By Kerry Dooley Young

US regulators may soon clear blood-based biomarker tests for colorectal cancer (CRC), expanding potential options for patients seeking more convenient forms of screening.

Most recently, Guardant Health, Inc, announced the completion of its US premarket approval application for its Shield blood test to screen for CRC. Approval by the US Food and Drug Administration (FDA) would position Guardant to later secure Medicare coverage for its test.

Rival companies, including CellMax Life, Freenome, and Exact Sciences, which already offers the stool-based Cologuard product, are pursuing similar paths in their development of blood tests for CRC.

If these companies succeed, clinicians and patients could have a choice of several FDA-approved tests in a few years.

"They're coming, and they will be increasingly widely used," said David A. Johnson, MD, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, who earlier in his career helped win broader insurance coverage of colonoscopy.

Blood tests for CRC have the potential to cause a shift in screening for colon cancer.

Screening colonoscopies ultimately could be largely phased out in the years ahead in favor of highly sensitive noninvasive tests, if the blood tests do as well as expected, said John M. Carethers, MD, president of the AGA.

"Holy Grail"?

"A blood test for cancer screening has been the 'holy grail' ever since the carcinoembryonic antigen blood test in the 1960s was claimed to have nearly 100% sensitivity and specificity — but turned out not to — for colorectal cancer," wrote David F. Ransohoff, MD, a gastroenterologist at the University of North Carolina (UNC), in a 2021 article. Ransohoff has studied noninvasive CRC screening for decades.

There is a great allure in the idea of such multicancer detection (MCD) tests.

This "technology offers the potential to detect asymptomatic cancer at several organ sites with a simple blood test, often called a 'liquid biopsy,'" the National Cancer Institute (NCI) said this month.

Several companies are selling MCD tests, some of which include CRC components.

Among the best-known MCD tests now sold is Grail's Galleri. At this time, however, the Galleri test, which tests for 50 types of cancer, should be used in addition to recommended colon cancer screening tests, such as colonoscopy, the company's website says.

Guardant has also noted that its CRC-specific blood test should only complement screening tools, including colonoscopy, not replace them.

The prospect of phasing out the standard CRC screening — colonoscopy — may be appealing, but it would require a big shift for a field in which procedures have dominated. According to a report from the Centers for Disease Control and Prevention, in 2018, 67% of US adults aged 50–75 years met the US Preventive Services Task Force (USPSTF) recommendations for CRC screening, and overall, 60.6% had a colonoscopy in the past 10 years.

Still, the NCI and the FDA have signaled the potential they see in MCD tests. The NCI highlighted its plans to aid MCD test development as part of its budget request for fiscal year 2024. The NCI is preparing to launch a 4-year pilot study for MCD tests to enroll 24,000 people aged 45–70 years. The study is intended as groundwork for a randomized controlled trial that will enroll 225,000 people.

The FDA has shown an interest in helping companies bring blood tests for cancer to market through its breakthrough device designation — a sign that the FDA places great priority on a product and seeks to streamline the application and review process.

CellMax Life appears to be the only CRC-specific screening blood test to have received a breakthrough device designation from the FDA, said Atul Sharan, MS, MBA, co-founder and chief executive officer of CellMax Life.

Lance Baldo, MD, Freenome's chief medical officer, said that the FDA may be reviewing parts of their application next year, allowing for a potential 2025 launch of a blood test for asymptomatic people at average risk for CRC.

A Spotty Track Record

Before anyone gets too excited about the prospect of phasing out screening colonoscopy, it's important to remember that CRC blood tests have proven disappointing in the past.

Germany's Epigenomics, for example, secured the first FDA approval for a CRC blood test, Epi ProColon, in 2016. But the company did not receive Medicare coverage for the test. In a 2021 memo explaining the decision, the Centers for Medicare & Medicaid Services (CMS) noted that, given more reliable alternatives, including stool-based tests, the Epi ProColon would result in harm to some patients.

CMS also does not cover Grail's blood test, which has a list price of $949, though the company has secured reimbursement arrangements with several self-insured employers and insurers, such as Point32Health.

