The American Cancer Society updated colorectal cancer screening guidelines published in 2026 include recommendations for new molecular-based screening tests that received regulatory approval after the 2018 guidelines were released.1 Options for molecular-based screening include a multitarget stool RNA test (mt-sRNA), a next-generation multitarget stool DNA test (ng-mt-sDNA), and a blood-based cell-free DNA assay. Both mt-sRNA and ng-mt-sDNA demonstrate performance that is equal to or better than other approved tests. Blood-based cell-free DNA assays, conversely, demonstrate lower sensitivity for both advanced precancerous lesions and stage I cancers, with modeling studies predicting lower effectiveness than that of already available screening tests (fecal immunochemical test FIT, ng-mt-sDNA, mt-sRNA, or colonoscopy) at reducing colorectal cancer incidence and mortality. At this time, the American Cancer Society recommends that blood-based tests be offered, but only to individuals who are unable or unwilling to complete preferred screening tests, which aligns with guidelines of the National Comprehensive Cancer Network.2 Blood-based tests for colorectal cancer screening analyze cell-free DNA using machine-learning algorithms to detect abnormal signals associated with cancer and precancerous lesions. The American Cancer Society recommendation is based on large studies, such as ECLIPSE (n = 7861 in the evaluation cohort; ClinicalTrials.gov identifier NCT04136002) and the PREEMPT CRC study (n = 27,010 in the evaluation cohort; ClinicalTrials.gov identifier NCT04369053), demonstrating moderate sensitivity for detecting cancer—higher for advanced stages than for early stage disease—but very low sensitivity (approximately 13%) for advanced precancerous lesions.3, 4 Although specificity is relatively high, it declines with age, increasing the risk of false positives in older adults. We applaud the American Cancer Society for these guidelines and for highlighting the need for ongoing evaluation of adherence, real-world implementation, and clinical outcomes to inform future updates to recommendations. Here, we offer our perspective on what such evaluations should consider—with the goal of optimizing colorectal cancer screening programs, supporting informed patient choice, and ultimately reducing mortality. Colonoscopy offers a unique advantage over noninvasive colorectal cancer screening by enabling both early cancer detection and prevention through the removal of advanced precursor lesions. Ongoing trials, such as CONFIRM and SCREESCO (ClinicalTrials.gov identifiers NCT01239082 and NCT02078804, respectively), comparing colonoscopy with stool testing (FIT), will clarify which approach better reduces incidence and mortality, with programmatic adherence likely a key determinant of outcomes.5, 6 Over the past 5 years, microsimulation models weighing the benefits of colorectal cancer screening have begun to consider the long-term impacts of screening using real-world data on adherence.7 It is important to note that adherence to first-line screening alone is an insufficient metric; we must consider adherence to repeat testing for those with normal test results, to follow-up colonoscopy for those with abnormal results, and adherence to continued testing as recommended. Because follow-up colonoscopy after an abnormal screening test is so important, the National Committee for Quality Assurance created a new HEDIS (Healthcare Effectiveness Data and Information Set) measure for this metric, to take effect as early as 2027.8 Most studies indicate that cancer presents at a more advanced stage after a colonoscopy lag of 9 months or more.9, 10 Thus expert recommendations encourage follow-up colonoscopy within 6 months.8, 11 Understanding adherence to follow-up colonoscopy among individuals who obtain a blood test because they were unwilling or unable to get a screening colonoscopy will be important. In our study of Guardant Health's SHIELD test, preliminary data show lower adherence to follow-up colonoscopy at 6 months in patients with an abnormal blood test result versus an abnormal FIT result (50% vs. 70%).12 Now, we need more granular data on adherence to advance understanding of what conditions drive nonadherence across population subgroups and to guide recommendations. We need to know which methods work best in achieving high adherence and at what cost. Importantly, future studies should measure trade-offs, such as how many patients complete a blood test who might have completed a more accurate test had conditions been optimized. In addition, although the guideline recommends blood-based testing for a limited group of people, we are concerned that the use of blood-based tests will not remain confined to the recommended group. Qualitative interviews by our team revealed that some patients incorrectly believed that a blood test would be more accurate than a stool-based test for detecting colorectal cancer.13 This could result in some patients opting for a poorer performing blood test instead of tests preferred by the American Cancer Society. Providers need information on real-world implementation to accurately communicate the risks and benefits of each test. For example, providers need to