Early Detection of Colorectal Cancer Following Changes to Screening Guidelines: A Population-Based Analysis of Adults Aged 45 to 49.

Progress and Challenges in Colorectal Cancer Screening and Surveillance

Screening For Colorectal Cancer in the Age of Simulation Models: A Historical Lens

Screening colonoscopy: option or preference?

Quality Measures for Colonoscopy: A Critical Evaluation

3577 Background: Current development in stool- and cell-free DNA (cfDNA)-based technologies have demonstrated promising potentials in colorectal cancer (CRC) diagnosis. However, early detection of CRC and advanced adenoma (AA) remains challenging. Also, better predicting the recurrence risk following initial treatment serves as an important factor influencing survival of CRC patients. Micronuclei (MN) are extranuclear bodies containing chromatin segments resulting from errors in DNA repair. Elevated levels of MN+ erythrocytes have been studied in genotoxicity testing and cancer diagnosis. We have developed a method (WO2021/228246 A1) for purifying and sequencing micronuclei DNA (MN-DNA) in erythrocytes from peripheral blood. By comparing MN-DNA from healthy donors (HDs) and CRC patients, we identified significant changes in read densities at specific genomic locations in patients, which were termed as tumor-associated MN-DNA (taMN-DNA) signatures. Here, we explored the potential of MN-DNA for early detection or recurrence risk prediction of CRC patients. Methods: Peripheral blood (1-2ml) was obtained from a training cohort of 1165 individuals, a validation cohort of 290 individuals, and a test cohort of 363 individuals. MN-DNA was isolated and sequenced from erythrocytes. Predictive models were developed using distinctive taMN-DNA features identified by genome-wide analysis to differentiate between HD and AA or CRC. A clinical trial comparing MN-DNA with an approved multitarget stool DNA test (sDNA-FIT) was also conducted on 60 individuals (42 HDs, 6 AAs, and 12 CRCs). In addition, we conducted a retrospective study on CRC patients after postoperative treatment for evaluating the potential of MN-DNA in predicting CRC recurrence risk, with 28 non-recurrent after initial surgery and treatment and 6 relapsed patients enrolled. Results: The predictive CRC model built on taMN-DNA features achieved an AUC of 97.93%, with 88.61% sensitivity at 95.05% specificity, especially 89.58% sensitivity for early-stage (stage I-II) CRC in the test cohort. The detection of AA achieved an AUC of 93.01%, with 68.29% sensitivity at 92.48% specificity in the test cohort. Comparing MN-DNA to sDNA-FIT showed superior overall sensitivity (83.33% vs. 61.11%), AA sensitivity (83.33% vs. 16.66%), with comparable specificity (85.71% vs. 88.10%). Finally, 92.86% patients who had no recurrence were detected with negative prediction results, whereas 83.33% patients who had relapsed were detected positive prediction result. Conclusions: Our results demonstrate that MN-DNA within erythrocytes from 1-2ml peripheral blood enable accurate detection of AA and early-stage CRC as well as recurrence risk prediction. A larger clinical study (NCT05875584) is ongoing and will further validate the application of MN-DNA in CRC detection.

Advancing Health Equity for Medicaid Beneficiaries by Adding Colorectal Cancer Screening to the Centers for Medicare and Medicaid Services Adult Core Set

The American Cancer Society's (ACS) Colorectal Cancer Advisory Group held a workshop on new technologies for the early detection of colorectal cancer and adenomatous polyps as part of a regular review of ACS guidelines for colorectal cancer screening. The Advisory Group formally reviewed CT colonography, immunochemical fecal occult blood tests (FOBT), and stool screening using molecular markers, and also addressed other technologies including capsule video endoscopy. With the exception of immunochemical stool testing, the ACS has determined that at this time there is insufficient evidence to recommend these technologies for routine colorectal cancer screening. Based on recommendations of the Advisory Group, only a minor modification has been made to the ACS's Recommendations for Screening and Surveillance of the Early Detection of Adenomatous Polyps and Colorectal Cancer.

