Blood tests for cancer detection aren’t yet ready for prime time

Multi-cancer early detection tests (MCEDs), sometimes called liquid biopsy tests, are a new method of detecting cancer early. While the concept is promising, these untested tests currently pose significant problems.

MCEDs look for circulating DNA or cells from cancers. The goal is to detect cancer in its earliest stages in people without any signs or symptoms of the disease. Earlier detection means earlier treatment, which generally leads to better outcomes, so this approach may be an attractive option to reduce cancer-related death.

There is unabashed enthusiasm for liquid biopsy tests in the medical device industry and some health systems.

So far, none of the multiple tests in development have been approved by the Food and Drug Administration. Yet because of a loophole in how diagnostic tests are regulated in the U.S., one of these tests is available for $949. While it must be ordered by a clinician, one company links on its website to a telemedicine provider that will order it, so anyone who can afford the test can purchase it.

Reducing death from cancer is not as simple as taking these tests.

As experts in critical appraisal and the practice of evidence-based medicine, we have significant concerns about MCEDs for one main reason: liquid biopsy tests have not been tested in randomized trials to assess if they reduce all-cause death (or any other meaningful benefits to patients).

We believe that reducing deaths should be the standard that must be met for FDA approval. Without showing that healthy people are better off being tested with MCEDs, these tests could do more harm than good.

First, people with “positive” MCED tests will need to undergo follow-up testing. These blood tests are for nonspecific markers, and cannot tell if and where a person may have cancer, so at least one imaging test, usually a PET-CT scan, is needed to confirm (or refute) the positive test. PET-CT scans deliver substantial radiation doses, which will undoubtedly lead to more cancers.

Second, while most follow-up PET-CT scans won’t detect any cancer, they will detect many other incidental findings — so called incidentalomas — that are clinically meaningless, meaning they won’t affect one’s health or longevity, but nonetheless make people worry. Such incidental findings make healthy people into patients by changing the way they think of themselves and how well they sleep at night, knowing they have something in their body that was picked up on an imaging test. Some will undergo invasive procedures like biopsies, and some will even have parts of their body removed that are feared to be cancerous — even if cancer is never found. Further, these people will continue to undergo additional tests for months and years, always living with great angst that they have cancer lurking somewhere in the body — even if they do not.

Third, even if a cancer is detected, some grow so slowly that they would never have affected an individual’s health. Other cancers would have been detected through routine clinical means, like testing for blood in the stool for colorectal cancer. Early detection of cancer by MCEDs may not only offer no advantages, but actually increase the time that people receive treatments that decrease their quality of life. Research has also shown that the most aggressive tumors are often missed by cancer screening.

What is certain is that any cancers that MCEDs detect — regardless of if and how they would have affected a person’s lifespan — will undoubtedly lead to treatments such as chemotherapy, radiation therapy, and surgery, all of which have significant risks, including no benefit and even death.

MCEDs are now being studied in trials focused on the benefits of diagnosing cancer early versus late, which advocates expect will lead to their approval and widespread adoption. Focusing on early versus late-stage cancer diagnosis, however, is the wrong endpoint. Research published recently in JAMA shows that identifying cancer in its later stages does not necessarily predict death, leading the researchers to write that, “cancer stage end points are an inadequate alternative for mortality end points in clinical trials of screening with multicancer early detection tests.”

Clinical trials of MCEDs should refocus on the outcome that matters to most people: will the test help me live longer. Focusing on any other endpoint means that, if these tests are approved, many people will be subjected to years of testing and toxic treatments accompanied by apprehension but may not live any longer.

To be sure, refocusing clinical trials of MCEDs on a meaningful endpoint of all-cause mortality would mean the trials take longer to run. However, it is doable and necessary to justify the annual cost of MCED testing, which could be about $100 billion a year if all people 50 years of age and older were to be tested this way. And it is better to get it right the first time, as many well-studied cancer screening tests already exist, and the potential for irreversible harms from liquid biopsy blood tests is significant, in addition to the staggering cost.

The most important next step would be randomized clinical trials to demonstrate whether liquid biopsy tests for cancer markers reduce all-cause death. In the meantime, anyone can reduce their cancer risk by focusing on healthy habits such as not smoking, eating healthy fresh foods, and being physically active.

Sanket S. Dhruva, M.D., is an assistant professor of medicine at the University of California, San Francisco, where Rita F. Redberg, M.D., is a professor of medicine.