Are new colorectal cancer screening options a match for 'the gold standard'?

Key takeaways:

• New blood and stool tests may improve uptake of colorectal cancer screening because of the discomfort around colonoscopies.
• PCPs should walk patients through their options so they can make informed decisions.

New testing options for colorectal cancer will likely expand access to screening, but they are not as reliable as a colonoscopy, according to experts.

Colorectal cancer (CRC) is one of the leading causes of cancer death and the third most common cause of cancer in the United States, Robert Smith, PhD, senior vice president of early cancer detection science at the American Cancer Society (ACS), told Healio. The ACS has estimated that, in 2024, there will be about 46,220 new cases of rectal cancer and 106,590 new cases of colon cancer in the U.S. The organization also anticipates CRC to be responsible for about 53,010 deaths this year.

“Screening for CRC has contributed to reducing CRC deaths when the disease is found early, and contributed to the prevention of CRC when precursor lesions are detected and removed,” he said. “Five-year survival of CRC is 91% when it is diagnosed while still localized (ie, not spread) but only 14% for advanced disease (ie, spread to distant organs).”

There has been some debate about when patients should start being screened for CRC; in 2020, the U.S. Preventive Services Task Force dropped the recommended age of screening to 45 years, while the American College of Physicians’ 2023 policy recommends starting screening at age 50 years. But the consensus is that screening for the disease is a critical, lifesaving preventive service that is not used enough, particularly considering changing trends in CRC incidence.

Namrata Vijayvergia, MD, assistant chief of gastrointestinal medical oncology at Fox Chase Cancer Center, said CRC prevalence is increasing “especially in the younger population,” and even young patients with no family history of these cancers can be affected.

“This is one cancer that, if you do proper screening, you'll identify at a precancerous stage or at an early stage, and we do know that the sooner we catch it, the better the outcomes are,” Vijayvergia said. “So, it is something we need to identify early. We need to identify more people, and for that, screening efforts are the most important thing.”

Current testing options and the role of PCPs in screening

Today, there are two main options for CRC screening, Smith said: a direct visual test (including colonoscopy, computed tomography colonoscopy and flexible sigmoidoscopy, all of which “allow the examiner to visualize the inside of the bowel”), or a stool test.

“I think the holy grail or the gold standard for screening is the colonoscopy,” Vijayvergia said. “It has a broad diagnostic utility and also some therapeutic utility, so that is the gold standard. But everything that’s perfect is not perfect; it comes with its own set of issues. There is no perfect test.”

Smith said the stool tests include fecal immunochemical tests (FIT), high-sensitivity guaiac stool tests and a multitarget stool DNA test (MTsDNA), “which combines a FIT test with a test for molecular markers associated with advanced adenomas and cancer.” He noted that Cologuard is the only MTsDNA on the market.

How frequently testing is done depends on the method, which can be an important factor in a patient’s decision. Smith said that, while guidelines currently recommend colonoscopies be conducted every 10 years, the other direct visual tests have 5-year follow-up periods. But stool tests must be conducted more regularly, with “MTsDNA testing every 3 years, or FIT or guaiac-based stool tests annually.”

“The evidence shows that when patients are given the option of being screened with one or the other, screening rates are higher,” Smith said. “The ACS recommends that they give their patients the options.”

Smith said primary care providers can play a crucial role in CRC screening uptake, partly because they can educate patients about their options.

“The single most important factor patients report about the reason they have been screened for CRC is that their doctor told them to get screened, and the reason they give for not having been screened is that their doctor hasn’t mentioned it,” he said.

Ashley Denmark, DO, an osteopathic physician specializing in family medicine and a member of the American Osteopathic Association (AOA), explained that PCPs are important figures in all stages of CRC diagnosis. She said they guide patients through screening decisions based on risk factors, family history and personal preference, and they also follow up with patients to ensure they “have received appropriate care.”

“In my clinic, if a test like FIT or Cologuard is positive, further evaluation is needed with a diagnostic colonoscopy to evaluate for CRC,” Denmark said. “Typically, we bring patients in to discuss results, answer questions, walk them through the process of a diagnostic colonoscopy and place the order. If a polyp is found with colonoscopy, typically, its biopsies and results are made available to patients. If cancer is detected, we will contact the patient for an appointment and discuss a referral to a cancer specialist.”

Although the PCP’s role is important, that does not mean it is an easy one. Brent Smith, MD, MSc, MLS, FAAFP, a family physician in Mississippi and member of the American Academy of Family Physicians board of directors, said that, in his experience, CRC screening (especially colonoscopy) “is the most uncomfortable conversation to have about cancer screening,” despite its effectiveness.

The discomfort around colonoscopies can come from the sedation, the sensitive nature of the procedure and the extensive preparation a patient has to go through to clean out their digestive system for a colonoscopy, Brent Smith said.

“It's a very important screening that we have that we're underutilizing, so we want to really push forward and try to get better uptake and better use in the community,” he said.

Naturally, to increase screening uptake and give patients more options, researchers are working to develop and improve tests.

‘Continued advances in diagnostics’

In March, a pair of studies published in The New England Journal of Medicine (NEJM) offered a snapshot of a new generation of CRC tests.

