagnosis and treatment, which would presumably offer a higher chance of survival. This is not always true, however. Unfortunately, diagnosing cancer earlier is not associated with increased survival for many cancers. Slow-growing cancers may not affect patients fast enough for earlier detection to make a difference, especially in the setting of other health conditions. For example, while increased thyroid-cancer screening in South Korea greatly increased the number of diagnoses, the increased screening did not improve thyroid cancer mortality. At the other end of the spectrum, more aggressive cancers may have low survival rates regardless of the stage of the cancer at detection.

Since MCED tests screen for multiple cancers, including those for which early detection with other modalities may be associated with increased survival and those for which it is not, a trial of MCED testing with an endpoint of detecting cancer at an earlier stage cannot evaluate whether MCED testing saves lives. To do so requires evaluating whether MCED tests detect, with a high degree of accuracy, clinically meaningful cancers that can be successfully treated. Without these characteristics, it is unlikely to reduce all-cause mortality (increase survival). Typically, studies of cancer screening analyze cancer-specific mortality because assessing an impact on all-cause mortality requires a very large sample size when studying a single cancer—sometimes millions of participants—and longer follow-up. As MCED tests screen for many cancers, however, the number of participants needed is much lower: one analysis estimated that the National Health Service-Galleri (NHS-Galleri) trial, the largest randomized controlled trial of an MCED test to date, had high enough enrollment to evaluate all-cause mortality.

Furthermore, unlike early detection and cancer-specific mortality, all-cause mortality accounts for deaths or other harms that could result from the follow-up care needed to determine which positive MCED test results are true positives. This follow-up imaging and testing, such as computed tomography (CT) scans and invasive procedures like biopsies, can have adverse effects. The radiation from CT scans, for example, may eventually cause cancers in a portion of scanned individuals, and invasive procedures can lead to complications such as infection and bleeding.

This is especially concerning as it is likely that many positive MCED test results will be false positives, since cancer screening with MCED tests is intended for those with no symptoms, a population with low cancer incidence. While the false-positive rate varies by the specific MCED test model, a systematic review found a median false-positive rate of 2.2%, and the most recent results for the GRAIL Galleri test show a false-positive rate of 0.4%, or 4 false positives for every 1,000 individuals screened. While these percentages by themselves may seem small, if MCED tests are used as intended for population screening, in which millions of asymptomatic individuals are tested, thousands of individuals will receive false-positive results for every million people screened.

Consequently, evaluating whether MCED tests reduce deaths from all causes is critical for establishing whether MCED testing saves lives. If MCED tests reduce all-cause mortality compared to standard care with acceptable risks of harm, then the lives saved by screening outnumber any potential harms from follow-up care.

Existing Evidence Does NOT Show That MCED Tests Save Lives
Unfortunately, no randomized controlled trial—the gold standard of evidence—has evaluated whether MCED tests reduce deaths from all causes or even cancer-specific mortality compared to standard care. The largest randomized controlled trial to date was the NHS-Galleri trial, a collaboration between the UK’s NHS and GRAIL, the manufacturer of the Galleri MCED test. The NHS-Galleri trial studied reduction of stage III and IV cancer diagnoses, and the results were negative: MCED testing with the Galleri test did not reduce late-stage cancer diagnoses. Even if the results had been positive, however, the NHS-Galleri test would not have been able to evaluate whether MCED tests save lives because reduction in late-stage cancer diagnoses is not consistently associated with a reduction in mortality across all cancers.

Challenge #2: Accounting for System-Wide Impacts from Follow-Up Care

Increased use of MCED tests may also overburden healthcare systems, as increased demand for follow-up care from MCED test findings may delay care for other persons and health issues. In one real-world study, patients who received positive MCED tests required an average of four additional lab tests and two imaging tests, and almost half required procedures such as biopsy or endoscopy, before receiving an actual diagnosis. Yet demand for specialist appointments, imaging, endoscopy, and other diagnostic services often already exceeds health system capacity. As a result, cancer diagnostic wait times have been a long-standing concern in the US, the UK, and around the globe, with patients waiting for months to learn whether they have cancer. Time to diagnosis is especially long for suspected cancers that MCED tests are more likely to come back positive for, including hematological and gastrointestinal cancers.

A recent analysis of the NHS-Galleri trial underscores this concern. In the regions of England that participated in the trial, cancer diagnostic delay rates increased immediately following the trial’s start, even as delay rates fell in nonparticipating regions. This suggests that MCED rollout could have system-wide effects on diagnostic wait times, potentially degrading access to care for all patients referred for investigation of suspected cancer. During a trial, this form of spillover could negatively affect outcomes for control group patients, leading MCED to appear more effective in comparison.

Implications for Patients, Insurers, and Regulators

Despite these evidentiary concerns, MCED tests are already available for use outside clinical trials. In the US, hundreds of thousands have been sold commercially even though no MCED test has received US FDA market authorization because a regulatory loophole allows tests from a single laboratory to be marketed. Similarly, MCED tests are available in Canada because the country’s federal regulatory agency (Health Canada) does not regulate laboratory-developed tests. In Asia, the developer of the Shield MCED test partnered with an insurer to offer the test to patients in Hong Kong, Singapore, and the Philippines. MCED tests are also widely promoted, including on social media and in an advertisement during the latest Super Bowl.

Even though the existing evidence, in our opinion, is insufficient to determine whether the potential benefits of MCED tests outweigh the risks, the first MCED test is currently under review by the FDA. If MCED tests receive regulatory authorization by the FDA or other regulatory bodies worldwide based upon the currently available evidence, we believe that the increased access may lead to premature widespread adoption, potentially exposing patients to unnecessary harm and overburdening health systems. Insurers may also face significant strain from the costs of follow-up care from positive tests. This is especially true in the US, where recent legislation has paved the way for Medicare coverage of MCED tests, contingent on FDA authorization.

To address system-wide consequences, evaluations of MCED tests should include not just patient-level outcomes data, but also system-level measures such as appointment availability and average wait times that could be affected by MCED rollout. Insurers and health systems considering adoption of MCED-based population screening should also carefully weigh whether existing capacity can absorb an influx of additional patients requiring investigation of suspected cancer. In some cases, downstream diagnostic services required for follow-up of positive results may need to be expanded in advance of MCED adoption.

Takeaway

Given these concerns, we are of the opinion that MCED tests should not be used for cancer screening at this time. Before MCED tests receive regulatory authorization and insurer coverage, the tests must be shown to improve patient outcomes and save lives without unduly harming patients or overburdening healthcare systems. To do so, more rigorous evaluations of MCED tests with meaningful clinical outcomes for an asymptomatic population, including survival and system-level measures, such as average wait times, are needed.