Biomarkers Beyond Colonoscopy: A Review of Stool and Blood Tools for Colorectal Cancer Management
Keywords:
Colorectal cancer, Biomarkers, Circulating tumour DNA, Fecal immunochemical test, Minimal residual disease, Non-invasive diagnostics, Precision oncology, SEPT9, Screening, Stool DNAAbstract
Colonoscopy remains the gold standard for colorectal cancer (CRC) detection, but its invasiveness, cost, and limited accessibility highlight the need for non-invasive biomarkers. To evaluate stool- and blood-based biomarkers as tools for CRC screening, surveillance, and disease monitoring, comparing their diagnostic accuracy, clinical utility, and limitations. A narrative review of recent evidence (2014–2024) on stool (FIT, multitarget DNA) and blood-based biomarkers (SEPT9, circulating tumour DNA, multi-analyte assays) was conducted, focusing on sensitivity, specificity, and real-world application. FIT demonstrates high specificity but modest sensitivity for advanced adenomas. Multitarget stool DNA improves sensitivity for CRC but at the expense of specificity. Blood-based assays, including SEPT9 methylation and ctDNA, show utility in non-invasive detection, minimal residual disease monitoring, and relapse prediction. However, challenges include cost, variability across populations, and infrastructural requirements. Stool- and blood-based biomarkers represent valuable adjuncts to colonoscopy, offering scalable, patient-friendly options for CRC management. Future directions include multi-omics platforms, artificial intelligence integration, and strategies to enhance accessibility in low-resource settings.
References
1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-49.
2. Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global patterns and trends in colorectal cancer incidence and mortality. Gut. 2017;66(4):683-91.
3. Siegel RL, Miller KD, Goding Sauer A, Fedewa SA, Butterly LF, Anderson JC, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70(3):145-64.
4. Rex DK, Boland CR, Dominitz JA, Giardiello FM, Johnson DA, Kaltenbach T, et al. Colorectal cancer screening: Recommendations for physicians and patients from the U.S. Multi-Society Task Force on colorectal cancer. Gastroenterology. 2017;153(1):307-23.
5. Schreuders EH, Ruco A, Rabeneck L, Schoen RE, Sung JJY, Young GP, et al. Colorectal cancer screening: A global overview of existing programmes. Gut. 2015;64(10):1637-49.
6. Niedermaier T, Weigl K, Hoffmeister M, Brenner H. Diagnostic performance of fecal immunochemical tests for hemoglobin (FIT) in CRC screening: A systematic review and meta-analysis. Gut. 2020;69(7):1184-94.
7. Imperiale TF, Ransohoff DF, Itzkowitz SH, Levin TR, Lavin P, Lidgard GP, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014;370(14):1287-97.
8. Symonds EL, Pedersen SK, Murray DH, Byrne SE, Roy A, Karapetis C, et al. Circulating epigenetic biomarkers for detection of colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2020;29(9):1828-34.
9. Cohen JD, Li L, Wang Y, Thoburn C, Afsari B, Danilova L, et al. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science. 2018;359(6378):926-30.
10. Church TR, Wandell M, Lofton-Day C, Mongin SJ, Burger M, Payne SR, et al. Prospective evaluation of methylated SEPT9 in plasma for detection of asymptomatic colorectal cancer. Gut. 2014;63(2):317-25.
11. Wan JCM, Massie C, Garcia-Corbacho J, Mouliere F, Brenton JD, Caldas C, et al. Liquid biopsies come of age: Towards implementation of circulating tumour DNA. Nat Rev Cancer. 2017;17(4):223-38.
12. Reinert T, Henriksen TV, Christensen E, Sharma S, Salari R, Sethi H, et al. Analysis of plasma cell-free DNA by ultradeep sequencing in patients with stages I to III colorectal cancer. JAMA Oncol. 2019;5(8):1124-31.
13. Oh M, McBride A, Yun S, Bhattacharjee S, Slack M, Martin JR, et al. The clinical utility of circulating tumor DNA in colorectal cancer: A systematic review. JCO Precis Oncol. 2018;2:PO.17.00269.
14. Tan Y, Lin J, Qin W, Zhu Y, Li Y, Wang J, et al. Multi-omics biomarker panels for colorectal cancer: Progress and prospects. Cancers (Basel). 2022;14(13):3126.
