Editorial 

August 28, 2023

The Need for Randomized Clinical Trials Demonstrating Reduction in All-Cause Mortality With Blood Tests for Cancer Screening

Sanket S. Dhruva, Rebecca Smith-Bindman, Rita F. Redberg

JAMA Intern Med. 2023;183(10):1051-1053. doi:10.1001/jamainternmed.2023.3610

In recent years, blood tests that look for circulating tumor DNA and biomarkers (termed liquid biopsies) have been developed. As Carr and Welch describe in this issue of JAMA Internal Medicine,¹ these tests are being explored for diagnosis of suspected cancer, cancer surveillance after treatment, response to therapy, and chemotherapeutic selection. Most importantly, these blood tests are also being explored as multicancer early detection (MCED) tests for cancer screening in asymptomatic persons. Before US Food and Drug Administration (FDA) approval, insurer coverage, and clinical adoption of these technologies, rigorously conducted randomized clinical trials (RCTs) must be conducted demonstrating reductions in all-cause mortality to ensure that potential harms associated with these novel technologies do not exceed potential benefits.

Consequences of MCED Blood Tests for Cancer Screening

In healthy asymptomatic people in the general population, the prevalence of cancer is very low and, therefore, by Bayes theorem, these MCED tests will often have positive results in persons without detectable cancer.² Most persons with a positive MCED test result will undergo additional testing, and while the regimen for follow-up of any cancer signal has not been established, full-body combined positron emission tomography–computed tomography (PET-CT) to search for the cancer site will almost certainly be widely pursued. In a feasibility study of persons receiving these blood tests for cancer screening, approximately 1 in 100 persons screened subsequently underwent full-body PET-CT,³ which is typically associated with approximately 36 mGy of radiation, the equivalent of 1800 chest radiographs.⁴ At this rate of PET-CT follow-up, 35 women and 25 men would be estimated to develop cancer for each 1 million persons who underwent these screening blood tests at 40 years of age.⁵ Thus, paradoxically, many people who undergo MCED blood testing for cancer screening actually will develop cancer because of this testing.

Additionally, many people will have incidental findings identified on subsequent imaging tests, which are likely to include a combination of PET-CT, CT, and magnetic resonance imaging. The prevalence of incidental findings varies, but they will occur in 20% to 40% of patients in these study types.^6-8 Even though incidental findings have no clinical importance—neither reducing life expectancy nor leading to any symptoms—they can cause anxiety and will lead to additional testing and invasive procedures such as biopsies that put people at further risk from complications.⁹ A study of MCED testing showed that 0.22% of people tested (an estimated 2200 per 1 million persons screened) ultimately underwent a futile invasive diagnostic procedure to evaluate a positive blood test.³ Additionally, as described by Carr and Welch,¹ patients and their loved ones experience stress and anxiety about a possible looming cancer diagnosis during the evaluation of positive test results that can linger even after follow-up test results are negative. Even worse, because of a software error, one manufacturer’s contractor recently sent 408 people a letter stating that they may have cancer, even though they did not.¹⁰

Some people receiving MCED tests will have a tumor detected, but some tumors detected by screening will never cause a problem. This overdiagnosis is well established due to screening for many cancer types, including prostate, thyroid, breast, kidney, and lung. Consistent with our tendency to act and not observe, nearly all tumors detected by MCED testing will be acted on, resulting in unnecessary treatments for cancers that would not have caused health problems.¹ Also, some tumors that are detected by MCED testing would have been identified in plenty of time for successful treatment through usual clinical means with no health advantage to earlier detection.³ The potential benefit of earlier curative treatment of cancers detected through blood tests must be balanced against the potential harm associated with identification and treatment of tumors that would have never progressed.

Marketing Ahead of Data

Though not FDA-approved for cancer screening, MCED tests are available in the US market through a loophole because some can be considered laboratory-developed tests. Laboratory-developed tests are generally not subject to FDA premarket review.¹¹ One manufacturer directly markets its screening test to consumers for $949, including linkage to a telemedicine clinician who can order the test.¹² This manufacturer anticipated that concierge practices and executive health programs provide a 1 million–person market.¹³ Thus, people with financial resources may obtain these tests by paying out of pocket; Medicare and private insurers are then on the hook for follow-up testing from positive blood test results.

