Non-invasive colorectal cancer screening: emerging tools and clinical evidence

Abstract

The fecal immunochemical test (FIT) is a widely used non-invasive screening method for colorectal cancer (CRC) in many countries, valued for its simplicity, affordability, and reasonable sensitivity. Typically recommended on an annual or biennial basis, the FIT is effective in reducing CRC incidence and mortality by facilitating early detection. Stool DNA tests, including multitarget DNA tests and DNA methylation assays, demonstrate higher sensitivity than FIT for CRC and advanced adenomas, although they have slightly lower specificity and higher cost. These tests are generally performed at longer intervals, such as every 3 years, and are useful alternatives for individuals who are unwilling or unable to undergo a colonoscopy. Emerging non-invasive CRC screening tools, such as liquid biopsy, microRNA, microbiome tests, and urine-based tests, are being developed to improve patient compliance and test convenience. In particular, liquid biopsy offers a minimally invasive option that may be more acceptable to populations hesitant to undergo stool-based tests. Furthermore, the integration of machine learning with metagenomic sequencing data has shown promise in distinguishing patients with CRC from healthy individuals. As CRC screening evolves, these novel approaches may enable the development of more personalized, accessible, and effective screening strategies, ultimately improving adherence and reducing CRC-related mortality.

INTRODUCTION

Colorectal cancer (CRC) is the third most commonly diagnosed cancer globally. According to GLOBOCAN estimates, there were approximately 1.9 million new CRC cases and 930,000 deaths in 2020.1 The global burden of CRC is projected to rise substantially, reaching an estimated 3.2 million new cases and 1.6 million deaths by 2040, with the majority of cases expected to occur in countries with a high or very high human development index.1 Furthermore, CRC ranked fourth in incidence and fifth in mortality among 35 cancer types in the GLOBOCAN 2022 report. CRCs are historically considered a predominantly Western disease, but are now increasingly reported in Asian countries, accounting for approximately half of all cases in recent years. In South Korea, CRC was the second most common cancer and the third leading cause of cancer-related death in 2022. CRC incidence among the Korean population ranks among the highest worldwide for both men and women, although CRC-related mortality remains relatively low.2

Given the well-established adenoma–carcinoma sequence in CRC development, early detection of neoplastic lesions is essential.3 CRC is largely preventable through the detection and removal of precancerous lesions.1 With the increasing incidence of CRC in transitioning countries and among younger adults, there is an urgent need to improve CRC screening tools to reduce the number of future cases and deaths.1 CRC screening not only improves survival but also allows for less aggressive treatment and helps reduce the overall public health and economic burden by lowering both CRC incidence and mortality. CRC screening can be delivered through organized or opportunistic approaches, with organized screening being particularly important because of its structured implementation, quality assurance, and potential population-based impact. A recent study demonstrated the effectiveness of organized CRC screening on screening uptake, incidence, and mortality in community-based populations in the USA.4 Initiation of organized CRC screening significantly increased the up-to-date status of screening, from 38.9% in 2000 to 82.7% in 2015. Higher rates of organized screening were associated with a 25.5% reduction in annual CRC incidence between 2000 and 2015, from 95.8 to 71.4 cases/100,000, and a 52.4% reduction in cancer mortality, from 30.9 to 14.7 deaths/100,000. Organized screening tests were performed systematically and comprehensively using validated methods, primarily fecal immunochemical testing (FIT), colonoscopy, and sigmoidoscopy. Although colonoscopy is considered the gold standard for CRC screening, it has several limitations as an organized screening tool. These limitations include its invasive nature, low participation rates, variable quality, substantial infrastructure and workforce requirements, and significant economic burden. Therefore, non-invasive tests such as stool, blood, and urine-based screening are preferred for CRC screening.

In this review, we searched for non-invasive CRC screening strategies, including validated and emerging tools, and their recent clinical evidence.