15. Allison JE, Tekawa IS, Ransom LJ, Adrain AL. A comparison of fecal occult-blood tests for colorectal-cancer screening. N Engl J Med. 1996;334(3):155-9.
16. Lee JK, Liles EG, Bent S, Levin TR, Corley DA. Accuracy of fecal immunochemical tests for colorectal cancer: Systematic review and meta-analysis. Ann Intern Med. 2014;160(3):171-81.
17. Niedermaier T, Weigl K, Hoffmeister M, Brenner H. Diagnostic performance of fecal immunochemical tests for hemoglobin (FIT) in CRC screening: A systematic review and meta-analysis. Gut. 2020;69(7):1184-94.
18. Ahlquist DA, Taylor WR, Mahoney DW, Zou H, Domanico M, Thibodeau SN, et al. The stool DNA test is more accurate than the fecal immunochemical test for detecting colorectal neoplasia. Clin Gastroenterol Hepatol. 2012;10(3):272-7.
19. Imperiale TF, Ransohoff DF, Itzkowitz SH, Levin TR, Lavin P, Lidgard GP, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014;370(14):1287-97.
20. Oh TJ, Oh HI, Seo YY, Jeong D, Kim C, Kang HW, et al. Feasibility of quantifying SDC2 methylation in stool DNA for early detection of colorectal cancer. Clin Epigenetics. 2017; 9:126.
21. Zou H, Allawi H, Cao X, Domanico M, Harrington J, Taylor WR, et al. Quantification of methylated markers with a multiplex methylation-specific technology. Clin Chem. 2012;58(2):375-83.
22. Yu J, Feng Q, Wong SH, Zhang D, Liang QY, Qin Y, et al. Metagenomic analysis of faecal microbiome as a tool towards targeted non-invasive biomarkers for colorectal cancer. Gut. 2017;66(1):70-8.
23. Liang JQ, Li T, Nakatsu G, Chen YX, Yau TO, Chu E, et al. A novel faecal Fusobacterium nucleatum test for colorectal cancer screening. Gut. 2017;66(7):1231-8.
24. Wan JCM, Massie C, Garcia-Corbacho J, Mouliere F, Brenton JD, Caldas C, et al. Liquid biopsies come of age: Towards implementation of circulating tumour DNA. Nat Rev Cancer. 2017;17(4):223-38.
25. Reinert T, Henriksen TV, Christensen E, Sharma S, Salari R, Sethi H, et al. Analysis of plasma cell-free DNA by ultradeep sequencing in patients with stages I to III colorectal cancer. JAMA Oncol. 2019;5(8):1124-31.
26. Alix-Panabières C, Pantel K. Clinical applications of circulating tumor cells and circulating tumor DNA as liquid biopsy. Cancer Discov. 2016;6(5):479-91.A
27. Church TR, Wandell M, Lofton-Day C, Mongin SJ, Burger M, Payne SR, et al. Prospective evaluation of methylated SEPT9 in plasma for detection of asymptomatic colorectal cancer. Gut. 2014;63(2):317-25.
28. Song L, Jia J, Peng X, Xiao W, Li Y. The performance of the SEPT9 gene methylation assay and a comparison with other CRC screening tests: A meta-analysis. Sci Rep. 2017; 7:3032.
29. Duffy MJ, Lamerz R, Haglund C, Nicolini A, Kalousová M, Holubec L, et al. Tumor markers in colorectal cancer: European Group on Tumor Markers (EGTM) guidelines for clinical use. Eur J Cancer. 2014;50(3):484-99.
30. Matsushita H, Matsumura T, Nomura F. Application of proteomics to cancer biomarker discovery. Cancer Sci. 2020;111(5):1257-67.
31. Peng Q, Zhang X, Min M, Zou L, Shen P, Zhu Y. The clinical role of microRNA-21 as a promising biomarker in the diagnosis and prognosis of colorectal cancer: A systematic review and meta-analysis. Oncotarget. 2017;8(27):44893-909.
32. Niedermaier T, Weigl K, Hoffmeister M, Brenner H. Diagnostic performance of faecal immunochemical tests for haemoglobin (FIT) in CRC screening: a systematic review and meta-analysis. Gut. 2020;69(7):1184-92.
33. Imperiale TF, Ransohoff DF, Itzkowitz SH, Levin TR, Lavin P, Lidgard GP, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014;370(14):1287-97.
