Non-advanced Adenomas Research Articles

Evaluating the use of environmental and polygenic risk scores to inform colorectal cancer risk-based surveillance intervals

Objective: U.S. Multi-Society Task Force colonoscopy surveillance intervals are based solely on adenoma characteristics, without accounting for other risk factors. We investigated whether a risk model including demographic, environmental and genetic risk factors could individualize surveillance intervals under an “equal management of equal risks” framework. Methods: Using 14,069 individuals from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial who had a diagnostic colonoscopy following an abnormal flexible sigmoidoscopy, we modeled the risk of colorectal cancer (CRC), considering the diagnostic colonoscopy finding, baseline risk factors (e.g., age and sex), 19 lifestyle and environmental risk factors, and a polygenic risk score (PRS) for CRC. Ten-year absolute cancer risks for each diagnostic colonoscopy finding [advanced adenoma (N=2446), ≥3 non-advanced adenomas (N=483), 1-2 non-advanced adenomas (N=4400) and no adenoma (N=7183)] were used as implicit risk thresholds for recommended surveillance intervals. Results: The area-under-the-curve (AUC) for the model including colonoscopy findings, baseline characteristics, and PRS was 0.658. Applying the “equal management of equal risks” framework, 28.2% of individuals with no adenoma and 42.7% of those with 1-2 non-advanced adenomas would be considered high risk and assigned a significantly shorter surveillance interval than currently recommended. Among individuals who developed cancer within 10 years, 52.4% with no adenoma and 48.3% with 1-2 non-advanced adenomas would have been considered high risk and assigned a shorter surveillance interval. Conclusion: Using a personalized risk-based model has the potential to identify individuals with no adenoma or 1-2 non-advanced adenomas, who are higher risk and may benefit from shorter surveillance intervals.

Early colorectal cancer diagnosis: A novel methylated stool DNA model enhanced the diagnostic efficiency.

Methylated stool DNA (sDNA) is a reliable noninvasive biomarker for early colorectal cancer (CRC) diagnosis. However, there are barely any diagnostic panels that can achieve both a sensitivity and specificity exceeding 90% simultaneously. We aimed to identify a novel methylated sDNA panel and model for the early diagnosis of CRC. We conducted methyl-CpG binding domain isolated genome sequencing (MiGS) on CpG island methylation phenotype (CIMP)-positive (n=3) and CIMP-negative CRC tissues (n=3) and their corresponding normal adjacent tissues. Subsequently, by utilizing both the aforementioned data and public datasets, we identified a set of promising methylated sDNA markers for CRC. Next, we validated 5 of these genes using pyrosequencing in CRC patients (n=31). Then, we developed a combined diagnostic model (CDM) for CRC based on the methylation status of PRDM12, FOXE1, and SDC2 by a Training cohort (n=231). Finally, the performance of CDM was evaluated in an independent multicenter Validation cohort (n=800). A total of 1062 participants were included in this study. The area under the curve (AUC) of the CDM was 0.979 (95% CI: 0.960-0.997), and the optimal sensitivity and specificity were 97.35% and 99.05%, respectively, in the training cohort (n=231). In the independent validation cohort (n=800), the AUC was 0.950 (95% CI: 0.927-0.973), along with the optimal sensitivity of 92.75% and specificity of 97.21%. When CRC and advanced adenoma (AAD) were used as diagnostic targets, the model AUC was 0.945 (95% CI: 0.922-0.969), with an optimal sensitivity of 91.89% and a specificity of 95.21%. The model sensitivity for nonadvanced adenoma patients was 68.66%. The sDNA diagnostic model CDM, developed from both CIMP-P and CIMP-N, exhibited exceptional performance in CRC and could serve as a potential alternative strategy for CRC screening.

Diagnostic Performance of Faecal Immunochemical Testing (FIT) in Patients with Lynch Syndrome Scheduled for Colonoscopic Surveillance

Background and Aims: Lynch syndrome (LS) carries a substantial lifetime risk of colorectal cancer which is currently mitigated by biennial colonoscopy surveillance. Paramount to the surveillance programme is the removal of adenomas before malignant transformation but there is an associated service burden and morbidity of repeated endoscopy. We investigated if faecal immunochemical testing (FIT) for faecal haemoglobin has the diagnostic performance to replace colonoscopy. Methods: In this retrospective cohort study, patients due to undergo planned surveillance for LS between November 2020 and April 2022 were sent two FIT kits prior to colonoscopy. Test diagnostic performance of colorectal cancer (CRC), advanced and non-advanced adenoma detection was calculated for single and double FIT strategies. A faecal-Hb of 10 µg Hb/g was considered positive. Results: In total, 78 patients, with 45 (57.7%) female, median age 52 years (IQR 41–63), completed at least one FIT and colonoscopy. The median time from FIT to colonoscopy was 47 days. A single FIT was positive in 7/30 cases of adenoma (2/3 advanced, 5/27 non-advanced). A total of 64 (82.1% of FIT1T returners) completed a second FIT. Using the greatest of the two FITs (FIT2TMAX) 8/26 (2/3 advanced, 4/23 non-advanced), patients with adenomas were identified. There were no cases of CRC. The sensitivity for adenoma detection was 23.3% and 23.1%, respectively. Conclusions: In patients with LS awaiting colonoscopy, FIT has a low sensitivity for detecting adenomas and advanced adenomas. This is not improved by the addition of a second FIT test.