FECAL IMMUNOCHEMICAL TEST

Many guidelines and expert recommendations endorse the FIT as a validated, non-invasive modality for CRC screening.5-7 In the US Multi-Society Task Force on CRC recommendations—representing the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy—CRC screening tests are stratified into three tiers based on test performance, cost, and practical considerations.5 Tier 1 tests included colonoscopy every 10 years and annual FIT in this recommendation. Furthermore, both the American Cancer Society and the US Preventive Services Task Force recommend annual FIT as an option for CRC screening.6,7

According to a systemic review and meta-analysis of 19 studies published between 1996 and 2013, the pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of FITs for CRC were 0.79 (95% confidence interval [CI], 0.69–0.86), 0.94 (95% CI, 0.92–0.95), 13.10 (95% CI, 10.49–16.35), and 0.23 (95% CI, 0.15–0.33), respectively, with an overall diagnostic accuracy of 95% (95% CI, 93%–97%).8 However, there was substantial heterogeneity between studies in the pooled sensitivity and specificity estimates. For positive likelihood ratios, a value greater than 10 is considered strong evidence for ruling in CRC. For a negative likelihood ratio, a value between 0.2 and 0.5 provides weak evidence for ruling out CRC. Therefore, FITs are moderately sensitive, are highly specific, and have a high overall diagnostic accuracy for detecting CRC.8

Consequently, a growing body of evidence supports the effectiveness of FIT-based screening for reducing CRC mortality. In the Minnesota Colon Cancer Control Study, 46,551 participants were randomly assigned to usual care or to annual or biennial fecal occult blood testing.9 Screening reduced CRC mortality (relative risk with annual screening, 0.68; 95% CI, 0.56–0.82; relative risk with biennial screening, 0.78; 95% CI, 0.65–0.93) through 30 years of follow-up. This randomized controlled trial demonstrated that the effect of screening with fecal occult blood testing on CRC mortality persists after 30 years.9 However, this study has a key limitation in that recruitment and randomization were conducted between 1975 and 1978, during which fecal occult blood testing (not FIT) was used for CRC screening.

Currently, four major studies comparing the reduction in CRC mortality by colonoscopy and FIT are being conducted worldwide. In 2025, the result of the long-awaited COLONPREV trial was finally published.10 This is the first randomized controlled trial to demonstrate that FIT is comparable to colonoscopy screening in terms of CRC incidence and mortality. This trial was a pragmatic, randomized, controlled, non-inferiority trial done at 15 tertiary hospitals across eight regions of Spain.10 Eligible participants were healthy, 50–69-year-old adults without a personal history of CRC, adenoma or inflammatory bowel disease, family history of hereditary or familial CRC, severe comorbidities, or previous colectomy. Participants were randomly assigned to a one-time colonoscopy (n=28,708) or biennial FIT (n=28,696) before invitation to screening between June 1, 2009, and December 31, 2021. Among 57,404 randomly assigned individuals, the intention-to-screen population consisted of 26,332 individuals in the colonoscopy group and 26,719 in the FIT group. In the intention-to-screen population, participation in any form of screening was 31.8% in the colonoscopy group and 39.9% in the FIT group. FIT was non-inferior to colonoscopy in terms of the risk of CRC mortality at 10 years, with risk of 0.22% in the colonoscopy group and 0.24% in the FIT group (risk ratio, 0.92; 95% CI, 0.64–1.32). Therefore, the FIT-based program was non-inferior to a colonoscopy-based program for CRC-related mortality owing to higher participation in screening among individuals invited for FIT screening than among those invited for colonoscopy screening.

