Pioneering colorectal cancer screening: blood-based DNA tests as a global strategy for early detection – editorial

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Highlights Colorectal cancer (CRC) is a growing global concern necessitating effective screening. Current CRC screening methods face low participation rates, urging the need for more accessible options. Blood-based DNA tests offer high sensitivity and specificity, potentially enhancing CRC screening. With advantages like noninvasiveness and higher compliance rates, blood-based DNA tests may improve upon traditional methods. Overcoming implementation challenges like adherence and cost barriers is crucial for the widespread adoption of blood-based DNA tests in CRC prevention and management. Colorectal cancer (CRC) ranks third globally in cancer incidence, with 1.4 million new cases annually in 2012, causing 694 000 deaths1. In 2020, there were around 1.93 million new cases of CRC worldwide, causing about 0.94 million deaths. Predictions indicate a rise to 3.2 million new cases globally by 2040. China and the United States are anticipated to have the highest number of new cases over the next two decades, with significant increases expected in both countries by 20402. Screening for CRC in asymptomatic individuals reduces disease occurrence and related deaths, endorsed unanimously by major professional bodies like the U.S. Preventive Services Task Force (USPSTF), the U.S. Multisociety Task Force on Colorectal Cancer, and the American Cancer Society (ACS)3. Despite this, late-stage diagnoses are common (approximately 60%), underscoring the need for robust screening programs. Existing screening methods suffer from high costs and complex preparatory steps, resulting in low participation rates, thus indicating their inadequacy4,5. This highlights a gap between screening recommendations and effective implementation. CRC incidence and mortality have significantly decreased in recent decades, partly due to screening that detects precancerous lesions and early-stage CRC. Medical societies strongly recommend CRC screening for healthy adults. However, screening adoption remains low, falling below 50% in many countries, despite guidelines suggesting initiation between ages 45 and 50 and completion between ages 70 and 756. Current screening strategies include stool tests (e.g. fecal occult blood tests like FIT and multitarget stool DNA tests) and structural examinations (e.g. colonoscopy and sigmoidoscopy), which warrant their limitations in several aspects of their accuracy, complications, acceptance, and cost6,7. Although screening methods like sigmoidoscopy and colonoscopy offer acceptable sensitivity and specificity, the need of sedation, risk of bleeding, high cost, and discomfort during procedure contributes to poor patient adoption which demand the need of a minimally invasive technique for early screening. However, the existing noninvasive or minimally invasive methods like guaiac fecal occult blood test (FOBT), FIT, sDNA-FIT, CT Colonography, etc. offer poor sensitivity and specificity3,8. A blood-based test holds promise for enhancing screening compliance, early CRC detection, and reducing related mortality. In an average-risk population, this Circulating cell-free DNA (ccfDNA) blood test demonstrated 83% sensitivity for CRC, 90% specificity for advanced neoplasia, and 13% sensitivity for advanced precancerous lesions3,6. Its noninvasiveness and low risk make it an appealing option, potentially boosting participation rates with its simplicity and increased frequency of testing5. These tests are still under development but have shown success in detecting DNA mutations for personalized cancer treatments4,8. However, concerted efforts are needed to bridge the translational gap between recommended screening strategies and their widespread adoption to realize substantial reductions in CRC-related deaths. Importance of early detection CRC incidence rates are four times higher in countries with very high Human Development Index (HDI) compared to those with low HDI. While highly developed nations are seeing stable or decreasing rates of CRC, the opposite trend is observed in less developed countries due to greater exposure to risk factors2. Early detection of CRC significantly enhances survival, boasting a 91% 5-year survival rate for localized disease versus 14% for metastatic disease. However, despite the promising survival rates for early-stage cases, only 40% are diagnosed at this stage, highlighting a substantial detection gap3,4. Cancer is a leading global cause of death, with projections indicating a rise in incidence. Population growth will slow, but aging populations will increase cancer burdens. As societies develop, cancer types may shift. Developing an adaptable, cost-effective diagnostic tool for CRC is imperative to mitigate future burdens2,5. CRC stands as the sole cancer for which screening has demonstrated a reduction in mortality among both average-risk women and men9. Screening programs require multiple considerations for effectiveness, including test performance and participant