Faecal Volatile Organic Compounds to Detect Colorectal Neoplasia in Lynch Syndrome-A Prospective Longitudinal Multicentre Study.

Non-invasive biomarkers may reduce post-colonoscopy colorectal cancer (CRC) rates and colonoscopy overuse in Lynch syndrome. Unlike faecal immunochemical test (FIT), faecal volatile organic compounds (VOCs) may accurately detect both advanced and non-advanced colorectal neoplasia. The aim of this study was to evaluate the potential of faecal VOCs-separately and with FIT-to guide optimal colonoscopy intervals in Lynch syndrome. Prospective longitudinal multicentre study in which individuals with Lynch syndrome collected faeces before and after high-quality surveillance colonoscopy. VOC-patterns were analysed using field asymmetric ion mobility spectrometry (FAIMS) and gas chromatography-ion mobility spectrometry (GC-IMS) followed by machine learning pipelines, and combined with FIT at 2.55 μg Hb/g faeces. Gas chromatography time-of-flight mass spectrometry analysed individual VOC abundance. Among 200 included individuals (57% female, median 51 years), 62 had relevant neoplasia at colonoscopy: 3 CRC, 6 advanced adenoma (AA), 3 advanced serrated lesion (ASL), and 50 non-advanced adenoma (NAA). Respective sensitivity and negative predictive value for CRC and AA (and also ASL in case of FAIMS) were 100% and 100% using FAIMS (54% specificity), and 89% and 99% using GC-IMS (58% specificity). Respective sensitivity and specificity for any relevant neoplasia were 88% and 44% (FAIMS) and 84% and 28% (GC-IMS); accuracy did not significantly improve upon VOC-FIT. VOC-patterns differed before and after polypectomy (AUC 0.70). NAA showed decreased faecal abundance of butanal, 2-oxohexane, dimethyldisulphide and dimethyltrisulphide. In Lynch syndrome, faecal VOCs may be a promising strategy for postponing colonoscopy and for follow-up after polypectomy. Our results serve as a stepping stone for large validation studies. NL8749.

Family History of Colorectal Cancer and the Risk of Colorectal Neoplasia: A Systematic Review and Meta-Analysis.

Although there is enough pooled evidence supporting the positive association between family history of colorectal cancer (CRC) in first-degree relatives (FDRs) and the risk of CRC, synthesized data on its association with the risk of other colorectal neoplasia are lacking. Therefore, we aimed to systematically assess this issue. We searched PubMed, Web of Science, and Embase from database inception through May 9, 2024, to identify observational studies investigating the association between family history of CRC in FDRs and the risk of colorectal neoplasia (excepting CRC). Adenoma, nonadvanced adenoma (NAA), advanced adenoma (AA), and advanced neoplasia (AN) were further chosen as main outcomes because of data availability. Random-effects model was used for data synthesis. Subgroup meta-analyses were performed to evaluate the robustness of results. Of 5,172 initial records screened, 75 studies (with 931,515 participants) were identified for analysis. Family history of CRC in FDRs was associated with increased risk of adenoma (pooled odds ratio [OR] 1.67, 95% confidence interval [CI] 1.46-1.91), NAA (pooled OR 1.35, 95% CI 1.21-1.51), AA (pooled OR 1.66, 95% CI 1.46-1.88), and AN (pooled OR 1.58, 95% CI 1.44-1.73). The positive associations persisted in all examined subgroups. The risk of adenoma (pooled OR 4.18, 95% CI 1.76-9.91), AA (pooled OR 2.42, 95% CI 1.72-3.40), and AN (pooled OR 2.00, 95% CI 1.68-2.38) was more evident among individuals with 2 or more affected FDRs. Family history of CRC is associated with increased risk of adenoma, NAA, AA, and AN totally, and in all available subgroups. The findings further strengthen the necessity and importance of an intensified screening strategy for individuals with a positive family history of CRC, which is very useful for related health resource allocation and policymaking.