The National CRC Screening Program in South Korea offers annual FIT-based screening for individuals aged 50 years and above. A recent Korean study investigated the long-term survival effects of CRC screening based on three national databases (Korea Central Cancer Registry, Korea National CRC Screening Program database, and Death Certificate).11 In this study, 32,509 patients diagnosed with CRC in 2008–2009, who underwent CRC screening between 2004 and 2009, were followed up until 2019, and their survival was assessed according to their CRC screening history. Long-term survival was significantly higher in screened patients than in non-screened individuals (68.2% vs. 57.2%). Compared with that in never-screened patients, the hazard ratio for CRC-specific death in screened patients was 0.77 (95% CI, 0.73–0.80). This study demonstrated that CRC screening is positively associated with a favorable prognosis in patients with CRC. Similarly, in a nationwide Taiwanese prospective cohort study conducted from 2004 to 2009, the effectiveness of FIT screening in reducing CRC mortality was 62% with a maximum follow-up of 6 years.12 The 21.4% coverage of the population receiving FIT significantly reduced CRC mortality by 10% (relative rate, 0.90; 95% CI, 0.84–0.95) after adjustments for a self-selection bias. Compared with CRCs detected through non-screening, those identified through FIT screening were more likely to be at an early stage and less likely to be at stage IV (7.2% versus 19.2%), i.e., a downstage shift.

Therefore, organized CRC screening programs in many countries rely primarily on FITs. However, the target age, screening interval, and fecal hemoglobin threshold for a positive FIT result vary according to the colonoscopy capacity of each country. In South Korea, for example, annual FIT screening begins at age 50 years, with a positivity threshold of 20 µg of hemoglobin per gram of feces. Similar to colonoscopy-based programs, FIT-based screening programs require careful attention to quality assurance.13 The US Multi-Society Task Force committee suggests an FIT completion rate for those offered testing of 60% or greater, as well as a colonoscopy completion rate for those with a positive FIT of 80% or greater.13 In many countries, however, the FIT completion rate remains below 60% and tends to decline further in subsequent screening rounds. Nevertheless, according to the National CRC Screening Program database, FIT completion rate increased from 25.0% in 2005 to 62.6% in 2019 and 64.4% in 2020 in South Korea.14

In summary, the FIT is recommended for organized CRC screening programs because it is non-invasive and well accepted by the general population, leading to higher participation rates. Its simplicity allows large-scale implementation with regular testing intervals, and positive results can be efficiently followed by diagnostic colonoscopy within a structured care pathway.

MULTITARGET STOOL DNA TEST

Stool DNA tests are a non-invasive, at-home screening option designed to detect abnormal DNA shed from CRCs. Current guidelines recommend stool DNA testing every 3 years for average-risk individuals who prefer a non-invasive option and are unwilling or unable to undergo a colonoscopy.6,7 The American Cancer Society recommends a multitarget stool DNA test every 3 years.6 According to the US Preventive Services Task Force, stool DNA testing every 1 to 3 years is recommended, offering a reasonable balance between life-years gained and the number of follow-up colonoscopies compared with no screening.7

Currently, the only stool DNA test approved by the US Food and Drug Administration (FDA) is the multitarget stool DNA test. This multitarget stool DNA test includes quantitative molecular assays for KRAS mutations, aberrant NDRG4 and BMP3 methylation, and β-actin, as well as a hemoglobin immunoassay.15 In 9,989 participants with an average risk for CRC, the sensitivity for detecting CRC was 92.3% with a multitarget stool DNA test and 73.8% with FIT (p=0.002). The sensitivity for detecting advanced precancerous lesions was 42.4% with the multitarget stool DNA test and 23.8% with FIT (p<0.001). This multitarget stool DNA test detected significantly more CRCs than FIT but yielded more false-positive results.15 This test was subsequently developed as Cologuard (Exact Sciences) in the USA.