be able to communicate that test performance of the ng-mt-sDNA test (done once every 3 years) is similar to that of annual FIT tests because the cumulative performance increases with each successive test. Our data, based on 50% FIT adherence estimates for second-year and third-year completion, show comparable sensitivity to ng-mt-sDNA, done once every 3 years (41% vs. 43.4%).14 Manufacturers of molecular-based tests, such as ng-mt-sDNA, mt-sRNA, and cell-free DNA, should be required to provide separate results for each test component, i.e., the FIT component as well as the molecular test component. Just as cholesterol panels report low-density lipoprotein and high-density lipoprotein values separately to guide clinical decision-making, knowing whether an abnormal result is driven by the presence of occult blood versus a genetic or epigenetic marker carries distinct clinical implications. This information would allow providers to more precisely guide patients on follow-up testing intervals and help alleviate the anxiety that can accompany an abnormal result—particularly when that result is not subsequently confirmed on colonoscopy. An emerging addition to the screening landscape is multicancer early detection tests, which may identify circulating free DNA associated with several cancers, including colorectal cancer. These tests are of unproven benefit, and their widespread adoption could result in several clinical challenges. First, if a test result is negative, patients may forgo proven recommendations for colon, breast, or cervical cancer, believing they are cancer-free. Second, if the test result is positive, it may initiate a prolonged diagnostic workup to search for cancer. Finally, it is not clear whether such testing will result in favorable stage shifting to enable patients to benefit from early detection. Estimates indicate that a patient with an abnormal FIT test has a one in 20 (5%) chance of having colorectal cancer, compared with less than 1% in patients undergoing screening colonoscopy.15, 16 Patients with low-risk adenomas undergoing surveillance have an even lower risk of colorectal cancer (0.22%).17 We believe that patients with abnormal stool tests should be prioritized for colonoscopy; this triage algorithm could ensure timely follow-up. Equally important is full adoption of updated surveillance guidelines that now extend the recommended interval to 7–10 years (the old guideline was 5–10 years) for those with low-risk adenomas found on index colonoscopy. Patient navigation, a service that supports patients in overcoming barriers in receiving health care services, should also be prioritized for patients with the highest risk of cancer and the lowest probability of getting screened without navigation.18 These efforts could drive completion rates and decrease colorectal cancer incidence and mortality. Because blood tests are less likely to find advanced adenomas than other available tests, the use of these tests in place of more effective screening tests could result in net harm (i.e., increased deaths from colorectal cancer).19 According to Ladabaum and colleagues, this harm could be counterbalanced if, for every three people who substitute blood tests for existing screening methods, at least two previously nonadherent individuals begin screening, assuming comparable colonoscopy follow-up rates.20 However, the proportion of patients declining all screening modalities is smaller than those already engaged in screening, making this scenario unlikely. Alternatively, for a blood test to be equivalent to stool tests, detection of advanced precursor lesions and stage I colorectal cancers would need to improve substantially, or the test would need to be applied at an interval of less than 3 years.21 Thus clinical outcome reports need to include data on precursor lesions detected, cancers found (including data on cancer stage), and cancer deaths based on real-world data. The updated American Cancer Society guidelines represent an important step forward in expanding colorectal cancer screening options, but their impact will depend on how well implementation is monitored and guided by real-world evidence. Achieving the full potential of these guidelines will require rigorous tracking of adherence across the full screening cascade; transparent reporting of test performance, including individual components; and sustained attention to clinical outcomes, including precursor lesion detection, cancer stage at diagnosis, and mortality. Ultimately, the goal must remain reducing colorectal cancer deaths through screening programs that prioritize accuracy, equity, and informed patient choice, ensuring that the convenience of newer tests complements rather than compromises the effectiveness of population-level cancer prevention. The research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number 3P30CA023074. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. National Cancer Institute of the National Institutes of Health; 3P30CA023074. David A. Lieberman reports personal/consulting fees from ColoWrap, Geneoscopy, and Universal Diagnostics outside the submitted work. Gloria D. Coronado disclosed no conflicts of interest.
Coronado et al. (Fri,) studied this question.