Overweight and obesity are associated with colorectal neoplasia in an Australian outpatient population.

Colorectal cancer is a major cause of cancer-related deaths within the Australian population. Colonoscopy and polypectomy represent effective forms of prevention. Factors such as diabetes, hypertension and dyslipidaemia have been linked to adenoma development across a range of ethnicities, however there are limited data from the Australian population. This study investigates established and potential risk factors for early colorectal neoplasia in an Australian population. This was a prospective, observational case-control study in subjects aged 20-85 years, referred for outpatient colonoscopy. Clinical, anthropometric, and biochemical variables were collected at baseline. Polyps were classified as conventional adenomas or sessile serrated lesions, and correlated with clinical and biochemical variables. The study included 357 subjects, median age 55 years (IQR: 43.0-64.0), and 52.9% were female. 41.7% had metabolic syndrome. Multiple positive associations were observed in those over 40 years and with a BMI ≥ 25, including any polyp (aOR: 2.26; 95%CI: 1.22-4.18); adenoma (aOR: 2.64; 95%CI: 1.31-5.31); and, non-advanced adenoma (aOR: 2.66; 95%CI: 1.25-5.68). Our study demonstrates that elevated BMI is an independent risk factor for colorectal neoplasia in Australians undergoing colonoscopy. Further efforts should be focused on both diet and weight optimization in the general population given these findings and the recent national statistics indicating that almost two-thirds of the population are either overweight or obese.

S390 Implementation of Colonoscopy Surveillance Guidelines for Non-Advanced Adenomas: Room for Improvement

S390 Implementation of Colonoscopy Surveillance Guidelines for Non-Advanced Adenomas: Room for Improvement

Hyperspectral imaging facilitating resect-and-discard strategy through artificial intelligence-assisted diagnosis of colorectal polyps: A pilot study.

The resect-and-discard strategy for colorectal polyps based on accurate optical diagnosis remains challenges. Our aim was to investigate the feasibility of hyperspectral imaging (HSI) for identifying colorectal polyp properties and diagnosis of colorectal cancer in fresh tissues during colonoscopy. 144,900 two dimensional images generated from 161 hyperspectral images of colorectal polyp tissues were prospectively obtained from patients undergoing colonoscopy. A residual neural network model was trained with transfer learning to automatically differentiate colorectal polyps, validated by histopathologic diagnosis. The diagnostic performances of the HSI-AI model and endoscopists were calculated respectively, and the auxiliary efficiency of the model was evaluated after a 2-week interval. Quantitative HSI revealed histological differences in colorectal polyps. The HSI-AI model showed considerable efficacy in differentiating nonneoplastic polyps, non-advanced adenomas, and advanced neoplasia invitro, with sensitivities of 96.0%, 94.0%, and 99.0% and specificities of 99.0%, 99.0%, and 96.5%, respectively. With the assistance of the model, the median negative predictive value of neoplastic polyps increased from 50.0% to 88.2% (p = 0.013) in novices. This study demonstrated the feasibility of using HSI as a diagnostic tool to differentiate neoplastic colorectal polyps invitro and the potential of AI-assisted diagnosis synchronized with colonoscopy. The tool may improve the diagnostic performance of novices and facilitate the application of resect-and-discard strategy to decrease the cost.

Fitting a progressive three-state colorectal cancer model to interval-censored surveillance data under outcome-dependent sampling using a weighted likelihood approach.

To optimize colorectal cancer (CRC) surveillance, accurate information on the risk of developing CRC from premalignant lesions is essential. However, directly observing this risk is challenging since precursor lesions, i.e., advanced adenomas (AAs), are removed upon detection. Statistical methods for multistate models can estimate risks, but estimation is challenging due to low CRC incidence. We propose an outcome-dependent sampling (ODS) design for this problem in which we oversample CRCs. More specifically, we propose a three-state model for jointly estimating the time distributions from baseline colonoscopy to AA and from AA onset to CRC accounting for the ODS design using a weighted likelihood approach. We applied the methodology to a sample from a Norwegian adenoma cohort (1993-2007), comprising 1, 495 individuals (median follow-up 6.8 years [IQR: 1.1 - 12.8 years]) of whom 648 did and 847 did not develop CRC. We observed a 5-year AA risk of 13% and 34% for individuals having non-advanced adenoma (NAA) and AA removed at baseline colonoscopy, respectively. Upon AA development, the subsequent risk to develop CRC in 5 years was 17% and age-dependent. These estimates provide a basis for optimizing surveillance intensity and determining the optimal trade-off between CRC prevention, costs, and use of colonoscopy resources.

A novel index combining fecal immunochemical test, DNA test, and age improves detection of advanced colorectal adenoma.