In 2024, a next-generation multitarget stool DNA test was developed to improve the performance of CRC screening, primarily with regard to specificity.16 With the next-generation test, sensitivity was 93.9% (95% CI, 87.1%–97.7%) for CRC and 43.4% (95% CI, 41.3%–45.6%) for advanced precancerous lesions; specificity was 90.6% (95% CI, 90.1%–91.0%) for advanced neoplasia and 92.7% (95% CI, 92.2%–93.1%) for non-neoplastic findings or negative colonoscopy. With the FIT, sensitivity was 67.3% (95% CI, 57.1%–76.5%) for CRC and 23.3% (95% CI, 21.5%–25.2%) for advanced precancerous lesions; specificity was 94.8% (95% CI, 94.4%–95.1%) for advanced neoplasia and 95.7% (95% CI, 95.3%–96.1%) for non-neoplastic findings or negative colonoscopy. Compared with FIT, the next-generation test had significantly superior sensitivity for CRC and advanced precancerous lesions but still had lower specificity for advanced neoplasia.

Table 1 summarizes the comparative performance of multitarget stool DNA tests and next-generation assays versus FIT for CRC screening.15,16 For CRC of any stage, multitarget stool DNA tests demonstrated higher sensitivity (92.3% and 93.3%) than FIT (73.8% and 67.3%). Sensitivity remained similarly high in stage I–III CRC (93.3% and 92.7% for stool DNA versus 73.3% and 64.6% for FIT), indicating that both stool DNA tests are effective in detecting early-stage CRCs. For advanced neoplasia, however, sensitivity was lower across all tests, with multitarget DNA and next-generation assays showing modest performance (42.4% and 43.4%, respectively) but still superior to FIT (23.8% and 23.3%). FIT outperformed both multitarget and next-generation stool DNA tests in terms of specificity. Among individuals without advanced neoplasia, FIT showed high specificity (94.9% and 95.7%) compared with multitarget DNA and next-generation assays (86.6% and 92.7%). In patients with negative colonoscopy results, FIT again had the highest specificity (96.4% and 96.0%), whereas the multitarget stool DNA test and next-generation assays showed slightly lower values (89.8%–93.4%). Although multitarget and next-generation stool DNA tests provide superior sensitivity for CRC detection, FIT offers better specificity, potentially reducing unnecessary follow-up procedures. The choice of screening modality may depend on population risk, resource availability, and patient preferences.

Table 1.

Sensitivity and Specificity of multitarget stool DNA test and next-generation assay compared with fecal immunochemical test for colorectal cancer screening

	Multitarget stool DNA test15	FIT15	Next-generation assay16	FIT16
Sensitivity
Colorectal cancer
Any stage	92.3 (83.0–97.5)	73.8 (61.5–84.0)	93.3 (87.1–97.7)	67.3 (57.1–76.5)
Stage I–III	93.3 (83.8–98.2)	73.3 (60.3–83.9)	92.7 (84.8–97.3)	64.6 (53.3–74.9)
Advanced neoplasia	42.4 (38.9–46.0)	23.8 (20.8–27.0)	43.4 (39.3–47.6)	23.3 (21.5–25.2)
Specificity
Non-neoplastic findings or negative colonoscopy	86.6 (85.9–87.2)	94.9 (94.4–95.3)	92.7 (92.2–93.1)	95.7 (95.3–96.1)
Negative colonoscopy	89.8 (88.9–90.7)	96.4 (95.8–96.9)	93.4 (92.8–93.9)	96.0 (95.5–96.4)

Values are presented as percentages (95% confidence interval).

FIT, fecal immunochemical test.

In a Markov model evaluating the comparative effectiveness and cost-effectiveness of CRC screening strategies, both annual FIT and colonoscopy every 10 years provided greater effectiveness at a lower cost compared with multitarget stool DNA testing every 3 years.17 Although the multitarget stool DNA test demonstrated comparable effectiveness to other strategies, it was associated with substantially higher costs. These findings highlight the need for cost-effective alternative stool DNA-based screening methods.