Patients with longstanding ulcerative colitis and colonic Crohn's disease have an increased risk of colorectal cancer (CRC) compared with the general population. This review assessed the evidence that endoscopic surveillance may prolong life by allowing earlier detection of CRC or its pre-cursor lesion, dysplasia, in patients with inflammatory bowel disease (IBD). To assess the effectiveness of cancer surveillance programs for diagnosis of IBD-associated colorectal cancer and in reducing the mortality rate from colorectal cancer in patients with IBD. We searched MEDLINE, EMBASE, CENTRAL and clinical clinicaltrials.gov from inception to 19 September 2016. We also searched conference abstracts and reference lists to identify additional studies. Potentially relevant articles were reviewed independently and unblinded by two authors to determine eligibility. Randomised controlled trials (RCTs) or observational studies (cohort or case control) assessing any form of endoscopic surveillance aimed at early detection of CRC were considered for inclusion. Studies had to have a no surveillance comparison group to be eligible for inclusion. Eligible studies were reviewed in duplicate and the results of the primary research trials were independently extracted by two authors. The primary outcome was detection of CRC. Secondary outcomes included death from CRC, time to cancer detection, time to death and adverse events. Deaths from CRC were derived from life tables, survival curves or where possible, by calculating life tables from the data provided. The presence of significant heterogeneity among studies was tested by the chi-square test. Because this is a relatively insensitive test, a P value of less than 0.1 was considered statistically significant. Provided statistical heterogeneity was not present, the fixed effects model was used for the pooling of data. The 2x2 tables were combined into a summary test statistic using the pooled odds ratio (OR) and 95% confidence intervals as described by Cochrane and Mantel and Haenszel. The methodological quality of the included studies was assessed using the Newcastle-Ottawa scale for non-randomised studies The overall quality of the evidence supporting the primary and selected secondary outcomes was assessed using the GRADE criteria. No RCTs were identified. Five observational studies (N = 7199) met the inclusion criteria. The studies scored well on the Newcastle-Ottawa scale, but due to the nature of observational studies, a high risk of bias was assigned to all the studies. Three studies were pooled to assess the rate of cancer detected in the surveillance group compared to the non-surveillance group. The studies found a significantly higher rate of cancer detection in the non surveillance group compared to the surveillance group. CRC was detected in 1.83% (53/2895) of patients in the surveillance group compared to 3.17% (135/4256) of patients in the non-surveillance group (OR 0.58, 95% CI 0.42 to 0.80; P = 0.0009). Four studies were pooled to assess the death rate associated with CRC in patients who underwent surveillance compared to patients who did not undergo surveillance. There was a significantly lower death rate associated with CRC in the surveillance group compared to the non-surveillance group. Eight per cent (15/176) of patients in the surveillance group died from CRC compared to 22% (79/354) of patients in the non-surveillance group (OR 0.36, 95% CI 0.19 to 0.69, P=0.002). Data were pooled from two studies to examine the rate of early stage versus late stage colorectal cancer (Duke stages A & B compared to Duke stages C & D) in patients who underwent surveillance compared to patients who do not undergo surveillance. A significantly higher rate of early stage CRC (Duke A & B) was detected in the surveillance group compared to the non-surveillance group. Sixteen per cent (17/110) of patients in the surveillance group had early stage CRC compared to 8% (9/117) of patients in the non-surveillance group (OR 5.40, 95% CI 1.51 to 19.30; P = 0.009). A higher rate of late stage CRC (Duke C & D) was observed in the non-surveillance group compared to the surveillance group. Nine per cent (10/110) of patients in the surveillance group had late stage CRC compared to 16% (19/117) of patients in the non-surveillance group (OR 0.46, 95% CI 0.08 to 2.51; P = 0.37). A GRADE analysis indicated that the quality of the data was very low for all of these outcomes. The included studies did not report on the other pre-specified outcomes including time to cancer detection, time to death and adverse events. The current data suggest that colonoscopic surveillance in IBD may reduce the development of both CRC and the rate of CRC-associated death through early detection, although the quality of the evidence is very low. The detection of earlier stage CRC in the surveillance group may explain some of the survival benefit observed. RCTs assessing the efficacy of endoscopic surveillance in people with IBD are unlikely to be undertaken due to ethical considerations.

