Englander Institute for Precision Medicine

Who’s Afraid of Early Cancer Detection?

Grail seeks FDA approval for its Galleri test, which can detect tumors long before symptoms develop. But critics worry that the costs are too high.

A diagnosis of pancreatic cancer usually means a quick death—but not for Roger Royse, who was in Stage II of the disease when he got the bad news in July 2022. The five-year relative survival rate for late-stage metastatic pancreatic cancer is 3%—which means that patients are 3% as likely to live five years after their diagnosis as other cancer-free individuals. But if pancreatic cancer is caught before it has spread to other organs, the survival rate is 44%. 

The trouble is that this cancer is almost never caught early. There’s no routine screening for it, and symptoms don’t develop until it is advanced. Mr. Royse, 64, had no idea he was sick until he took a blood test called Galleri, produced by the Menlo Park, Calif., startup Grail. He had surgery and chemotherapy and is now cancer-free. 

Early diagnosis is the best defense against most cancers, as President Biden noted when he announced his Cancer Moonshot initiative two years ago. But only a handful of cancers—of the breast, lung, colon and cervix—have screening tests recommended by the U.S. Preventive Services Task Force, an independent panel that evaluates medical screenings.

Many companies are developing blood tests that can detect cancer signals before symptoms occur, and Grail’s is the most advanced. A study found it can identify more than 50 types of cancer 52% of the time and the 12 deadliest cancers in Stages I through III 68% of the time.

There’s a hitch. The test costs $949 and isn’t covered by Medicare or most private insurance. Mr. Royse, a lawyer who works with Silicon Valley startups, paid out of pocket for the test and follow-up imaging to confirm his cancer. Most Americans can’t afford to do so, and some public-health experts think that’s just as well. They fret that widespread use of multicancer early-detection tests would cause healthcare spending to explode. Those fears have snarled Galleri and similar tests in a web of red tape. 

Mr. Royse learned about Grail’s test in April 2022 and asked his physician about it. “He said it was unnecessary, and you don’t have symptoms,” Mr. Royse says. A second doctor also refused to prescribe it. So Mr. Royse visited Grail’s website, which referred him to a telemedicine provider who ordered a test. Another telemedicine doctor walked him through his results, which showed a cancer signal likely emanating from the pancreas, gallbladder, stomach or esophagus. 

An MRI revealed a suspicious mass on his pancreas, which a biopsy confirmed was cancerous. Mr. Royse had three months of chemotherapy, surgery and another three months of chemotherapy, which ended last February. Because pancreatic cancer often recurs, he gets CT and MRI scans every three months. In addition, he has signed up for startup Natera’s Signatera customized blood test, which checks DNA specific to the patient’s cancer and can signal its return before signs are visible on the scans.

Grail’s test likewise looks for DNA shed by cancer cells, which is tagged by molecules called methyl groups that are specific to a cancer’s origin. Grail uses genetic sequencing and machine learning to recognize links between DNA methyl groups and particular cancers. The test “is based on how much DNA is being shed by tumor,” Grail’s president, Josh Ofman, says. “Some tumors shed a lot of DNA. Some shed almost none. But slow-growing tumors typically aren’t shedding a lot of DNA.” That reduces the probability that Grail’s test will identify indolent cancers that pose no immediate danger.

Grail’s test has a roughly 0.5% false-positive rate, meaning 1 in 200 patients who don’t have cancer will get a positive signal. Its positive predictive value is 43%, so that of every 100 patients with a positive signal, 43 actually have cancer. That may sound low, but the positive predictive value for some recommended cancer screenings is far lower. Fewer than 1 in 10 women with an abnormal finding on a mammogram are diagnosed with breast cancer.

Because Grail uses machine learning to detect DNA-methylation cancer linkages, the Grail test’s accuracy should improve as more tests and patient data are collected. Dr. Ofman says the company also aims to reduce the test’s cost by scaling up manufacturing and detecting cancers with less genetic sequencing.

But therein lies a chicken-and-egg problem. Patient access is limited by Galleri’s lack of Food and Drug Administration approval and insurance coverage. These could help reduce the test’s costs and improve its accuracy. But regulators may balk at approving the test, and insurers at covering it, until it becomes cheaper and more reliable.

Regulators classify Galleri as a lab-developed test. Such tests are overseen by the Centers for Medicare and Medicaid Services and can be prescribed without FDA approval. This regulatory pathway allows hospitals, research centers and startups to develop tests without running the FDA’s bureaucratic gantlet. Since diagnostic tests can’t injure patients, no safety review is necessary. 