adherence. Colonoscopy, while effective, may face challenges with real-world adherence. Blood-based tests offer an additional screening option, potentially improving participation and early detection rates3. Existing methods such as endoscopy, radiology, and carcinoembryonic antigen levels, fecal immunochemical test/ immunochemical fecal occult blood test (FIT/iFOBT) can detect CRC early and monitor disease progression during treatment. However, they lack the sensitivity and specificity needed for timely intervention, potentially causing treatment delays or overtreatment10. Nonspecific symptoms and patient reluctance delay CRC diagnosis, especially in the elderly. Early-stage diagnostic tests could improve outcomes by reducing resource burden and enabling timely interventions. Early diagnosis allows for curative treatment, and noninvasive tests enhance treatment efficacy. Population-based evidence can revolutionize CRC prevention and management, advancing early detection strategies11,12. The potential of blood-based DNA tests In studies led by Chung et al. and Bessa et al., the evaluation of blood-based tests for CRC detection yielded promising results. Chung et al.’s3 test, ‘Shield’, showed 83% sensitivity for CRC and 90% specificity for advanced neoplasia, meeting FDA criteria. However, sensitivity for advanced precancerous lesions was low at 13%. Bessa et al.’s6 test demonstrated a higher sensitivity of 93% for CRC detection, with a potential improvement to 23% for advanced precancerous lesions in exploratory analysis. Both studies confirm the clinical validity of blood-based tests, suggesting broader clinical applications. Their diverse populations and wide geographic coverage enhance their relevance. They offer a valuable supplementary option for CRC screening, potentially improving participation and early detection. However, assessing participant adherence and long-term outcomes remains crucial3,4,6. Understanding the concept of blood-based DNA tests ccfDNA has been found in human plasma and originates from various cell types10. CcfDNA concentration increases in conditions of cell lysis and turnover, including pregnancy, intensive exercise, inflammation, infection, autoimmune diseases, diabetes, or soft tissue injury either from direct secretion or as a byproduct of phagocytosis from macrophages or other scavenger cells. Circulating Tumor DNA (ctDNA) is a subset of ccfDNA and originates from cancer cells. Detection of tumorigenic features like hypermethylation, aberrant mutation, microsatellite alterations, and mitochondrial DNA in blood circulation in ctDNA makes it a cancer biomarker. The proportion of ctDNA in the bloodstream depends on the cancer stage and ranges from 0.01 to 0.0001 to more than 50% of the total5,10. Comparative analysis of Blood-Based DNA Tests and Traditional Colorectal Cancer Screening Methods have been elaborated in Table 1. Table 1 - Comparative analysis of blood-based DNA tests and traditional colorectal cancer screening methods. Test Strategy Guaiac FOBT FIT/iFOBT sDNA-FIT CT Colonography Sigmoidoscopy Colonoscopy ctDNA (Epi proColon) ctDNA (ECLIPSE Study) Approach/Assay Peroxidase reaction with heme in stool Antibody against globin moiety of heme Algorithm using results of testing for 7 DNA markers in occult blood CT scan of the colon requiring bowel preparation and oral contrast The flexible endoscope is used to evaluate the rectum and distal colon The flexible endoscope is used to evaluate the rectum and the entire colon Detects methylated Sept9 DNA in plasma derived from a whole blood sample Detection of cfDNA genomic alterations, aberrant methylation status, and fragmentomic patterns CRC Sensitivity 50–75% 74–81% 93% 86–100% 95% 95% 68% 83.1% (95% CI: 72.2–90.3) CRC Specificity 96–98% 93–94% 85% 75% 87% 86–89% 79% NR AN Sensitivity 7–21% 25–27% 47% 89% 95% 95% 22% 13.2% (95% CI: 11.3–15.3) AN Specificity 96–99% 95–96% 89% 94% 87% 86–89% 79% 89.6% (95% CI: 88.8–90.3) Positivity Rate 10.10% 6.40% 13.50% 13.40% 17.3–23.4% 35.30% NR NR Relative Impact on CRC Incidence 0 to 20% decrease 10% decrease NR NR 22% decrease 47–69% decrease NR NR Relative Impact on CRC Mortality 9–22% decrease 10% decrease NR NR 26% decrease 50–68% decrease NR NR Advantages Noninvasive Noninvasive; specific for human hemoglobin NonInvasive, more sensitive than FIT13 Minimally invasive14 No sedation required9 Highly sensitive Higher compliance than stool-based tests Higher compliance than stool-based tests Disadvantages False positives: not fully specific for human hemoglobin Restricted specificity considering other bowel diseases may also cause blood in stool Less Specific than FIT Complex collection process leading to 6 fold higher technical failures as compared to FIT Radiation exposure, less accurate than colonoscopy Discomfort, risk of bleeding, limted inspection Requires sedation, Risk for perforations and bleeding Low concentrations, limited sensitivity Low concentrations, limited sensitivity Data on sensitivity, specificity, positivity rate, and relative impact on CRC incidence/mortality were aggregated from an article by Toth et