But CMS officials have acknowledged the strong interest in CRC blood tests.

In that 2021 memo, the agency also outlined its requirements for Medicare coverage. CMS said it will cover blood-based screening tests for certain patients if these products meet the following standards:

Receive FDA market authorization with an indication for CRC screening

Have proven test performance characteristics for a blood-based screening test with sensitivity ≥74% and specificity ≥90% in the detection of CRC compared to the recognized standard (which at this time is colonoscopy) as minimal threshold levels, based on the pivotal studies included in the FDA labeling

In February 2023, CellLife Max presented data at ASCO Gastrointestinal Cancers Symposium that its blood test had sensitivity of 92.1% for detection of CRC and 54.5% for detection of advanced adenomas, at 91% specificity.

Prior to that, in December 2022, Guardant issued a press release with study results that met the CMS standard. The test had sensitivity of 83% in detecting individuals with CRC. Specificity was 90%, the company said. That translates to a false positive rate of just 10%.

While such results look promising, Asad Umar, DVM, PhD, the chief of gastrointestinal and other cancers at NCI's Division of Cancer Prevention, said physicians should be cautious when giving advice or answering questions about MCD tests, given limited data from prospective studies about their effect on health outcomes.

Even among physicians already using some MCD tests to screen patients, there is a lot of concern about false positive results that require diagnostic workup and false negative results that lead to a false sense of assurance, Umar said.

"Screening is a process and not just a test. The process involves follow-up testing for any positive test findings," Umar said. "At this point, doctors should inform patients that there is not sufficient data to know how best to use these tests."

Hurdles to Broad Acceptance

For companies seeking broad acceptance of a CRC blood test, two of the three major steps needed are securing FDA approval and Medicare coverage. The last step would be getting an A or B recommendation from the USPSTF, which would mandate coverage by health plans.

This is the "big trifecta," Baldo said.

In the USPSTF's current colon cancer screening recommendations, issued in 2021, it gave an A grade for CRC screening for adults aged 50–75 years and a B grade for those aged 45–49 years. The USPSTF's recommended forms of screening include colonoscopy, as well as stool, high-sensitivity guaiac fecal occult blood, and fecal immunochemical tests. But it said more research is needed to establish the accuracy and effectiveness of emerging screening technologies, such as blood or serum tests.

If CRC blood tests eventually win FDA approval, the USPSTF would likely provide guidance to clinicians on how patients can use them as a screening option.

Ransohoff noted that the mission of the USPSTF is different from that of the FDA and CMS. The FDA's approach on medical tests is to consider overall safety and efficacy, as does CMS, but neither agency makes recommendations, nor does it perform its own rigorous quantitative assessment of benefit vs harm. The USPSTF, however, does its own detailed evidence-based reviews of the benefit vs harm of products, Ransohoff said.

"To me, the Task Force is the gold standard," Ransohoff said. "You have to jump through the hoops with the FDA and CMS for making claims, to enable use, and to help get payment. But the Task Force looks at the choices and the consequences in a quantitative way and makes specific practice recommendations."

What the Future May Hold

Carethers sees a future in which highly sensitive blood tests are able to largely replace screening colonoscopies. He said that colonoscopies would be used for people who are most in need of diagnosis and treatment. Carethers addressed these points during an AGA podcast released in January 2023.

In 20–25 years, colonoscopies may be only a therapeutic procedure, much like endoscopic retrograde cholangiopancreatography is now, Carethers added.

Even if CRC-specific blood tests prove to be effective screening tools, Ransohoff of UNC stressed that colonoscopy will survive. Many people will eventually need to undergo colonoscopy as a diagnostic procedure following a positive blood-based test result, and some may also opt for screening colonoscopies in lieu of frequent blood tests.

And, overall, physicians and patients will need to weigh the tradeoffs of a noninvasive test that can only diagnose CRC vs a screening colonoscopy that offers preventative treatment as well.

"The best intent for screening is prevention of cancer, not detection of cancer," said Johnson of Eastern Virginia Medical School.