34. Berger BM, Schroy PC, Dinh TA. Screening for colorectal cancer using a multitarget stool DNA test: a review of the literature. Clin Colorectal Cancer. 2016;15(2):93-9.
35. Ahlquist DA, Zou H, Domanico M, Mahoney DW, Yab TC, Taylor WR, et al. Next-generation stool DNA test accurately detects colorectal cancer and large adenomas. Gastroenterology. 2012;142(2):248-56.
36. Reinert T, Henriksen TV, Christensen E, Sharma S, Salari R, Sethi H, et al. Analysis of plasma cell-free DNA by ultradeep sequencing in patients with stages I to III colorectal cancer. JAMA Oncol. 2019;5(8):1124-31.
37. Tie J, Cohen JD, Wang Y, Christie M, Simons K, Lee M, et al. Serial circulating tumour DNA analysis during multimodality treatment of locally advanced rectal cancer: a prospective biomarker study. Gut. 2019;68(4):663-71.
38. Cohen JD, Li L, Wang Y, Thoburn C, Afsari B, Danilova L, et al. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science. 2018;359(6378):926-30.
39. Song L, Jia J, Peng X, Xiao W, Li Y. The performance of the SEPT9 gene methylation assay in colorectal cancer screening and detection: a meta-analysis. PLoS One. 2017;12(9):e0183285.
40. Ng K, Schrag D. Colorectal cancer screening: controversies and challenges. J Clin Oncol. 2016;34(33):3839-46.
41. Keller L, Belloum Y, Wikman H, Pantel K. Clinical relevance of blood-based ctDNA analysis: mutation detection and beyond. Br J Cancer. 2021;124(2):345-58.
42. Schreuders EH, Ruco A, Rabeneck L, Schoen RE, Sung JJ, Young GP, et al. Colorectal cancer screening: a global overview of existing programmes. Gut. 2015;64(10):1637-49.
43. Niedermaier T, Weigl K, Hoffmeister M, Brenner H. Diagnostic performance of faecal immunochemical tests for haemoglobin (FIT) in CRC screening: a systematic review and meta-analysis. Gut. 2020;69(7):1184-92.
44. Imperiale TF, Ransohoff DF, Itzkowitz SH, Levin TR, Lavin P, Lidgard GP, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014;370(14):1287-97.
45. Ng K, Schrag D. Colorectal cancer screening: controversies and challenges. J Clin Oncol. 2016;34(33):3839-46.
46. Song L, Jia J, Peng X, Xiao W, Li Y. The performance of the SEPT9 gene methylation assay in colorectal cancer screening and detection: a meta-analysis. PLoS One. 2017;12(9):e0183285.
47. Reinert T, Henriksen TV, Christensen E, Sharma S, Salari R, Sethi H, et al. Analysis of plasma cell-free DNA by ultradeep sequencing in patients with stages I to III colorectal cancer. JAMA Oncol. 2019;5(8):1124-31.
48. Tie J, Cohen JD, Wang Y, Christie M, Simons K, Lee M, et al. Serial circulating tumour DNA analysis during multimodality treatment of locally advanced rectal cancer: a prospective biomarker study. Gut. 2019;68(4):663-71.
49. Parikh AR, Van Seventer EE, Siravegna G, Hartwig AV, Jaimovich A, He Y, et al. Minimal residual disease detection using a plasma-only circulating tumor DNA assay in colorectal cancer patients. Clin Cancer Res. 2021;27(20):5586-94.
50. Tarazona N, Gimeno-Valiente F, Gambardella V, Zuniga S, Rentero-Garrido P, Huerta M, et al. Targeted next-generation sequencing of circulating-tumor DNA for tracking minimal residual disease in localized colon cancer. Ann Oncol. 2019;30(11):1804-12.
51. Keller L, Belloum Y, Wikman H, Pantel K. Clinical relevance of blood-based ctDNA analysis: mutation detection and beyond. Br J Cancer. 2021;124(2):345-58.
52. Ladabaum U, Mannalithara A, Meester RG, Gupta S, Schoen RE. Cost-effectiveness and national effects of initiating colorectal cancer screening for average-risk persons at age 45 years instead of 50 years. Gastroenterology. 2019;157(1):137-48.