STOOL DNA-BASED METHYLATION TEST

Hypermethylation of CpG islands in gene promoter regions is a common epigenetic alteration in human carcinogenesis.18 DNA methylation biomarkers are stable across various specimen types—including stool, blood, and tissue—and offer high diagnostic sensitivity.18 As such, the stool DNA-based methylation test may enhance the detection of CRC.19

In a case-control study of 585 patients (245 had CRC, 44 had adenomatous polyps, and 245 had negative colonoscopy results), the stool DNA-based methylation test demonstrated an overall sensitivity of 90.2% with an area under the curve (AUC) of 0.902 and a specificity of 90.2% in detecting CRC.20 Sensitivity for detecting early-stage (0–II) CRCs was 89.1%.20 This test also detected 66.7% and 24.4% of advanced and non-advanced adenomas, respectively. The stool DNA-based methylation test was validated in a multicenter prospective study in Korea.21 Of the 1,124 asymptomatic high-risk patients, 20 had CRC, 73 had advanced adenomas ≥1.0 cm, 469 had non-advanced adenomas <1.0 cm, 178 had non-neoplastic polyps, and 384 had negative colonoscopy results. This test had a sensitivity and specificity of 95.0% and 81.5%, respectively, for detecting CRC, whereas the sensitivity for detecting advanced adenomas and CRC was 58.1%.21 This study demonstrated that the stool-based DNA methylation test attained a high sensitivity for CRC detection in an asymptomatic high-risk population.

Stool DNA-based methylation tests and multitarget stool DNA tests differ in several key aspects (Table 2).15,20 The methylation test uses a single DNA methylation marker, providing greater molecular stability and enabling processing within 4 weeks. In contrast, the multitarget stool DNA test combines multiple DNA targets with FIT and requires processing within 3 days. In terms of diagnostic performance, both tests demonstrate high sensitivity (90%–95% for methylation tests and 94% for multitarget DNA tests) and comparable specificity (88%–91% versus 93%, respectively). However, the methylation test is significantly less expensive (approximately 90 US dollars [USD] versus 650 USD) and technically simpler, requiring only 1–2 g of stool compared with a full stool sample for the multitarget test. Therefore, methylation tests are easier to handle, show better patient compliance, and are considered more suitable for organized population-based screening programs because of their simplified logistics and cost-effectiveness. In contrast, the multitarget stool DNA test, despite its high diagnostic performance, poses challenges in terms of complexity, cost, and feasibility of large-scale implementation.

Table 2.

Comparison of stool DNA-based methylation test versus multitarget stool DNA

Category	Stool DNA-based methylation test20	Multitarget stool DNA test15
Marker	Single methylation marker	Multitarget DNA+FIT
Stability of marker	More stable (processed within 4 weeks)	Less table (processed within 3 days)
Clinical performance
Sensitivity (%)	90–95	94
Specificity (%)	88–91	93
Cost (USD)	Low (~90)	High (650)
Tool complexity	Simple	More complex
Sample volume	1-2g of stool	Whole stool
Sample handling	Easier	More stringent
Patient compliance	Good	Moderate
Suitability for organized screening	More suitable	More limited

FIT, fecal immunochemical test; USD, United States dollar.

EMERGING NON-INVASIVE SCREENING TESTS

Liquid biopsy

Liquid biopsy refers to a blood-based testing modality designed to detect tumor-related components, including circulating tumor DNA, tumor cells, and extracellular vesicles.22 Among these, circulating tumor DNA derived from malignant cells and cell-free DNA (cfDNA) originating from both normal and cancerous tissues serve as primary targets for CRC detection. For coverage eligibility, the Centers for Medicare & Medicaid Services stipulates that blood-based CRC screening tests must demonstrate a sensitivity of at least 74% and a specificity of at least 90%. Table 3 presents a comparative analysis of the two FDA-approved blood-based tests for CRC screening: EpiproColon (Epigenomics AG), which detects methylated Septin 9 (SEPT9) DNA,23 and Shield (Guardant Health), a next-generation cfDNA test.24

Table 3.