al.15, Chung et al.3 AN refers to advanced neoplasia, NR, data not reported. Accuracy and reliability of blood-based DNA tests A blood-based test enhances screening compliance, identifies CRC sooner, and lowers mortality linked to CRC. Reasons for poor screening adherence encompass the time needed for screening, worries about test discomfort and invasiveness, fear of the procedure, discomfort or embarrassment linked to endoscopic exams, etc. Adherence rates for blood-based tests are higher than for stool-based tests or direct visualization examinations3,5. The minimal sensitivity for CRC and specificity for advanced neoplasia as reported in the ECLIPSE (Evaluation of the ctDNA LUNAR Test in an Average Patient Screening Episode) study, conducted by Chung et al.3 adhered to the criteria for acceptance set by other FDA-approved screening tests for CRC. Implementation and global impact Adherence to CRC screening falls short of the 80% target, with a shift to Multi-Target Stool DNA (mt-sDNA) tests and a decline in traditional methods. Colonoscopy uptake is hindered by cost and logistical issues, while FIT testing’s annual follow-up increases administrative burdens. Despite initiatives boosting screening rates, ensuring follow-up colonoscopies post positive results remains challenging16. Despite substantial evidence demonstrating the reduction in CRC mortality linked to screening, implementing blood-based DNA tests for CRC screening encounters challenges such as achieving high adherence rates, addressing racial disparities in screening preferences, managing high costs, potential diversion from more effective methods like colonoscopy, enhancing detection of precancerous polyps, ensuring adherence to follow-up colonoscopy, addressing age-related effectiveness variations, and overcoming access barriers due to cost and insurance coverage discrepancies17–19. Integration of blood-based DNA tests, particularly liquid biopsy using ctDNA, offers transformative potential across cancer management, encompassing screening, diagnosis, residual disease monitoring postsurgery, recurrence detection, prognosis, treatment response prediction, and resistance tracking8. However, extensive, well-designed trials are essential to compare ctDNA performance with other techniques like circulating tumor cells and optimize their clinical utility. Prospective trials are also necessary to assess whether early recurrence detection via ctDNA improves survival over standard imaging and if adjuvant chemotherapy reduces recurrence in patients with elevated ctDNA levels preoperatively and/or postoperatively6,8. Overcoming these obstacles is imperative for the successful global implementation of blood-based CRC screening. Is ctDNA the future standard for CRC treatment? While ctDNA holds potential as a pioneering force in transforming cancer screening and management approaches for CRC, multiple global clinical trials are currently investigating two primary designs: ctDNA-based strategies and ctDNA-treatment interaction. ctDNA has demonstrated superior prognostic value compared to conventional clinicopathological biomarkers in early-stage colon cancer, suggesting its potential for personalized postsurgery treatment adjustments20. Multiple studies indicate that ctDNA serves as a robust predictor for recurrence and survival following surgery and adjuvant chemotherapy. Continual monitoring of ctDNA demonstrates significant potential as a prognostic marker and treatment response indicator in early-stage colon cancer21,22. The Danish and Swedish studies suggest that detecting ctDNA in CRC patients at stages I–III strongly predicts a higher risk of cancer recurrence, highlighting its potential for proactive patient management23,24. In an Australian study of 230 stage II colon cancer patients by Merk C et al.21, Postoperative ctDNA positivity in stage II colon cancer patients significantly predicts poorer 3-year recurrence-free survival compared to ctDNA negativity, surpassing the influence of any single clinicopathological factor or a combination thereof. Future directions and conclusion Continued development of blood-based DNA tests for CRC screening aims to enhance early detection and thus reduce CRC mortality by addressing barriers to widespread adoption, such as cost and adherence. Blood-based DNA tests hold the potential to improve early detection due to their noninvasive option and hence overcoming the major shortcoming of the traditional screening methods. However, certain areas must be addressed with existing blood-based DNA tests. Current blood-based DNA tests show high specificity for CRC but their sensitivity, particularly for advanced precancerous lesions, must be improved with simultaneous strategies to reduce the cost to make a global impact. Overcoming challenges in screening adherence and access is essential for their global implementation, requiring collaborative efforts in research and healthcare delivery. With sustained innovation, these tests can significantly impact CRC prevention and management. Ethical approval Not applicable. Consent Not applicable. Source of funding Not applicable.