CRC screening programs focused on the average-risk population have been recommended, as they have been shown to reduce CRC incidence and mortality[19]. Early detection and removal of precursor lesions halt malignant transformation, thus preventing CRC and improving treatment outcomes and prognosis. At present, to maximize the impact of secondary prevention strategies, most national health systems aligned with the agenda of the European Plan to Fight Cancer have committed to set out plans to improve coverage and participation rates of screening programs, such as reducing the age to enroll in the program or lowering the FIT cut off. These measures will undoubtedly lead to more polyps/adenomas and cancers being detected, albeit at the same time implying more people being referred for colonoscopy. Hence, these objectives would lead to a greater demand for endoscopic resources, which currently limits their viability. This shows the need to introduce strategies to ensure that screening programs are capable of overcoming rate-limiting factors.
One potential strategy to create the capacity to cope with the future demand is increasing the diagnostic specificity of current CRC detection techniques. This will permit more accurate referrals for colonoscopy. Improving diagnostic accuracy also makes it possible to address other current needs and challenges of screening programs. Unscreened patients report that the main barriers to participation in CRC screening programs are fear related to the procedure, sedation, logistics, and discomfort with the procedure or preparation[20]. Patients report that colonoscopies negatively impact their quality of life, with high levels of pain reported in association with post-colonoscopy abdominal complaints[21, 22]. Likewise, they entail an increase in the care burden and contribute to the saturation of the health system due to the increase in waiting lists, intensifying the pressure of a system already in tension due to the limited availability of endoscopic resources. Taken together these factors entail an economic cost which, if optimized, would permit alleviation of the budgetary pressure suffered by the health system. In this context, we evaluated the capacity of the RAID-CRC Screen triage test to reduce the false-positivity rate of FIT20 alone by using it as an additional positivity criterion in a German cohort of patients at average risk for CRC.
Adding the bacterial signature of RAID-CRC Screen as an additional positivity criterion to FIT20 in CRC screening programs resulted in a significant reduction in false positive rates of 20% and 22% for the AN and CRC endpoints, respectively. For the CRC endpoint this was achieved while maintaining the same level of sensitivity as that obtained using FIT20 alone, but the sensitivity of detecting advanced adenomas, and hence the overall sensitivity in detecting AN, was significantly reduced (from 21.8–17.5%, a reduction of approximately 20%). These results are in line with and confirm previous results obtained in a clinical study which was restricted to participants preselected by a positive FIT in clinical practice [7].
The gain in specificity and reduction in unnecessary colonoscopies of approximately 20% estimated for the additional use of RAID-CRC Screen in our study, should be weighed against the loss in sensitivity of approximately 20% in detecting advanced neoplasms. An additional consideration is the time course of colorectal carcinogenesis. The development from advanced neoplasm to CRC typically takes many years, and a substantial proportion of advanced neoplasms will not develop into clinically manifest CRC during screenees’ lifetime [23]. The lower sensitivity for advanced neoplasm detection (in contrast to a lower sensitivity for CRC detection) might therefore be of limited concern (or might potentially even be advantageous) as it would preferentially concern early advanced neoplasms (or those that would never evolve to CRC during the patient’s lifetime). Most FIT-based screening programs offer annual or biennial screening, which implies that there is a good chance of early detection of advanced neoplasms that progress towards CRC, which may reduce concerns about the potential loss of sensitivity in detecting all advanced neoplasms found. Likewise, repeat screening rounds are expected to be accompanied by gradually decreasing prevalences of advanced neoplasms and further decreases in the positive predictive values of FIT-based CRC screening, which would increase the need for enhanced specificity.
As stated by the Colorectal Cancer Screening Committee of the World Endoscopy Organization, when considering the introduction of a new test and its clinical accuracy in the screening context, the effect on other variables in the screening pathway should be considered [24]. In particular, the feasibility of implementation with minimal changes in the clinical pathway may be important. For the RAID-CRC Screen, sample handling was adapted to the current pathway of the Catalan CRC screening program, optimizing sample collection in the FIT collectors so that both FIT analysis and bacterial DNA extraction can be performed using the same container [7, 25]. With respect to the workload, an automated DNA extraction procedure has been optimized, and the quantification of the bacterial markers included in the algorithm has been multiplexed for parallel quantification, thereby minimizing the increase in time and resources. A particularly relevant aspect with respect to resources and costs is that the bacterial signature would be selectively determined in FIT20 positive individuals only, in whom savings due to avoiding unnecessary colonoscopies would be the goal. One limitation of the study is that it does not replicate the real-world performance of FIT, which is done on fresh stool. However, previous assays in which the qPCR results obtained from fresh and frozen fecal samples collected with the FIT collector were compared, showed reproducibility.
While the bacterial signature of RAID-CRC Screen was shown to increase specificity in our study, its use should be further compared with alternative approaches to increase specificity, such as an increase or decrease in FIT positivity cut-offs [26, 27] or the combination of FIT with other non-invasive tests [28]. Given, however, that at the moment the new test is proposed as a triage test, it would seem more promising to test it when using a lower (not a higher) FIT cut-off. In such a scenario, the high specificity of the new test and the high sensitivity for CRC would allow the detection rate to be increased without increasing the number of colonoscopies. Using lower cut-off levels would also permit more lesions to be detected with a more precise estimate of sensitivity and specificity of the test among FIT positive subjects. Alternative options to be considered in FIT-based screening programs might include extending FIT screening intervals in subjects with low FIT values in preceding screening rounds [29], which would also reduce false positive rates and increase sensitivity and positive predictive values through increased prevalence rates of advanced neoplasms in subsequent screening rounds. Future research should aim for a more comprehensive, comparative evaluation of different approaches (or their combination) to enhance current FIT-based screening, and include both head-to-head comparisons of different screening strategies and thorough modeling of their long-term impact and cost-effectiveness.
The study has strengths and weakness. Major strengths are the large overall sample size in an average-risk screening population, and the availability of screening colonoscopy results for all participants. However, despite the large overall size, the number of participants with CRC was still rather small (n = 15) which reflects the low prevalence of CRC in screening settings. Estimates of sensitivity for CRC detection and the impact of adding RAID-CRC Screen to FIT20 on that sensitivity, therefore, need to be interpreted with caution. Likewise, the results were restricted to the use of RAID-CRC Screen in the FIT20 cut-off of one specific FIT brand only. Future studies should assess the performance of the combination of RAID-CRC Screen with other FIT brands and other positivity thresholds. In particular, based on the data obtained it would be promising to explore the combination when the FIT cut-off is lowered. In such a scenario, it is expected that the increased sensitivity provided by FIT and the potential higher specificity achieved when adding RAID-CRC Screen as a triage test would lead to higher detection rates with greater precision, thus requiring fewer colonoscopies than when using FIT alone. Even though the results were highly consistent with those from a preliminary Spanish clinical study [7], further replication in other, larger studies is highly desirable. Further studies should also aim to evaluate the performance of the test in other populations from other countries.