Although the fecal immunochemical test for hemoglobin (FIT) is a widely used screening test for colorectal cancer, it is not sensitive enough to detect advanced colorectal adenoma. To address this issue, we performed this study to investigate whether combining the FIT and fecal DNA testing of methylated somatostatin (SST) could improve diagnostic performance for advanced colorectal adenoma. We collected feces from 79 healthy subjects with negative results on colonoscopy, 43 patients with non-advanced colorectal adenoma, 117 patients with advanced colorectal adenoma, and 126 patients with colorectal cancer. After fecal DNA was incubated with methylation-sensitive restriction enzymes, SST methylation levels were measured by droplet digital PCR. Using logistic multivariate analysis, we established a prediction formula for detecting colorectal neoplasia and named it the FAMS (FIT, age, methylated SST) index. The diagnostic performance of a single use of FIT for advanced colorectal adenoma showed a sensitivity of 29.1% (34/117) and specificity of 89.3% (109/122). In contrast, the FAMS index showed a sensitivity of 56.4% (66/117) at a similar specificity point of 91.0% (111/122). Furthermore, even at the higher specificity point of 94.3% (115/122), the sensitivity was still higher than that of FIT, reaching 42.7% (50/117). As the FAMS index showed better diagnostic performance for advanced colorectal adenoma than a single use of FIT, the FAMS index could be a promising tool for detecting advanced colorectal adenoma.

Fecal Immunochemical Test to Detect Colorectal Neoplasia in Lynch Syndrome: A Prospective Multicenter Study.

Colonoscopy surveillance for Lynch syndrome is burdensome and postcolonoscopy colorectal cancers (CRCs) still occur. The noninvasive fecal immunochemical test (FIT) might guide optimal colonoscopy intervals. Prospective, multicenter observational study in which individuals with Lynch syndrome performed a quantitative FIT before high-quality surveillance colonoscopy. Diagnostic performance of FIT at various thresholds ≤20 μg Hb/g feces was assessed for relevant neoplasia, including advanced neoplasia (CRC, advanced adenomas [AAs] and advanced serrated lesions [ASLs]) and non-advanced adenomas (NAAs). Of the 217 included individuals (59% female, median age 51 years), 4 had CRC, 5 AA, 4 ASL, and 57 NAA as most relevant neoplasia. The lowest FIT positivity threshold (2.5 μg Hb/g feces, 14% positivity rate) maximized detection: 4/4 CRCs, 4/5 AA, 1/4 ASL, and 9/57 NAA were detected, resulting in a sensitivity and negative predictive value of, respectively, 89% and 99% for CRC plus AA, 69% and 97% for advanced neoplasia, and 26% and 72% for all relevant neoplasia (91% specificity for all groups). At equal sensitivity and negative predictive value, specificity for advanced neoplasia optimized to 94% at threshold 4.1 μg/g. Per 100 FITs at threshold 4.1 μg/g, 11 individuals would test positive and thus proceed to colonoscopy, 2 individuals with advanced neoplasia would be missed and 3 individuals would need colonoscopy to detect 1 advanced neoplasia. FIT at thresholds ≤4.1 μg Hb/g feces may be a promising strategy to postpone colonoscopy in approximately 9 of 10 individuals with Lynch syndrome. Large validation studies that also provide gene variant-specific outcomes should be prioritized.

Different modifiable risk factors for the development of non-advanced adenoma, advanced adenomatous lesion, and sessile serrated lesions, on screening colonoscopy

The development of premalignant colorectal polyps is significantly influenced by various lifestyle and modifiable risk factors. In our study, we used a large cohort of 9025 patients, who underwent screening colonoscopies at a university hospital, to assess the risk factors associated with the development of three different colorectal cancer precursor lesions: non-advanced adenomas (NAs), advanced adenomatous lesions (ADLs), and sessile serrated lesions (SSLs). Among the participants, 3641 had NAs, 836 had ADLs, and 533 had SSLs. We identified obesity, current smoking, and appendicular skeletal muscle mass as modifiable lifestyle risk factors that increase the development of NAs and ADLs (all P < 0.05). Furthermore, we found a positive correlation between the degree of obesity and an increased risk of developing NAs and ADLs (all P for trend < 0.001), while non-smoking was associated with a decreased risk (P for trend < 0.001 and 0.003, respectively). Smoking was the only modifiable risk factor for developing SSLs (adjusted odds ratio [aOR] 1.58; 95% confidence interval [CI] 1.20–2.07), and the risk was even higher in patients with metabolic syndrome (aOR 1.71; 95% CI 1.05–2.77). Addressing modifiable lifestyle factors such as smoking and obesity could play an important role in reducing the risk of both non-advanced and advanced adenomatous lesions. Smoking cessation is especially important as it is a significant modifiable risk factor for sessile serrated lesions.

