Non-Invasive Stool- and Blood-Based Biomarkers in Colorectal Cancer: A Review of Emerging Alternatives

Abstract

Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide. Colonoscopy is the gold standard for screening, but its invasiveness, cost, and limited acceptance highlight the need for non-invasive alternatives. Stool- and blood-based biomarkers have emerged as promising tools for early detection, surveillance, and minimal residual disease (MRD) monitoring. This review evaluates the current evidence on stool- and blood-based biomarkers for CRC, focusing on their diagnostic performance, clinical utility, challenges, and future prospects in comparison with colonoscopy. A comprehensive review of recent literature (2010–2025) was conducted using PubMed, Scopus, and Web of Science databases. Studies evaluating fecal immunochemical tests (FIT), multitarget stool DNA (mt-sDNA), circulating tumor DNA (ctDNA), methylated SEPT9, protein biomarkers, and microRNAs were included, with emphasis on sensitivity, specificity, and clinical applications. FIT and mt-sDNA demonstrate sensitivities of 70–92% and specificities of 87–90% for CRC detection, though their effectiveness in identifying advanced adenomas is lower. Blood-based assays, particularly methylated SEPT9 and ctDNA, show moderate sensitivity (60–75%) but provide unique value in MRD detection and recurrence monitoring. Combination strategies integrating stool and blood biomarkers improve diagnostic yield. However, limitations include variability across populations, high cost, limited access in low- and middle-income countries (LMICs), and lack of assay standardization. Stool- and blood-based biomarkers are important complements to colonoscopy, enhancing CRC detection and surveillance while improving patient compliance. FIT remains the most cost-effective for large-scale screening, while ctDNA coupled with standardization and global accessibility efforts, could transform CRC prevention and management. Wider implementation of biomarkers in risk-stratified screening, investment in cost-effective approaches for LMICs, assay standardization, and adoption of multi-omics innovations are essential for equitable global CRC care.