53. Niedermaier T, Weigl K, Hoffmeister M, Brenner H. Diagnostic performance of faecal immunochemical tests for haemoglobin (FIT) in CRC screening: a systematic review and meta-analysis. Gut. 2020;69(7):1184-92.
54. Imperiale TF, Ransohoff DF, Itzkowitz SH, Levin TR, Lavin P, Lidgard GP, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014;370(14):1287-97.
55. Song L, Jia J, Peng X, Xiao W, Li Y. The performance of the SEPT9 gene methylation assay in colorectal cancer screening and detection: a meta-analysis. PLoS One. 2017;12(9):e0183285.
56. Ladabaum U, Mannalithara A, Meester RG, Gupta S, Schoen RE. Cost-effectiveness and national effects of initiating colorectal cancer screening for average-risk persons at age 45 years instead of 50 years. Gastroenterology. 2019;157(1):137-48.
57. Ng K, Schrag D. Colorectal cancer screening: controversies and challenges. J Clin Oncol. 2016;34(33):3839-46.
58. Keller L, Belloum Y, Wikman H, Pantel K. Clinical relevance of blood-based ctDNA analysis: mutation detection and beyond. Br J Cancer. 2021;124(2):345-58.
59. Potter NT, Hurban P, White MN, Whitlock KD, Lofton-Day CE, Tetzner R, et al. Validation of a real-time PCR–based qualitative assay for the detection of methylated SEPT9 DNA in human plasma. Clin Chem. 2014;60(9):1183-91.
60. Reinert T, Henriksen TV, Christensen E, Sharma S, Salari R, Sethi H, et al. Analysis of plasma cell-free DNA by ultradeep sequencing in patients with stages I to III colorectal cancer. JAMA Oncol. 2019;5(8):1124-31.
61. Parikh AR, Van Seventer EE, Siravegna G, Hartwig AV, Jaimovich A, He Y, et al. Minimal residual disease detection using a plasma-only circulating tumor DNA assay in colorectal cancer patients. Clin Cancer Res. 2021;27(20):5586-94.
62. Schreuders EH, Ruco A, Rabeneck L, Schoen RE, Sung JJ, Young GP, et al. Colorectal cancer screening: a global overview of existing programmes. Gut. 2015;64(10):1637-49.
63. Keller L, Belloum Y, Wikman H, Pantel K. Clinical relevance of blood-based ctDNA analysis: mutation detection and beyond. Br J Cancer. 2021;124(2):345-58.
64. Ng K, Schrag D. Colorectal cancer screening: controversies and challenges. J Clin Oncol. 2016;34(33):3839-46.
65. Reinert T, Henriksen TV, Christensen E, Sharma S, Salari R, Sethi H, et al. Analysis of plasma cell-free DNA by ultradeep sequencing in patients with stages I to III colorectal cancer. JAMA Oncol. 2019;5(8):1124-31.
66. Li Y, Xu J, Chen H, Bai J, Li S, Zhao Z, et al. Machine learning in colorectal cancer risk prediction and screening: a review. Cancers (Basel). 2022;14(3):681.
67. Ladabaum U, Mannalithara A, Meester RG, Gupta S, Schoen RE. Cost-effectiveness and national effects of initiating colorectal cancer screening for average-risk persons at age 45 years instead of 50 years. Gastroenterology. 2019;157(1):137-48.
68. Sethi N, Joshi A, Bajaj A, Sharma R. Public–private partnerships for advancing cancer diagnostics in low-resource settings. Lancet Oncol. 2020;21(12):e555-63.
69. Potter NT, Hurban P, White MN, Whitlock KD, Lofton-Day CE, Tetzner R, et al. Validation of a real-time PCR–based qualitative assay for the detection of methylated SEPT9 DNA in human plasma. Clin Chem. 2014;60(9):1183-91.
70. Schreuders EH, Ruco A, Rabeneck L, Schoen RE, Sung JJ, Young GP, et al. Colorectal cancer screening: a global overview of existing programmes. Gut. 2015;64(10):1637-49.
71. Parikh AR, Van Seventer EE, Siravegna G, Hartwig AV, Jaimovich A, He Y, et al. Minimal residual disease detection using a plasma-only circulating tumor DNA assay in colorectal cancer patients. Clin Cancer Res. 2021;27(20):5586-94.