Study on the application value of fecal SDC2 gene methylation detection in colorectal cancer screening of urban residents in Zengcheng District in Guangzhou City

Objective: To investigate the application value of fecal Syndecan-2 (SDC2) gene methylated SDC2 (mSDC2) detection in colorectal cancer (CRC) screening among urban residents in Guangzhou City. Methods: A cross-sectional study was conducted in Shitan Town, Zengcheng District, Guangzhou City from July to December 2022. A community-based screening program for CRC was conducted among residents aged 40-74 years old. mSDC2 detection was employed in the participants, and those with positive results should be recommended to receive colonoscopy examination. The positive rate of mSDC2 detection, colonoscopy compliance rate, detection rate of intestinal lesions and clinicopathological characteristics were observed. The relationship between cycle threshold (CT) value of mSDC2 and intestinal lesions was explored. Further, the cost-effectiveness of screening was evaluated. Results: A total of 8 189 fecal samples were collected from 8 877 participants with the recovery rate of 92.25%. 8 048 qualified samples were enrolled in this study, consisted of 3 182 males (39.54%) and 4 866 females (60.46%), with the average age of 56 years old (40-74 years). The positive rate of mSDC2 detection was 7.99% (643/8 048), and the compliance rate of colonoscopy was 73.10% (470/643). 20 cases (4.25%) of colorectal cancer, 109 cases (23.19%) of advanced adenoma, 145 cases (30.85%) of non-advanced adenoma, 79 cases (16.81%) of polyps were detected. The detection rate of intestinal lesions was 75.11% and indicated significant differences in gender and age. 20 CRCs included 15 of stage 0-I, 4 of stage Ⅱ-Ⅲ and 1 of unknown stage. The CT value of mSDC2 was negatively correlated with the proportion of advanced colorectal neoplasms (χ2=16.063, P<0.001). The total cost of the screening was 4.339 5 million yuan, the screening benefit was 28.506 2 million yuan, and the benefit-cost ratio was 6.57. Conclusion: The CRC screening strategy of fecal mSDC2 detection combined with colonoscopy has high colonoscopy compliance and detection rate of intestinal lesions, which is conducive to the detection of early CRCs, and has good cost-effectiveness. This study suggests that this method may be applied to the general CRC screening in China and contribute to the prevention of CRC. The CT value of mSDC2 may have a certain suggestion on the malignant degree of intestinal tumors.

Enhancing Colorectal Cancer Screening with Droplet Digital PCR Analysis of Fusobacterium nucleatum in Fecal Immunochemical Test Samples.

Fecal immunochemical test (FIT) followed by colonoscopy in positive cases is commonly used for population-based colorectal cancer screening. However, specificity of FIT for colorectal cancer is not ideal and has poor performance for advanced adenoma detection. Fecal Fusobacterium nucleatum (Fn) detection has been proposed as a potential noninvasive biomarker for colorectal cancer and advanced adenoma detection. We aimed to evaluate the diagnostic performance of Fn detection using droplet digital PCR (ddPCR) in FIT samples from individuals enrolled in a colorectal cancer screening program with colorectal adenoma or cancer. We evaluated Fn presence in DNA isolated from FIT leftover material of 300 participants in a colorectal cancer screening program using ddPCR. The Fn DNA amount was classified as Fn-low/negative and Fn-high, and the association with patients' clinicopathological features and accuracy measurements was calculated. Fn-high levels were more prevalent in FIT-positive (47.2%, n = 34 of 72) than FIT-negative samples (28.9%, n = 66 of 228; P < 0.04). Among FIT-positive samples, high Fn levels were significantly more frequent in patients with cancer (CA, n = 8) when compared to normal (NT, n = 16; P = 0.02), non-advanced adenomas (NAA, n = 36; P = 0.01), and advanced adenomas (AA, n = 12; P = 0.01). Performance analysis of Fn in FIT-positive samples for colorectal cancer detection yielded an AUC of 0.8203 [confidence interval (CI), 0.6464-0.9942], with high sensitivity (100%) and specificity of 50%. Concluding, we showed the feasibility of detecting Fn in FIT leftovers using the ultrasensitive ddPCR technique. Furthermore, we highlighted the potential use of Fn levels in fecal samples to ameliorate colorectal cancer detection. Prevention Relevance: Fusobacterium nucleatum detection by droplet digital PCR could prioritize the selection of fecal immunochemical test-positive individuals who might benefit the most from the colonoscopy procedure.