Genome-Wide Identification and Validation of a Novel Methylation Biomarker, SDC2, for Blood-Based Detection of Colorectal Cancer

IA16: Current and emerging molecular diagnostic assays for colorectal cancer

Background: Current development in stool- and cell-free DNA (cfDNA)-based technologies have demonstrated promising potentials in colorectal cancer (CRC) diagnosis. However, the early detection of CRC and advanced adenomas (AA) remains a challenge. Micronuclei (MN) are hallmarks of genomic instabilities. Elevated levels of MN+ erythrocytes have been studied in genotoxicity testing and cancer diagnosis. We utilized previously developed methods to isolate and sequence MN-DNA from erythrocytes in 1-2 mL peripheral blood, revealing significant differences between patients and healthy donors (WO2021/228246 A1). Here, we established an independent cohort to further evaluate the value of MN-DNA in identifying CRC and AA. Methods: We enrolled 1251 samples with complete colonoscopy reports, comprising 360 CRC patients, 330 AA patients, and 561 non-cancer individuals. We collected 1-2 mL of peripheral blood from each enrolled individual, and the MN-DNA was isolated and performed on whole genome sequencing. We used 80% of these samples for the CRC- and AA-associated MN-DNA features identification and model development, while the remaining 20% were designated as the test set to evaluate the model performance and determine the cutoff. Based on the specificity and sensitivity in the test set, we launched a prospective observational case-control clinical trial (NCT05875584), which was used as an independent cohort to validate the model and to perform a comparative analysis with quantitative fecal immunochemical test (qFIT). A total of 598 samples were enrolled in this study (585 were available, including 299 HDs, 206 AAs, and 80 CRCs). Results: The predictive CRC model built on MN-DNA features achieved an AUC of 96% and the detection of AAachieved an AUC of 88% in the independent cohort. Comparing MN-DNA with qFIT, the overall sensitivity was generally consistent (90% vs. 88%), with MN-DNA achieving 91% sensitivity in early-stage (stage I) CRC, significantly higher than 68% in qFIT. Additionally, MN-DNA showed superior sensitivity in detecting AA (70% vs. 18%), with comparable specificity (90% vs. 96%). Conclusions: Our results demonstrate that MN-DNA within erythrocytes from 1-2ml peripheral blood enables accurate detection of AA and early-stage CRC. Research sponsor: Timing Biotech. Citation Format: Xingyun Yao, Haobo Sun, Yurong Jiao, Chengcheng Liu, Xiangxing Kong, Honghao Liang, Fei Meng, Jun Li, Kefeng Ding, Xiaofei Gao. Early detection of colorectal cancer using micronuclei DNA [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B020.

