Colon Cancer Screening: Invasive and Non-Invasive

Colonoscopy remains the gold standard for colorectal cancer screening with its high sensitivity and specificity for cancer as well as precancerous lesions. Most current guidelines recommend average risk screening for patients 45-75 years of age with colonoscopy every 10 years.1,2 However recent research continues to refine our practice and provide nuance to screening strategies.

A pragmatic, muthlticentred randomized controlled trial from Europe (NordICC trial) randomized 84,585 patients aged 55-64 years in a 1:2 ratio to either receive an invitation for a single screening colonoscopy or usual care with no screening invitation.3 The trial found that colonoscopy screening significantly reduces colorectal cancer incidence but failed to show a mortality benefit at 10 years in intention-to-screen analysis. However, the study was limited by low participation rates, suboptimal ADRs (Adenoma Detection Rates) and per-protocol analysis showed substantial benefits for those who actually undergo screening.

In recent years, improvements in non-invasive testing have provided more screening options for individuals who are reluctant to undergo colonoscopy. Traditional stool-based testing includes fecal immunochemical test (FIT) as well as multitarget stool DNA (mt-sDNA) based tests. The BLUE-C trial evaluated a next-generation mt-sDNA and demonstrated 93.9% sensitivity for colorectal cancer and 43.4% for advanced precancerous lesions, significantly outperforming FIT.4 Blood based testing uses circulating tumor DNA for the detection of patterns of CpG (cytosine followed by guanine) dinucleotide methylation associated with advanced colorectal neoplasia in plasma samples. While non-invasive testing provides a more convenient option, positive results require follow-up colonoscopy and they suffer from a limited ability to detect precancerous lesions.5,6

Ultimately, the best screening test is the one which ends up getting done. This sentiment was echoed by the findings of the COLONPREV trial.7 This was another RCT from Europe which randomized 53,302 adults to invitation to screening with biennial FIT versus one-time colonoscopy. The study found that FIT was non-inferior to colonoscopy for colorectal cancer mortality at 10 years (risk ratio 0.92) driven largely by higher participation rates (39.9% vs. 31.8% for colonoscopy).

References

  1. National Comprehensive Cancer Network. Colon Cancer (Version 2.2025). NCCN.org. Published March 2025.
  2. Shaukat A, Kahi CJ, Burke CA, Rabeneck L, Sauer BG, Rex DK. ACG Clinical Guidelines: Colorectal Cancer Screening 2021. Am J Gastroenterol. 2021 Mar 1;116(3):458-479. doi: 10.14309/ajg.0000000000001122. PMID: 33657038.
  3. Bretthauer M, Løberg M, Wieszczy P, Kalager M, Emilsson L, Garborg K, Rupinski M, Dekker E, Spaander M, Bugajski M, Holme Ø, Zauber AG, Pilonis ND, Mroz A, Kuipers EJ, Shi J, Hernán MA, Adami HO, Regula J, Hoff G, Kaminski MF; NordICC Study Group. Effect of Colonoscopy Screening on Risks of Colorectal Cancer and Related Death. N Engl J Med. 2022 Oct 27;387(17):1547-1556. doi: 10.1056/NEJMoa2208375. Epub 2022 Oct 9. PMID: 36214590.
  4. Imperiale TF, Porter K, Zella J, Gagrat ZD, Olson MC, Statz S, Garces J, Lavin PT, Aguilar H, Brinberg D, Berkelhammer C, Kisiel JB, Limburg PJ; BLUE-C Study Investigators. Next-Generation Multitarget Stool DNA Test for Colorectal Cancer Screening. N Engl J Med. 2024 Mar 14;390(11):984-993. doi: 10.1056/NEJMoa2310336. PMID: 38477986. 
  5. Shaukat A, Burke CA, Chan AT, Grady WM, Gupta S, Katona BW, Ladabaum U, Liang PS, Liu JJ, Putcha G, Robertson DJ, Schoen RE, Meng Z, Piscitello A, Sun CK, Xu C, Lin CJ, Lee LC, Baldo L, Levin TR; PREEMPT CRC Investigators. Clinical Validation of a Circulating Tumor DNA-Based Blood Test to Screen for Colorectal Cancer. JAMA. 2025 Jul 1;334(1):56-63. doi: 10.1001/jama.2025.7515. PMID: 40455622; PMCID: PMC12131177. 
  6. Shaukat A, Ladabaum U, Kanth P, Lieberman D. AGA Clinical Practice Update on Current Role of Blood Tests for Colorectal Cancer Screening: Commentary. Clin Gastroenterol Hepatol. 2025 Aug;23(9):1486-1491. doi: 10.1016/j.cgh.2025.04.003. Epub 2025 Apr 21. PMID: 40267995. 
  7. Castells A, Quintero E, Bujanda L, Castán-Cameo S, Cubiella J, Díaz-Tasende J, Lanas Á, Ono A, Serra-Burriel M, Frías-Arrocha E, Hernández C, Jover R, Andreu M, Carballo F, Morillas JD, Salas D, Almazán R, Alonso-Abreu I, Banales JM, Hernández V, Portillo I, Vanaclocha-Espí M, de la Vega M; COLONPREV study investigators. Effect of invitation to colonoscopy versus faecal immunochemical test screening on colorectal cancer mortality (COLONPREV): a pragmatic, randomised, controlled, non-inferiority trial. Lancet. 2025 Apr 12;405(10486):1231-1239. doi: 10.1016/S0140-6736(25)00145-X. Epub 2025 Mar 27. Erratum in: Lancet. 2025 Apr 12;405(10486):1230. doi: 10.1016/S0140-6736(25)00687-7. PMID: 40158525.

Author

Angad Uberoi, MD is an Advanced Endoscopy Fellow in the Division of Gastroenterology at Mount Sinai Hospital, Icahn School of Medicine at Mount Sinai in New York City. He was previously a Chief Gastroenterology Fellow at Mount Sinai Morningside/West.

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