Developing an optimal stratification model for colorectal cancer screening and reducing racial disparities in multi-center population-based studies

BackgroundEarly detection of colorectal neoplasms can reduce the colorectal cancer (CRC) burden by timely intervention for high-risk individuals. However, effective risk prediction models are lacking for personalized CRC early screening in East Asian (EAS) population. We aimed to develop, validate, and optimize a comprehensive risk prediction model across all stages of the dynamic adenoma-carcinoma sequence in EAS population.MethodsTo develop precision risk-stratification and intervention strategies, we developed three trans-ancestry PRSs targeting colorectal neoplasms: (1) using 148 previously identified CRC risk loci (PRS148); (2) SNPs selection from large-scale meta-analysis data by clumping and thresholding (PRS183); (3) PRS-CSx, a Bayesian approach for genome-wide risk prediction (PRSGenomewide). Then, the performance of each PRS was assessed and validated in two independent cross-sectional screening sets, including 4600 patients with advanced colorectal neoplasm, 4495 patients with non-advanced adenoma, and 21,199 normal individuals from the ZJCRC (Zhejiang colorectal cancer set; EAS) and PLCO (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; European, EUR) studies. The optimal PRS was further incorporated with lifestyle factors to stratify individual risk and ultimately tested in the PLCO and UK Biobank prospective cohorts, totaling 350,013 participants.ResultsThree trans-ancestry PRSs achieved moderately improved predictive performance in EAS compared to EUR populations. Remarkably, the PRSs effectively facilitated a thorough risk assessment across all stages of the dynamic adenoma-carcinoma sequence. Among these models, PRS183 demonstrated the optimal discriminatory ability in both EAS and EUR validation datasets, particularly for individuals at risk of colorectal neoplasms. Using two large-scale and independent prospective cohorts, we further confirmed a significant dose–response effect of PRS183 on incident colorectal neoplasms. Incorporating PRS183 with lifestyle factors into a comprehensive strategy improves risk stratification and discriminatory accuracy compared to using PRS or lifestyle factors separately. This comprehensive risk-stratified model shows potential in addressing missed diagnoses in screening tests (best NPV = 0.93), while moderately reducing unnecessary screening (best PPV = 0.32).ConclusionsOur comprehensive risk-stratified model in population-based CRC screening trials represents a promising advancement in personalized risk assessment, facilitating tailored CRC screening in the EAS population. This approach enhances the transferability of PRSs across ancestries and thereby helps address health disparity.Graphical

A novel, noninvasive, multimodal screening test for the early detection of precancerous lesions and colorectal cancers using an artificial intelligence–based algorithm.

3627 Background: Colorectal cancer (CRC) ranks as the second leading cause of cancer-related mortality worldwide, and its incidence is increasing in younger populations. Detection of early-stage CRC and its precursor lesions, such as advanced adenomas (AA), is crucial for successful treatment and reduces CRC-related mortality. Although non-invasive methods for early detection are available and increase screening compliance, their performance with respect to detection of advanced adenomas and early-stage cancers is limited. Here, we describe a novel and non-invasive stool-based approach combining diagnostic biomarkers with an algorithm generated by machine learning/artificial intelligence (ML/AI) resulting in significantly improved diagnostic performance for the detection of not only CRC, but especially precancerous lesions like AA. Methods: Data were generated from a combined cohort of stool samples collected at 10 clinical sites in Europe (COLOFUTURE study) and 21 clinical sites in the US (eAArly DETECT study). The evaluable study cohort consists of 690 subjects, including 78 CRC, 146 AA, 147 with non-advanced adenoma (AD) and 319 normal colonoscopy negative control (NC) subjects (49% female, 51% male, average age 61.8 years). Results were compared with colonoscopy and pathology findings to determine sensitivity and specificity for detection of early-stage CRC and AA vs. AD and NC. Nucleic acids were extracted from stabilized stool samples using a silica bead-based extraction method. Expression of mRNA biomarkers was analyzed utilizing Real-Time PCR. Human hemoglobin was quantified using FIT. The Emerge Quantitative Evolution ML/AI platform was leveraged to develop classifiers capable of distinguishing CRC and AA from AD and NC. Results: Applying the combined approach of non-invasive diagnostic testing with an AI/ML generated algorithm, the sensitivity for detection of CRC overall was 92.3%. In addition, this method enabled AA detection with a sensitivity of 82.2%. Specificity turned out to be 90.1 % (AD+NC). Conclusions: This innovative, non-invasive, multimodal screening strategy based on self-collected stool samples which combines mRNA expression patterns and FIT analysis with an AI/ML-generated algorithm represents a substantial improvement in the effectiveness of non-invasive CRC screening. Such improvements in usability and performance leading to reliable detection of early-stage CRC and precursor lesions, such as advanced adenomas, are required for wide-spread availability and adaption of non-invasive screening tests to accepted clinically relevant usage and to prevent the development of CRC effectively.

