NEW YORK – Researchers from the Stanford University School of Medicine have used decision analytic modeling to determine the potential long-term clinical and economic impacts of novel blood- and stool-based colorectal cancer screening tests, such as those from Guardant Health and Exact Sciences.
In a study published in Annals of Internal Medicine on Monday, the researchers described their findings, which compared blood-based and stool-based screening tests to fecal immunochemical tests and colonoscopies. The researchers used their Model of Screening and Surveillance for Colorectal Cancer (MOSAIC), which the team has previously utilized for other studies looking at different aspects of colorectal cancer screening, such as the potential impact of lowering the initial screening age from 50 to 45 years old, said Uri Ladabaum, director of the Gastrointestinal Cancer Prevention Program at Stanford and one of the paper's authors.
The team decided to perform the newest study after the "very exciting scientific development of blood tests that can detect colorectal cancer with various degrees of sensitivity," he said. However, many of these tests do not perform as well when detecting advanced precancerous polyps, so the researchers wanted to see how the performance characteristics would potentially stack up in the long term.
Without modeling, it is "difficult to know how to interpret [test performance characteristics] when you're talking about colorectal cancer screening being a long-term programmatic endeavor where people are supposed to come in every few years over decades, and when there's a certain cost of testing that could potentially be traded off against potential savings, if you prevent cancers or find cancers early," he said.
According to Ladabaum, novel screening tests "have some potential upsides and some potential downsides." The question is, "How does the whole story play out over the long term, in terms of the population-level impact, the population-level downsides, and the economic balance sheet compared to the current established alternatives of stool-based testing and colonoscopy?"
He and his colleagues looked at novel tests that have high-quality data in the public domain, including Exact Sciences' stool-based Cologuard test and its next-generation Cologuard Plus test, Geneoscopy's stool-based ColoSense test, Guardant's blood-based Shield assay, and Freenome's blood-based test that is under development, and modeled the relative rate of colorectal cancer and deaths among 100,000 average-risk people who used each screening method. Guardant's Shield test received approval from the US Food and Drug Administration in July, while Cologuard Plus received FDA approval earlier this month, and ColoSense nabbed FDA approval in May.
In addition to the blood-based testing data, the researchers validated the model with data for cancer and cancer death in people who undergo colonoscopies and calibrated it with contemporary data for precancerous polyps found during colonoscopies. They wanted to do a "rigorous synthesis of all the information that's out there in an organized way, in a validated model, to try to make long-term projections that can inform the application of these new tests," Ladabaum said.
Among 100,000 people who receive a colonoscopy every 10 years, 1,543 would develop colorectal cancer and 672 would die from the disease, the researchers found. For patients who undergo stool-based testing every one to three years depending on the test, the incidence of colorectal cancer was between 2,181 when using FIT every year and 2,498 cases when using Cologuard Plus every three years. The number of deaths with FIT was 904, while the number of deaths with Cologuard Plus was 1,025.
For the new blood-based tests, which are recommended for use every three years, the number of colorectal cancer cases was 4,310 for the Freenome test and 4,365 for Guardant Shield, and the number of deaths was 1,679 for Freenome's assay and 1,604 for Guardant Shield.
Among those who receive no screening, 7,470 would develop colorectal cancer and 3,624 would die from it.
According to the model's predictions, "the blood tests aren't really stacking up yet compared to alternatives," but one potential advantage could be increased participation in patients who are not willing to do a stool test or colonoscopy, Ladabaum said.
The researchers found that if three people replaced colonoscopy or stool-based testing with a blood-based test, two people who wouldn’t have been screened with other methods would also have to use a blood-based test for the current number of colorectal cancer deaths to remain even. This assumes the patients who use blood-based tests undergo a follow-up colonoscopy if their results indicate need for follow-up.
The research team also determined that as the colonoscopy follow-up rate after an abnormal blood-based test result decreased, the effectiveness of screening "eroded substantially," according to the study. Failure to follow up with colonoscopy also eroded cost-effectiveness.
When 5 percent of the population shifted from no screening to Guardant Shield, the additional number of deaths prevented was 70 per 100,000 people. When 25 percent shifted, the additional number of deaths prevented was 348 per 100,000 people.
A spokesperson for Guardant noted via email that colonoscopy is still the gold standard, but many patients remain unscreened. The company has collaborated with the FDA and developed physician brochures and patient fact sheets to "clearly outline" the benefits and limitations of Shield for CRC screening. "As a result, through shared decision-making, clinicians and patients can determine the best screening option that is likely to be completed," the spokesperson added.
"The best test is the one that gets done," the spokesperson added. Data from Guardant has shown that in the two years since Shield has been available as a laboratory-developed test, the adherence rate has been greater than 90 percent with the test, considerably higher than the 28 percent to 71 percent with other current methods.
In a study published earlier this year, researchers at Kaiser Permanente Northwest showed a three times increase in the odds of completing colorectal cancer screening when Shield was integrated as a screening option alongside stool-based tests and colonoscopy, the spokesperson noted.
Ladabaum noted that if the next generation of blood-based screening tests have better performance characteristics, "the calculus changes."
"For the future, if it's possible scientifically to have noninvasive tests that get better at stage I cancer, they get substantially better at advanced polyps," he said, "and where the cost is much more competitive, that could really be a change in the paradigm."
Paul Limburg, Exact Sciences' chief medical officer for screening, said via email that both Cologuard and Cologuard Plus have high sensitivity for detecting stage I colorectal cancer, and both detect stages I, II, and III colorectal cancer at 94 percent sensitivity. Cologuard Plus also detects high-grade dysplasia in advanced pre-cancers at 74 percent.
Modeling data presented this week at the American College of Gastroenterology annual meeting show that Cologuard Plus "delivers the highest life-years gained with fewest number of colonoscopies among noninvasive colorectal cancer screening strategies," he added.
Limburg also noted that "to increase screening participation, patients and providers need to have full understanding and clear conversations about the benefits and limitations of the available test options."
"Healthcare providers should counsel people about the limitations of current blood tests with respect to early detection of cancers and pre-cancers to achieve the full benefits of colorectal cancer screening," he added.
Cologuard "far outperforms blood-based screening in pre-cancer and early-stage cancer sensitivity." In addition, it can be completed at home with no special diet or preparation, Limburg said.
Exact Sciences is also developing a blood-based screening test, for which it presented data at the European Society for Medical Oncology Congress in September. Limburg noted that Exact's test is intended as "an additional option to get more people screened, particularly those who are unable or unwilling to complete any of the other tests that are currently recommended in national screening guidelines, which include colonoscopy, Cologuard, or other stool tests."
"Currently, FDA-approved blood-based tests are limited in sensitivity for both early-stage cancers and advanced pre-cancers, limiting the opportunities for maximally effective cancer treatment and prevention interventions," he noted.
The Stanford researchers also found that colonoscopies and stool-based tests are more cost-effective than blood-based tests. According to the study, in people who will absolutely not take up screening colonoscopy or stool tests, blood-based testing "emerges as cost-effective versus no screening, assuming a high colonoscopy follow-up rate." They noted that the costs of various emerging blood-based tests are yet to be established, and competition may affect test costs.
But Ladabaum added that blood-based tests are "an incredible development in the colorectal cancer screening world" and that "even with their limitations, it's a tremendous scientific advance."