Comparison of liquid biopsy tests

Category	EpiproColon	Shield (Guardant Health)
FDA approval	2016	2024
Marker	mSEPT9 (DNA methylation)	DNA alternation, methylation, fragmentation
Method	PCR based analysis of tumor cfDNA	Analysis of cfDNA
Sample volume	3.5 mL of plasma	2–8 mL of plasma
Sensitivity (%)	~70	83.1 (95% CI, 72.2–90.3)
Specificity (%)	~85	89.6 (95% CI, 88.8–90.3)
Medicare coverage	No	Yes
Out-of-pocket cost (USD)	192	895

FDA, Food and Drug Administration; PCR, polymerase chain reaction; cfDNA, cell-free DNA; USD, United States dollar.

The first FDA-approved blood-based CRC screening test (EpiproColon) detects methylated SEPT9 DNA, a validated epigenetic biomarker associated with CRC.23 A prospective study enrolled 7,941 individuals, and results from 53 CRC cases and 1,457 individuals without CRC yielded a standardized sensitivity of 48.2% (95% CI, 32.4%–63.6%; crude rate, 50.9%); for CRC stages I–IV, values were 35.0%, 63.0%, 46.0%, and 77.4%, respectively.23 Specificity was 91.5% (95% CI, 89.7%–93.1%; crude rate, 91.4%). Its performance does not yet meet the coverage thresholds (≥74% sensitivity and ≥90% specificity) set by the Centers for Medicare & Medicaid Services for blood-based CRC screening tests.

Recently, a blood-based cfDNA test, Shield, was evaluated in a large prospective study involving 10,258 participants, of whom 7,861 were included in the final analysis.24 This test demonstrated a sensitivity of 83.1% (95% CI, 72.2%–90.3%) for the detection of CRC and 87.5% (95% CI, 75.3%–94.1%) for stage I–III CRC. However, the sensitivity for detecting advanced precancerous lesions was relatively low at 13.2% (95% CI, 11.3%–15.3%). Among individuals without any advanced colorectal neoplasia on colonoscopy, 89.6% had a negative test result, yielding a specificity of 89.6% (95% CI, 88.8%–90.3%) for any advanced neoplasia. Specificity for those with negative colonoscopy findings was 89.9% (95% CI, 89.0%–90.7%).

In a Markov model analysis comparing the effectiveness and cost-effectiveness of liquid biopsy, FIT, multitarget stool DNA test, and colonoscopy, liquid biopsy reduced CRC incidence by 40% and CRC mortality by 52% compared with no screening.25 However, these reductions were less profound than the 68%–79% and 73%–81%, respectively, achieved with multitarget stool DNA every 3 years, annual FIT, or colonoscopy every 10 years.25 Assuming the same cost as multitarget stool DNA, FIT, colonoscopy, and multitarget stool DNA were less costly and more effective than liquid biopsy. Therefore, traditional CRC screening methods perform better than liquid biopsies.

MicroRNA

MicroRNAs (miRNAs) are short, non-coding RNA segments that can be aberrantly expressed by colorectal neoplasms and detected in a variety of clinical samples, including serum, stool, and urine.26 While miRNAs were initially known for their effect on post-translational gene expression, recent studies have shown them to be promising biomarkers for the detection of CRC owing to their molecular stability.26 A good example of this is a cross-sectional study, in which miRNA profiles were investigated in fecal samples from an Italian and a Czech cohort.27 A predictive miRNA signature for CRC detection was defined by a machine learning strategy and tested in additional fecal samples from 141 patients with CRC and 80 healthy volunteers.27 A 5-miRNA signature, including miR-149-3p, miR-607-5p, miR-1246, miR-4488, and miR-6777-5p, distinguished patients from control individuals (AUC, 0.86; 95% CI, 0.79-0.94) and was validated in an independent cohort (AUC, 0.96; 95% CI, 0.92–1.00). The signature classified control individuals from patients with low-/high-stage tumors and advanced adenomas (AUC, 0.82; 95% CI, 0.71–0.97). The tissue miRNA profiles mirrored those of stool samples, and the fecal profiles of different gastrointestinal diseases highlighted miRNAs that were specifically dysregulated in CRC.