Early-onset Colorectal Cancer Patients Do Not Require Shorter Intervals for Post-surgical Surveillance Colonoscopy

Early-onset colorectal cancer (EO-CRC), diagnosed before age 50, is rising in incidence worldwide. Although post-surgical colonoscopy surveillance strategies exist, appropriate intervals in EO-CRC remain elusive, as long-term surveillance outcomes remain scant. We sought to compare findings of surveillance colonoscopies of EO-CRC with patients with average onset colorectal cancer (AO-CRC) to help define surveillance outcomes in these groups. Single-institution retrospective chart review identified EO-CRC and AO-CRC patients with colonoscopy and no evidence of disease. Surveillance intervals and time to development of advanced neoplasia (CRC and advanced polyps [adenoma/sessile serrated]) were examined. For each group, 3 serial surveillance colonoscopies were evaluated. Statistical analyses were performed utilizing log-ranked Kaplan-Meier method and Cox proportional hazards. A total of 1259 patients with CRC were identified, with 612 and 647 patients in the EO-CRC and AO-CRC groups, respectively. Compared with patients with AO-CRC, patients with EO-CRC had a 29% decreased risk of developing advanced neoplasia from time of initial surgery to first surveillance colonoscopy (hazard ratio, 0.71; 95% confidence interval, 0.52-1.0). Average follow-up time from surgical resection to first surveillance colonoscopy was 12.6 months for both cohorts. Overall surveillance findings differed between cohorts (P= .003), and patients with EO-CRC were found to have less advanced neoplasia compared with their counterparts with AO-CRC (12.4% vs 16.0%, respectively). Subsequent colonoscopies found that, while patients with EO-CRC returned for follow-up surveillance colonoscopy earlier than patients with AO-CRC, the EO-CRC cohort did not have more advanced neoplasia nor non-advanced adenomas. Patients with EO-CRC do not have an increased risk of advanced neoplasia compared with patients with AO-CRC and therefore do not require more frequent colonoscopy surveillance than current guidelines recommend.

Abstract 1061: Diagnostic application of a novel blood CDH17 immunoassay in the detection of colorectal adenoma

Abstract Background: Colorectal cancer (CRC) is the most prevalent gastrointestinal (GI) cancer and contribute significantly to global cancer deaths. The mechanism of CRC development is a complex multistage process from hyperplastic lesions to the formation of adenomas, followed by the progression into malignancy. Hence, early detection during hyperplastic and adenomatous stages warrants new screening tests for effective interception of malignancy progression. Cadherin-17 (CDH17) is a biomarker characterized by its overexpression in several GI cancers, but restricted expression in intestinal mucosal epithelium of normal tissues. We have developed a blood immunoassay using a panel of RUO grade antibodies that unveiled CDH17 as a potential marker with high detection sensitivity and specificity for detecting adenomas. Our immunoassay is useful in identifying high-risk individuals with adenomas that may develop into CRC, which can significantly improve the diagnostic efficiency of colonoscopy that is currently lacking. Methods: The study recruited 66 patients (54 adenoma and 12 hyperplasia) and 39 normal samples (no abnormality by colonoscopy). CDH17 level in plasma samples were measured using the CDH17 immunoassay. Results: The novel CDH17 diagnostic assay showed an operating dynamic range from 90ng to 123pg. We observed a progressive and significant increase in the circulating CDH17 level from normal samples to the hyperplasia group, followed by the adenoma group (mean: 1.66ng/mL, 3.20ng/mL, 4.93ng/mL, respectively P&amp;lt;0.0001). The assay performance by ROC curve demonstrated an AUC of &amp;gt;0.9, with a sensitivity of 85% and specificity of 86%. NPV and PPV were 84% and 87%, respectively. The assay outperforms two market available FIT-DNA tests at predicting adenomas (Table. 1). Conclusion: The novel CDH17 immunoassay is potentially a powerful tool for the detection of aberrant plasma CDH17 expression, improving the surveillance and the detection of high-risk individuals for CRC. CDH17 immunoassay outperforms market availalble FIT-DNA tests at detecting hyperplasia and adenoma FIT-DNA test 1 FIT-DNA test 2 CDH17 blood immunoassay Age 40-74 Age 50-84 Age 45-93 Sensitivity (%) Advanced adenoma 63.5 42.4 85.0 Non-advanced adenoma (i.e Hyperplasia) Unavailable 17.2 58.3 Specificity (%) Normal control (no abnormality by colonoscopy) 87.1 89.8 86.1 NPV (%) Advanced adenoma Unavailable Unavailable 83.8 Non-advanced adenoma (i.e Hyperplasia) Unavailable Unavailable 86.1 PPV (%) Advanced adenoma Unavailable Unavailable 87.2 Non-advanced adenoma (i.e Hyperplasia) Unavailable Unavailable 58.3 Citation Format: Ng Lui, Felix Hon, Stella Sun, Pauline Leung, David Ho, John Moon Luk, Dominic Chi-Chung Foo. Diagnostic application of a novel blood CDH17 immunoassay in the detection of colorectal adenoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1061.