The FDA in October proposed regulating lab-developed tests as medical devices, which generally require agency approval. That could severely curtail patient access and slow test development since the FDA doesn’t have the personnel to evaluate the tens of thousands of lab-developed tests on the market. The rule’s public comment period closed on Dec. 4.

How would the FDA weigh the risk that a false positive on a test like Grail’s could require invasive follow-up testing against the dire but hard-to-quantify risk that a deadly cancer wouldn’t be caught until it’s much harder to treat? It’s unclear. But some experts urge the FDA to require large randomized controlled trials before approving blood cancer tests. “Multicancer screening would entail tremendous costs and potentially substantial harms,” H. Gilbert Welch and Tanujit Dey of Brigham and Women’s Hospital wrote in the Journal of the American Medical Association on Aug. 28.

Dr. Welch and Mr. Dey also suggested that companies should be required to prove their tests reduce overall mortality, even though the FDA doesn’t require drugmakers to prove their products reduce deaths or extend life. Clinical trials for the mRNA Covid vaccines didn’t show they reduced deaths.

Requiring randomized controlled trials and FDA approval for multicancer early-detection tests could restrict access for years. Hundreds of thousands of patients would likely have to be enrolled in trials, some receiving the test with the others in a control group. They would have to be followed over many years to determine whether patients who received the test were diagnosed with specific cancers earlier than those in the control group and how much longer they lived as a result. Proving a statistically significant benefit could take a decade or longer.

One alternative is to rely on real-world studies, which Grail is already doing. One study of patients 50 and older without signs of cancer showed that the test doubled the number of cancers detected. The FDA could also approve the test, and CMS could provide Medicare coverage, on the condition that providers collect patient data that can be used to analyze the benefits.

Dana Goldman, the University of Southern California’s dean of public policy, likes that idea: “There will be a lot of suffering if we have to wait 10 years for the tests to be approved.” Mr. Goldman has spent decades studying the economics of medical treatments. One recurring problem he has seen: “Epidemiologists are always getting cancer wrong,” he says. “Epidemiologists a decade ago said U.S. overtreats cancers. Well, no, the EU undertreats cancer.”

2012 study that he co-authored found that the higher U.S. spending on cancer care relative to Europe between 1983 and 1999 resulted in significantly higher survival rates for American patients than for those in Europe. By his study’s calculation, U.S. spending on cancer treatments during that period resulted in $556 billion in net benefits owing to reduced mortality.

He expects Galleri and other multicancer early-detection tests to reduce deaths and produce public-health and economic benefits that exceed their monetary costs. Cancers caught early are cheaper to treat—less likely to require a cocktail of expensive therapies, and in some cases removable without the need for chemotherapy. Preventing cancer deaths would expand the workforce. 

Expanding access to multicancer early-detection tests could also help solve the chicken-and-egg problem of drug development. Because few patients are diagnosed at early stages of some cancers, it’s hard to develop treatments for them. “How do you develop a drug for Stage I pancreatic cancer when you don’t have patients for trials?” Mr. Goldman asks.

Grail hopes to obtain FDA approval for its test. But while that would help patients with private insurance, Medicare doesn’t pay for screening tests unless they are recommended by the U.S. Preventive Services Task Force.

The task force has historically been slow to back cancer screenings, in part owing to fear of overtreatment. Mr. Royse says it has twice recommended against early-detection cancer screenings for pancreatic cancer in asymptomatic patients. When asked why, he says the task force told him that “screening tests are invasive, cause pain, and lead to unnecessary and risky treatment.” 

Congress had to pass legislation requiring Medicare to cover screening for breast, colorectal, cervical and prostate cancers. Legislation in the House and Senate would allow Medicare to cover Grail and other multicancer early-detection tests if they obtain FDA approval. The Senate bill has 59 co-sponsors, 31 Democrats, 26 Republicans and two independents. A House version has 243 co-sponsors, 134 Democrats and 109 Republicans. “Not only will this bill save lives, but it will also help reduce the glaring racial disparities in cancer diagnosis and death,” said co-sponsor Rep. Terri Sewell (D., Ala.).

But the legislation’s price tag could reduce political support. According to one private company’s estimate, the test could cost the government $39 billion to $145 billion over a decade. Mr. Goldman counters that analysts usually overestimate the costs and underestimate the benefits of medical interventions.

Mr. Royse makes the same point with personal force. “I would be dead right now if not for multicancer early-detection testing,” Mr. Royse told an FDA advisory committee last fall. “The longer the FDA waits, the more people are going to die. It’s that simple.”

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The above article by Allysia Finley appeared in the Wall Street Journal on February 02, 2024.

EIPM Clinical Director Dr. Cora N. Sternberg is leading a Grail clinical trial at Weill Cornell Medicine enrolling patients through July or August 2024.

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