This same manufacturer has also stated that “annual screening provides the opportunity to detect more cancers early.”¹⁴ A webinar conducted by the manufacturer included a panelist who stated that a blood test was “as good as”¹⁵ other established cancer screening modalities and that 39% of anticipated cancer deaths could have been averted within 5 years, which is based on modeling from a study funded by the manufacturer using unproven assumptions.¹⁶ The FDA and Federal Trade Commission should closely review marketing for MCED blood tests to ensure there is no false or misleading promotion.

FDA Approval

The standard for FDA approval of all tests is “reasonable assurance of safety and effectiveness.” Screening tests are performed in healthy people, and thus the standard for FDA approval for MCED tests should be a benefit on all-cause mortality to demonstrate effectiveness. Other end points, such as cancer stage or reducing cancer-specific mortality, do not mean that the tests “save lives.” Further, in cancer screening, healthy people will all be exposed to the downstream harms from radiation risk, overdiagnosis, and incidental findings related to MCED tests. Although some have called for conditional approvals focused on surrogate end points,¹⁷ subjecting healthy people to testing that will not help them to live longer and has the potential to lead to considerable harm is not in patient interest. Some have argued that shared decision-making would enable informed decisions that balance the potential benefits with the potential harms.¹⁸ However, shared decision-making is difficult given that we have very little data from RCTs to estimate benefits and risks. Shared decision-making has also not been effectively used in situations where we do have data; fewer than 10% of people are informed about overdiagnosis and overtreatment when discussing cancer screening.¹⁹

Approval of MCED testing by the FDA for cancer screening would likely lead to marketing campaigns targeting large numbers of people. The FDA has already given a blood test for cancer screening a breakthrough designation in its Breakthrough Devices Program.²⁰ This designation provides many benefits to manufacturers, including priority review and the opportunity for FDA authorization based on “greater extent of uncertainty of the benefit-risk profile” than would otherwise be acceptable, contingent on adequate postmarket controls.²¹ Breakthrough devices have been shown to have evidence of low quality, with most high-risk therapeutic breakthrough devices supported by a single, small study and sometimes no effectiveness end points.²² Disappointingly, postmarket studies for devices are usually neither rigorous nor completed in a timely manner.²³ Use of the “breakthrough” terminology is potentially deceiving to both patients and physicians; research has shown this terminology gives the false impression that a medical product is more effective than the evidence has actually demonstrated.^24,25

Insurer Coverage

Approval by the FDA would lead to pressure on insurers from MCED test manufacturers and related groups to cover these tests that may predict cancer. However, predictive ability is unimportant without evidence that these tests inform management approaches that help people live better and longer.

Congress is already pressuring the Centers for Medicare & Medicaid Services to cover these blood tests before evidence of benefits to patients has been generated. The Nancy Gardner Sewell Medicare Multi-Cancer Early Detection Screening Coverage Act introduced in Congress on March 30, 2023,²⁶ would create authority for the Centers for Medicare & Medicaid Services to cover annual MCED tests once approved by the FDA. The prior Congress had 258 House cosponsors and 54 Senate cosponsors to an earlier version of the bill. Responsible stewardship of the Medicare program, avoiding large expenditures hastening program insolvency and leading to higher premiums, means only covering care that is “reasonable and necessary,” which requires evidence of clinical benefit that outweighs harms.

Carr and Welch¹ estimate that MCED testing could cost insurers about $100 billion per year if performed annually among individuals 50 years or older; half of these costs would be billed to Medicare. There would also be huge additional costs for follow-up evaluation among persons with positive test results.

The Rational Path Forward

Randomized clinical trials to study the effect of MCED testing on all-cause mortality would need to be large but are feasible. An ongoing RCT conducted with England’s National Health Service²⁷ has enrolled 140 000 healthy volunteers aged 50 to 77 years. However, the primary outcome is stage III and IV cancer diagnosis, which is not necessarily associated with reduction in all-cause mortality.^28,29 It would be a huge benefit for patients and society if this ongoing trial increased sample size or follow-up duration to provide adequate statistical power to determine effects on all-cause mortality. The US National Cancer Institute is also exploring a large RCT, with the end point of mortality due to cancer.³⁰ Although evaluating the effect of MCED screening on all-cause mortality means a longer and/or larger study, the significant potential harms and costs to individual patients and society at large warrant such a trial to avoid rushing a dangerous blood test to market. Such a study unfortunately never occurs after marketing approval. Although the potential for early cancer detection may have broad appeal, we need actual evidence from RCTs that screening reduces all-cause mortality with acceptable levels of harm before MCED tests are approved, covered, or adopted into clinical practice.