Background: Current development in stool- and cell-free DNA (cfDNA)-based technologies have demonstrated promising potentials in colorectal cancer (CRC) diagnosis. However, early detection of CRC and advanced adenoma (AA) remains challenging. Micronuclei (MN) are extranuclear bodies containing chromatin segments resulting from errors in DNA repair. Elevated levels of MN+ erythrocytes have been studied in genotoxicity testing and cancer diagnosis. We further performed whole-genome sequencing on purified and isolated micronuclei DNA (MN-DNA) from erythrocytes in peripheral blood using the approach (WO2021/228246 A1) we previously developed. By comparing MN-DNA from colorectal cancer (CRC) patients and healthy individuals, we identified a series of tumor-associated MN-DNA features (taMN- DNA) with significant differences in read counts and developed a classification model. Here, we established an independent cohort to clinically validate the CRC model and explore its application in early cancer diagnosis. Methods: We launched a prospective observational case- control clinical trial (NCT05875584), which was used as an independent cohort to validate taMN-DNA features in CRC and to perform a comparative analysis with quantitative fecal immunochemical test (qFIT). A total of 598 samples were enrolled in this study (585 was available, including 299 HDs, 206 AAs, and 80 CRCs). We gathered peripheral blood (1-2ml) from a training cohort of 1226 individuals, a test cohort of 309 individuals and this independent cohort of 598 individuals for the MN-DNA isolation from erythrocytes and whole-genome sequencing. Predictive models were developed using distinctive taMN-DNA features identified by genome-wide analysis from training cohort to differentiate between HD and AA or CRC. Results: The predictive CRC model built on taMN-DNA features achieved an AUC of 93% and the detection of AA achieved an AUC of 82% in this clinical validation cohort. Comparing MN-DNA with qFIT, the overall sensitivity was generally consistent (91.3% vs. 87.5%), with MN-DNA achieving 86.4% sensitivity in early-stage (stage I) CRC, significantly higher than 68.2% in qFIT. Additionally, MN-DNA showed superior sensitivity in detecting AA (71.4% vs. 18.4%), with comparable specificity (90.3% vs. 96.3%). Conclusions: Our results demonstrate that MN-DNA within erythrocytes from 1-2ml peripheral blood enable accurate detection of AA and early-stage CRC. Research sponsor: Timing Biotech. Citation Format: Yurong Jiao, Xingyun Yao, Haobo Sun, Chengcheng Liu, Xiangxing Kong, Honghao Liang, Fei Meng, Jun Li, Kefeng Ding, Xiaofei Gao. Evaluating the potential of micronuclei DNA from erythrocytes for early detection of colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A045.

Optimizing Colorectal Cancer Screening by Getting FIT Right

Early detection and treatment of colorectal adenomatous polyps (AP) and colorectal cancer (CRC) is associated with decreased mortality for CRC. However, accurate, non-invasive and compliant tests to screen for AP and early stages of CRC are not yet available. A blood-based screening test is highly attractive due to limited invasiveness and high acceptance rate among patients. To demonstrate whether gene expression signatures in the peripheral blood mononuclear cells (PBMC) were able to detect the presence of AP and early stages CRC. A total of 85 PBMC samples derived from colonoscopy-verified subjects without lesion (controls) (n = 41), with AP (n = 21) or with CRC (n = 23) were used as training sets. A 42-gene panel for CRC and AP discrimination, including genes identified by Digital Gene Expression-tag profiling of PBMC, and genes previously characterised and reported in the literature, was validated on the training set by qPCR. Logistic regression analysis followed by bootstrap validation determined CRC- and AP-specific classifiers, which discriminate patients with CRC and AP from controls. The CRC and AP classifiers were able to detect CRC with a sensitivity of 78% and AP with a sensitivity of 46% respectively. Both classifiers had a specificity of 92% with very low false-positive detection when applied on subjects with inflammatory bowel disease (n = 23) or tumours other than CRC (n = 14). This pilot study demonstrates the potential of developing a minimally invasive, accurate test to screen patients at average risk for colorectal cancer, based on gene expression analysis of peripheral blood mononuclear cells obtained from a simple blood sample.

Colorectal cancer (CRC) screening has come of age in Canada, with every province now having a screening program either implemented or well underway. These programs are based on the detection of fecal occult blood, with positive results triggering colonoscopy for definitive diagnosis. This approach is supported by high-level evidence demonstrating a mortality benefit for individuals screened in this manner. Fecal occult blood testing (FOBT) uses indirect methods to test for
\nthe presence of hemoglobin, which can be affected by chemicals, such as vitamin C, or heme from other sources such as red meat. In contrast, fecal immunochemical tests (FIT) use an antibody to detect human globin directly. These assays may offer advantages of greater specificity
\nand sensitivity, and improved adherence. Most FITs produce a visual colour change on a strip to indicate a positive result, but some are analyzed using automated systems in a laboratory to provide a quantitative result.