“Blood-based screening and more accurate stool-based testing options hold promise to close the gap for the 41% of eligible persons 45 years of age or older who are not adherent to screening guidelines, especially considering the cost implications of these screening tests when compared to colonoscopy and that only 39% of uninsured individuals are up to date with CRC screening,” Richard C. Calderone, DO, MPH, FAA, an osteopathic physician specializing in general public health and preventive medicine and internal medicine and AOA member, told Healio.

In the first NEJM study, Daniel C. Chung, MD, a professor at Harvard Medical School and medical co-director of the Center for Cancer Risk Assessment at Massachusetts General Hospital, and colleagues evaluated the performance of a cell-free DNA (cfDNA) blood-based test — named SHIELD and developed by Guardant Health — in 7,861 participants. They found that the blood-based test had 13% sensitivity for advanced precancerous lesions, 83% sensitivity for CRC and 90% specificity for advanced neoplasia.

Because the results indicated poor sensitivity for advanced adenomas but good sensitivity for CRC — 87.5% (95% CI, 75.3-94.1) for the first three stages — Robert Smith said “this test can principally be thought of as a test to detect colorectal cancer but not to prevent colorectal cancer.”

He also commented on the potential cost of the test, noting that “insurance plans would not be required to cover it until it receives an A or B rating by the USPSTF.”

“It remains to be seen what the uptake of the SHIELD test will be,” Robert Smith said. “At this time, it will be expensive as a noncovered test. A blood test for circulating cfDNA that has good sensitivity for cancer but poor specificity for adenomas has been considered to be a useful option for people who are consistently nonadherent to a recommendation to get screened for CRC. It is believed that a blood test, which is available in the doctor’s office, could result in more cancers detected due to the simplicity of the testing process.”

Robert Smith also said that FDA approval is still pending, but the cfDNA test is “available directly from the manufacturer as a laboratory-developed test.”

“It presently is not recommended for CRC screening by any guideline-issuing organization, including the ACS and the USPSTF,” he said. “For patients who wish to be screened with this test, PCPs should advise patients that it has poor performance for detecting precursor lesions, and that alternative tests have similar or better sensitivity for cancer and precursor lesions.”

In the second study, Thomas F. Imperiale, MD, a distinguished professor at the University of Indiana School of Medicine, and colleagues assessed a next-generation MTsDNA with 20,176 participants. They found that, compared with a FIT, the test had a slightly lower specificity for advanced neoplasia but improved sensitivity for advanced adenomas and CRC (sensitivity for CRC = 93.9% [95% CI, 87.1-97.7]; sensitivity for advanced precancerous lesions = 43.4% [95% CI, 41.3-45.6]; specificity for non-neoplastic findings or negative colonoscopy = 92.7% [95% CI, 92.2-93.1]; and specificity for advanced neoplasia = 90.6% [95% CI, 90.1-91]).

Robert Smith said the test “can be regarded as an improvement over the current test” because “each year, a growing number of adults are being screened with a MTsDNA test, which has better single-test performance than the other two stool testing options.” Additionally, like current MTsDNA tests, the new test “should be covered by insurance.”

“The new MTsDNA test has better performance at finding colorectal cancer and advanced adenomas, which is a good thing. Although there is a slight degradation in specificity, this is not uncommon when sensitivity improves,” he said. “The next-generation MTsDNA test is an improvement over the current one, and it can be done every 3 years and is covered by insurance.”

Calderone said the studies “demonstrate continued advances in diagnostics for this important disease” and “are likely to influence the next iteration of multi-organization guidelines for consensus-approved screening.”

“With improvements in accuracy and improved ease of screening implementation — and as these modalities become more cost-effective — early detection of CRC is expected for more and more individuals,” Calderone said. “Due to the frequency of blood draws for patients in the primary care setting, blood testing in particular holds promise to broaden screening to otherwise reluctant individuals. A combination of these tests will likely yield the most cost-effective initial screening, with colonoscopy remaining the ultimate destination for positive screening tests.”

Take-home message

Overall, Robert Smith said there are a few key messages for PCPs: “not all patients are willing to undergo colonoscopy for screening,” so offering options is important, and PCPs have a “critically important role in preventing colorectal cancer and detecting it early.”

“Patients have a range of insurance-covered options, and among the recommended tests, the best test is the one you get,” Robert Smith said. “PCPs should have a system that ensures every one of their patients is assessed for being adherent with CRC screening recommendations, and they should advise their patients that CRC screening is an important part of their preventive health plan. Going forward, screening for CRC may become easier and more accurate.”

Brent Smith said that, with CRC screening, PCPs have the opportunity to “change our patients’ health.”

“These procedures are not just screening; they're potentially life-changing and cancer-preventing,” Brent Smith said. “We need to be aware of the alternatives so that we can deal with patients who potentially may not be open or appropriate for colonoscopy and still meet our goal, which is to try to prevent as much CRC as we can or to catch it early and treat it aggressively to prevent the bad outcomes down the road. If we can focus on providing the best we can there, then we really can change our patients’ lives with this.”

References:

• Chung DC, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2304714.
• Imperiale TF, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa1311194.
• Key statistics for colorectal cancer. https://www.cancer.org/cancer/types/colon-rectal-cancer/about/key-statistics.html. Updated Jan. 29, 2024. Accessed April 4, 2024.