“What if you found cancer early enough to make a difference,” says the website for the Galleri test. Galleri is a new multi-cancer early detection (MCED) screening test that doctors can now order. Other MCEDs, like CancerSEEK and PanSeer, may be coming soon. The question is: Do these blood tests help people live longer?

What are multi-cancer early detection tests?

How do the new tests work?

“They’re quite remarkable,” says H. Gilbert Welch, an internist and senior investigator at Brigham and Women’s Hospital in Boston. “They test your blood for cancer signals like cell-free DNA from tumors. We all have DNA in our blood, because we’re always breaking down cells. The tests separate DNA that’s coming from the normal breakdown of cells from DNA that’s coming from tumors.”

Until recently, these tests—often called liquid biopsies—were largely used by doctors to identify which treatments a patient’s cancer might be sensitive to.

“But treating cancers isn’t the big market,” notes Welch. “The big market is whether you can screen healthy people for cancer. That way, instead of testing tens of thousands of cancer patients, you’re testing tens of millions of people. There’s a very strong economic incentive to make MCEDs a screening test.”

Anyone with a doctor’s prescription can now get the Galleri test, which is pitched as a tool to detect 50-plus cancers in people with no symptoms. (Like other “lab developed tests,” Galleri can be marketed without approval by the Food and Drug Administration.)

So what’s the problem?

“On its face, a test that requires a simple blood draw to tell a symptom-free person whether they may have a cancer and where it is in their body seems like an amazing advance,” explained Philip Castle, director of the National Cancer Institute’s Division of Cancer Prevention, on NCI’s website in April.

“This is particularly true for cancers like pancreatic, ovarian, and brain cancers, for which no screening tests exist and that typically are not diagnosed until they are advanced, very difficult to treat, and highly lethal.”

“However, as with much of medicine and public health, it’s not that simple.”

Potential pitfalls of multi-cancer early detection tests

Among the potential problems with MCEDs, four stand out.

1. People may not live longer.

“We may find advanced cancers earlier, but that may not change the time of death,” says Welch.

“People will know about their bad cancer diagnosis earlier, they will be treated earlier, and they will suffer the side effects of cancer treatment earlier.”

“I see that as a harm. I don’t want to know about a cancer that’s going to kill me three years from now any earlier than before I have symptoms.”

Why wouldn’t finding cancer earlier save lives? Cancers are not all equal. Some spread so rapidly that nothing can save the patient. Others spread more slowly or not at all.

“By the time you have a cancer signal in your blood, you likely have evidence of an aggressive or advanced cancer,” says Welch.

“Finding them early could lead to major harm, because you’re just diagnosing the cancer sooner without changing when the patient dies.”

How often might that happen? We only have a few hints so far.

For example, researchers recently used CancerSEEK, an early version of a test being developed by Exact Sciences, to screen roughly 10,000 women aged 65 to 75 who had no symptoms. (Some of the authors work for Exact Sciences.) The test detected 26 cancers.

“That’s not a lot,” says Welch.

And 17 of the 26 were stage III or IV—that is, they were large or had already spread to lymph nodes or beyond—so early diagnosis might not have helped.

“At the time the study was published, three of the women had already died and one was in palliative care, so those women were not helped,” notes Welch.

The study did find nine stage I or II cancers, he adds. But one was a uterine cancer that caused bleeding.

“That cancer was found because her physician ordered an ultrasound to evaluate her postmenopausal bleeding,” says Welch. “And there was a cancer of the appendix that was found because it caused symptoms.”

So those cancers would have been found without an MCED test. And one was a thyroid cancer that was likely harmless and “overdiagnosed,” adds Welch.

2. Slow-growing cancers may be overdiagnosed. 

A key potential harm of MCEDs, explained the NCI’s Philip Castle, is “the diagnosis of slow-growing cancers that may never cause symptoms, a phenomenon called overdiagnosis.”

MCEDs might not pick up slow-growing cancers, but they can pick up benign conditions that can look like a cancer signal.

“The MCED test then leads to other tests, usually a PET-CT scan, which is a total body CT scan that also looks for metabolic activity,” says Welch. “Well, guess what? Those tests can lead to a lot of overdiagnosis.”

Many thyroid, prostate, and melanoma skin cancers are overdiagnosed.

“And overdiagnosis, unfortunately, can sometimes lead to overtreatment,” noted Castle.

3. False alarms linger.

“Let’s say I’m your doctor, and I find a cancer signal on your MCED test,” says Welch. “I repeat it. You still have a cancer signal. So I send you for a PET-CT and it shows nothing.”

The MCED result could be a false positive—that is, you have no cancer.

“How do we know if it’s a false positive or if it’s simply a cancer that we’re not able to find with current imaging technology?” asks Welch. “We don’t, and the patients and doctors will live with that uncertainty.”

“They’ll be doing a whole bunch of tests more often. I think that will be very hard on the patient. I don’t know how we can put a worrisome unconfirmed MCED result to rest.”

4. The tests are expensive.

“Those are the potential harms before you talk money,” says Welch. “And the money is going to be real.”

“First, the tests are expensive. GRAIL is selling its Galleri test for $949, and they want to do it every year for everybody over age 50. That’s a lot of people.”

Yet the Medicare Multi-Cancer Early Detection Screening Coverage Act of 2021 would require Medicare to cover annual MCED testing if the FDA approves the tests. The bipartisan bill has 233 cosponsors in the House and 46 cosponsors in the Senate.

“Given some 60 million Medicare beneficiaries, that would cost $60 billion a year—just for the test itself,” says Welch. “That’s without all the downstream costs of those subsequent tests.”

And taxpayers—and Medicare recipients paying higher premiums and copays—will have to foot the bill.

What’s the answer?

“The bottom line is: We need more research on MCED tests,” concluded Castle. That includes large randomized trials, which have yet to be done.

“You think you’ve got something good?” asks Welch. “Okay. Do a randomized trial in which half the participants have routine MCEDs and half do not.”

In the United Kingdom, the National Health Service is randomly assigning 140,000 people to get the Galleri test annually or to have their blood samples stored for possible future testing. (The trial is funded by GRAIL.)

“But it’s only a three-year trial, and all the early results will suggest that the test works, because the time from diagnosis to death will go up, even if no one dies a day later than they otherwise would,” argues Welch.

That’s because people will be diagnosed earlier.

“And you’ll have people who are convinced that their lives were saved by the test,” adds Welch. “But the trial may not tell us what we really need to know: Will it help people live longer and better?”

The U.S. National Cancer Institute is considering launching its own trial with around 300,000 people that would run for 7 to 8 years, Castle told the journal Science in June.

“But if the bill requiring Medicare coverage passes, the NCI may not be able to enroll enough people in the trial because no one will want to be in the group that isn’t tested,” says Welch. “Let’s find out if these tests work before we spend billions of dollars, and millions of people are potentially hurt.”  

Castle’s take is similar.

“We don’t have screening tests for the lethal cancers like pancreas and ovarian,” he told Science. “We’re desperate.”

“But we have to put our emotions aside and do our due diligence to evaluate these technologies and be able to speak with confidence about what this can and can’t do.”