Microbiome test

Recent evidence indicates that alterations in the gut microbiome are associated with the development of CRC. Changes in microbial composition have been implicated as a potentially important etiological factor in both the initiation and progression of CRC.28 Metagenomic analyses enable the comparison of fecal microbiota between patients with CRC and healthy individuals. Accordingly, stool-based microbiome profiles may serve as potential biomarkers for CRC when analyzed using quantitative polymerase chain reaction. A good example of this is a case-control study of 1,012 patients by Liang et al.29 Metagenomic analysis identified that m3 from a Lachnoclostridium sp., Fusobacterium nucleatum, and Clostridium hathewayi were significantly enriched in colorectal neoplasia. Fecal m3 and F. nucleatum significantly increased from normal to adenoma to CRC in 698 participants, which was validated in 313 participants. At 78.5% specificity, m3 and F. nucleatum showed sensitivities of 62.1% and 77.8% for CRC, respectively. The combination of m3 with F. nucleatum, C. hathewayi, Bacteroides clarus, and FIT performed best in diagnosing CRC (specificity, 81.2%; sensitivity, 93.8%). Therefore, m3 was suggested as a novel stool-based non-invasive biomarker for patients with CRC. However, the true performance of stool-based microbiome markers cannot be established from the case-control studies. Therefore, further validation of these microbiome markers is required in a large cohort representative of CRC screening populations.

Urine-based test

Recently, putative biomarkers of CRC were identified in urine in the form of volatile organic compounds, modified cytosine nucleosides, and polyamines. In a prospective study using urine samples from 342 participants (171 had CRC and 171 are healthy controls), a panel of 17 metabolites was identified as possible biomarker for CRC.30 Using only two of the selected metabolites, namely diacetylspermine and kynurenine, a predictor for detecting CRC was developed with an AUC of 0.864, a specificity of 80.0%, and a sensitivity of 80.0%. However, the mechanisms by which diacetylspermine and kynurenine act as CRC markers require further investigation. Further research is required to confirm the utility of these profiles for prospective population-based CRC screening.

PERSPECTIVE OF EMERGING TESTS

Despite the promising potential of emerging non-invasive screening tests, a substantial translational gap remains before these tools can be implemented in population-level screening programs. There is still a lack of standardized methodologies, the variability in analytic platforms, and the urgent need for harmonization across studies. Furthermore, large-scale, prospective, and multicenter validation studies are essential to establish the clinical utility, cost-effectiveness, and real-world feasibility of these emerging biomarkers. Artificial intelligence (AI) is a powerful tool for enhancing emerging screening tools. AI-based models applied to microbiome and metagenomic profiles have shown improved discriminatory capacity compared with conventional analytical approaches.31,32 AI-based analyses are increasingly being integrated with circulating DNA signatures, miRNAs, and multi-omics platforms, thereby enabling more precise risk stratification and potentially individualized screening algorithms. However, data remain insufficient for the standardization of analytical methods, interpretability of algorithms, and validation across diverse populations. Taken together, AI-driven methods represent a promising yet unproven frontier that may substantially reshape the future landscape of population-based CRC screening.

CONCLUSIONS

Currently, CRC screening is predominantly performed using the FIT, which has demonstrated efficacy in reducing CRC incidence and mortality through early detection. Stool DNA tests, such as the multitarget stool DNA test and stool DNA-based methylation test, have shown higher sensitivity than FIT for detecting both CRC and advanced adenomas, albeit with slightly lower specificity and higher costs. Emerging non-invasive CRC screening tests, such as liquid biopsy, miRNA, stool-based microbiome tests, and urine-based putative tests, are being developed to improve the accuracy, convenience, and participation rates in CRC screening. As CRC screening evolves, these novel approaches may enable more personalized, accessible, and effective screening strategies, ultimately improving patient adherence and reducing CRC-related mortality in the near future.