Next-Generation Multitarget Stool DNA Test for Colorectal Cancer Screening

BackgroundA next-generation multitarget stool DNA test, including assessments of DNA molecular markers and hemoglobin level, was developed to improve the performance of colorectal cancer screening, primarily with regard to specificity.MethodsIn a prospective study, we evaluated a next-generation multitarget stool DNA test in asymptomatic adults 40 years of age or older who were undergoing screening colonoscopy. The primary outcomes were sensitivity of the test for colorectal cancer and specificity for advanced neoplasia (colorectal cancer or advanced precancerous lesions). Advanced precancerous lesions included one or more adenomas or sessile serrated lesions measuring at least 1 cm in the longest dimension, lesions with villous histologic features, and high-grade dysplasia. Secondary objectives included the quantification of sensitivity for advanced precancerous lesions and specificity for nonneoplastic findings or negative colonoscopy and comparison of sensitivities for colorectal cancer and advanced precancerous lesions between the multitarget stool DNA test and a commercially available fecal immunochemical test (FIT).ResultsOf 20,176 participants, 98 had colorectal cancer, 2144 had advanced precancerous lesions, 6973 had nonadvanced adenomas, and 10,961 had nonneoplastic findings or negative colonoscopy. With the next-generation test, sensitivity for colorectal cancer was 93.9% (95% confidence interval [CI], 87.1 to 97.7), and specificity for advanced neoplasia was 90.6% (95% CI, 90.1 to 91.0). Sensitivity for advanced precancerous lesions was 43.4% (95% CI, 41.3 to 45.6), and specificity for nonneoplastic findings or negative colonoscopy was 92.7% (95% CI, 92.2 to 93.1). With the FIT, sensitivity was 67.3% (95% CI, 57.1 to 76.5) for colorectal cancer and 23.3% (95% CI, 21.5 to 25.2) for advanced precancerous lesions; specificity was 94.8% (95% CI, 94.4 to 95.1) for advanced neoplasia and 95.7% (95% CI, 95.3 to 96.1) for nonneoplastic findings or negative colonoscopy. As compared with FIT, the next-generation test had superior sensitivity for colorectal cancer (P<0.001) and for advanced precancerous lesions (P<0.001) but had lower specificity for advanced neoplasia (P<0.001). No adverse events occurred.ConclusionsThe next-generation multitarget stool DNA test showed higher sensitivity for colorectal cancer and advanced precancerous lesions than FIT but also showed lower specificity. (Funded by Exact Sciences; BLUE-C ClinicalTrials.gov number, NCT04144738.)

Downregulation of SMOC1 is associated with progression of colorectal traditional serrated adenomas

BackgroundAberrant DNA methylation is prevalent in colorectal serrated lesions. We previously reported that the CpG island of SMOC1 is frequently methylated in traditional serrated adenomas (TSAs) and colorectal cancers (CRCs) but is rarely methylated in sessile serrated lesions (SSLs). In the present study, we aimed to further characterize the expression of SMOC1 in early colorectal lesions.MethodsSMOC1 expression was analyzed immunohistochemically in a series of colorectal tumors (n = 199) and adjacent normal colonic tissues (n = 112).ResultsSMOC1 was abundantly expressed in normal colon and SSLs while it was significantly downregulated in TSAs, advanced adenomas and cancers. Mean immunohistochemistry scores were as follows: normal colon, 24.2; hyperplastic polyp (HP), 18.9; SSL, 23.8; SSL with dysplasia (SSLD)/SSL with early invasive cancer (EIC), 15.8; TSA, 5.4; TSA with high grade dysplasia (HGD)/EIC, 4.7; non-advanced adenoma, 21.4; advanced adenoma, 11.9; EIC, 10.9. Higher levels SMOC1 expression correlated positively with proximal colon locations and flat tumoral morphology, reflecting its abundant expression in SSLs. Among TSAs that contained both flat and protruding components, levels of SMOC1 expression were significantly lower in the protruding components.ConclusionOur results suggest that reduced expression of SMOC1 is associated with progression of TSAs and conventional adenomas and that SMOC1 expression may be a biomarker for diagnosis of serrated lesions and risk prediction in colorectal tumors.