Liquid Biopsy and Machine Learning for Early Colorectal Cancer, Adenomas, Lynch Cancers, and Residual Disease Detection (BEACON)

This is an multicenter study that will test the diagnostic accuracy of a blood test (i.e., a liquid biopsy) for the diagnosis of colorectal cancer (CRC), advanced adenomas (AAs), as well as Lynch-syndrome associated cancers. Additionally, a pre-planned analysis will evaluate the use of this liquid biopsy as a tool for molecular residual disease monitoring purposes.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer; Lynch Syndrome; Colo-rectal Cancer; Colon Adenoma; Colon Disease; MLH1 Gene Mutation; Adenoma Colon; Colon Neoplasm; Mismatch Repair Deficiency; Lynch Syndrome I (Site-specific Colonic Cancer); MSH2 Gene Mutation; MSH6 Gene Mutation; PMS2 Gene Mutation; EPCAM Gene Mutation; Lynch Syndrome II; Mismatch Repair Gene Mutation; Adenoma Colon Polyp; Lynch Syndrome I; LYN Gene Mutation
• Intervention / Treatment: Diagnostic test: BEACON

Detailed Description

Colorectal cancer (CRC) remains a significant public health burden as the third-most commonly diagnosed and second-deadliest malignancy. While CRC is potentially preventable through the removal of precursor lesions known as advanced adenomas (AAs), current screening modalities have limitations. The fecal immunochemical test (FIT) exhibits reduced sensitivity for early-stage CRC and AAs, primarily lowering mortality rather than incidence. Colonoscopy, while effective, is invasive, costly, and suffers from suboptimal adherence. Additionally, individuals with Lynch syndrome (LS), who carry a pathogenic germline variant in mismatch repair (MMR) genes, lack effective and reliable methods for early-stage detection of non-CRC tumors associated with the syndrome.

The rationale of this study, BEACON/2026, is to develop and validate two blood-based tests to address these clinical gaps. The first is a screening test sensitive to both CRC and AAs to complement existing screening options; the second is a multi-cancer early detection (MCED) test tailored to the LS spectrum. The central hypothesis is that a liquid biopsy approach combining cell-free microRNAs (cf-miRNAs, which are sensitive) and exosome-bound microRNAs (exo-miRNAs, which are specific) can effectively distinguish patients with AAs, CRC, and LS-associated cancers from controls.

This study follows the Early Detection Research Network (EDRN) recommendations for biomarker development, including biomarker discovery, prioritization, training, and independent validation (Phases I through III). The experimental design complies with PROBE recommendations for prospectively collected biospecimens that are blindly evaluated. The procedure involves the collection of peripheral blood to isolate RNA from plasma or serum for reverse transcription, quantitative polymerase chain reaction (RT-qPCR) analysis and machine-learning modeling . This non-invasive approach aims to provide a cost-effective, patient-friendly alternative to improve screening participation and disease monitoring

• Study Type: Observational
• Enrollment (Estimated): 1200

Contacts and Locations

• Study Contact: Name: Giulia Martina Cavestro, MD, PhD; Phone Number: 0226437217; Email: cavestro.giuliamartina@hsr.it
• Study Contact Backup: Name: Giulia Martina Cavestro; Phone Number: 0226437217; Email: cavestro.giuliamartina@hsr.it

Study Locations

• Italy
  • Lombardy
    • Milan, Lombardy, Italy, 20132
      • Not yet recruiting
      • Gastronterology and Gastrointestinal Endoscopy Unit, IRCCS San Raffaele Hospital
      • Principal Investigator: Alessandro Mannucci, MD
      • Contact: Giulia Martina Cavestro, MD, PhD; Email: cavestro.giuliamartina@hsr.it
      • Principal Investigator: Marta Puzzono, MD, PhD
      • Principal Investigator: Clelia Di Serio, PhD
      • Sub-Investigator: Chiara Brombin, PhD
      • Sub-Investigator: Paola MV Rancoita, PhD
    • Milan, Lombardy, Italy, 20132
      • Not yet recruiting
      • Prof Giulia Martina Cavestro, MD PhD
      • Contact: Giulia Martina Cavestro, MD, PhD; Phone Number: +39 0226435508; Email: cavestro.giuliamartina@hsr.it
      • Principal Investigator: Alessandro Mannucci, MD
      • Principal Investigator: Marta Puzzono, MD, PhD
    • Milan, Lombardy, Italy, 20132
      • Recruiting
      • San Raffaele Scientific Institute, Gastroenterology and Gastrointestinal Endoscopy Unit
      • Contact: Giulia Martina Cavestro, MD PhD; Email: cavestro.giuliamartina@hsr.it
  • MI
    • Milan, MI, Italy
      • Not yet recruiting
      • Dipartimento di Chirurgia Oncologica e Dipartimento di Oncologia Sperimentale Istituto Nazionale Tumori
      • Contact: Marco Vitellaro, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Seven independent cohorts of individuals who belong to one of the following seven:

• Lynch syndrome, without any Lynch-syndrome-associated cancer
• Lynch syndrome, with one or more Lynch-syndrome-associated cancer(s)
• Sporadic colorectal cancer
• Sporadic advanced adenoma (at most)
• Colonoscopy-negative controls
• Treatment-naive blood samples
• Post-treatment blood samples

Description

Inclusion Criteria:

• All individuals included in the study need to have had a colonoscopy at the time of blood sampling.
• Received standard diagnostic and staging (as necessary) procedures as per local guidelines, and at least one sample was drawn before receiving any curative-intent treatment.
• Received standard pathological and endoscopic diagnosis and assessment for cohort assignment

Exclusion Criteria:

• Lack of informed consent
• Inflammatory bowel disease

Study Plan

How is the study designed?

Number of groups / cohorts

7

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Lynch syndrome, without Lynch-syndrome associated cancers; Individuals with Lynch syndrome, who are free of Lynch-syndrome associated cancers at the time of blood drawing	Diagnostic test: BEACON; A panel of circulating microRNA, whose expression level is tested in cell-free and exosome-derived samples
Lynch syndrome, with Lynch-syndrome associated cancers; Individuals with Lynch syndrome, who have one (or more) Lynch-syndrome associated cancer(s) at the time of blood drawing	Diagnostic test: BEACON; A panel of circulating microRNA, whose expression level is tested in cell-free and exosome-derived samples
Colorectal cancer; Individuals with sporadic biopsy-proven colorectal cancer, as identified during routine colonoscopy and diagnosed via pathological review	Diagnostic test: BEACON; A panel of circulating microRNA, whose expression level is tested in cell-free and exosome-derived samples
Advanced adenoma; Individuals with sporadic advanced adenomas, defined as (i) more than 3 colorectal polyps, (ii) presence of high-grade dysplasia in one or more polyp, or (iii) polyp(s) >10 mm	Diagnostic test: BEACON; A panel of circulating microRNA, whose expression level is tested in cell-free and exosome-derived samples
Colonoscopy-negative controls; Individuals whose colonoscopy was negative for colorectal cancer and for advanced colorectal adenomas	Diagnostic test: BEACON; A panel of circulating microRNA, whose expression level is tested in cell-free and exosome-derived samples
Pre-treatment samples; Individuals with (i) colorectal cancer, or (ii) advanced adenomas, or (iii) Lynch syndrome associated cancer(s) will have the possibility to participate to a sub-analysis of this study, where their circulating plasma levels of biomarkers will be evaluated prior to resection (treatment-naive) and post-resection (to measure the molecular persistence of the disease after the resection)	Diagnostic test: BEACON; A panel of circulating microRNA, whose expression level is tested in cell-free and exosome-derived samples
Post-treatment samples; Individuals with (i) colorectal cancer, or (ii) advanced adenomas, or (iii) Lynch syndrome associated cancer(s) will have the possibility to participate to a sub-analysis of this study, where their circulating plasma levels of biomarkers will be evaluated prior to resection (treatment-naive) and post-resection (to measure the molecular persistence of the disease after the resection)	Diagnostic test: BEACON; A panel of circulating microRNA, whose expression level is tested in cell-free and exosome-derived samples

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sensitivity	True positive rate: the probability of a positive test result, conditioned on the individual truly being positive	Through study completion, an average of 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Specificity	True negative rate: the probability of a negative test result, conditioned on the individual truly being negative	Through study completion, an average of 1 year
Proportion of correct predictions (true positives and true negatives) among the total number of cases (i.e., accuracy)	A measure of trueness: proportion of correct predictions (both true positives and true negatives) among the total number of cases examined	Through study completion, an average of 1 year

Collaborators and Investigators

• Sponsor: San Raffaele University
• Investigators: Principal Investigator: Giulia Martina Cavestro, MD, PhD, IRCCS San Raffaele Hospital

Publications and helpful links

General Publications

• Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, Bartlett BR, Wang H, Luber B, Alani RM, Antonarakis ES, Azad NS, Bardelli A, Brem H, Cameron JL, Lee CC, Fecher LA, Gallia GL, Gibbs P, Le D, Giuntoli RL, Goggins M, Hogarty MD, Holdhoff M, Hong SM, Jiao Y, Juhl HH, Kim JJ, Siravegna G, Laheru DA, Lauricella C, Lim M, Lipson EJ, Marie SK, Netto GJ, Oliner KS, Olivi A, Olsson L, Riggins GJ, Sartore-Bianchi A, Schmidt K, Shih lM, Oba-Shinjo SM, Siena S, Theodorescu D, Tie J, Harkins TT, Veronese S, Wang TL, Weingart JD, Wolfgang CL, Wood LD, Xing D, Hruban RH, Wu J, Allen PJ, Schmidt CM, Choti MA, Velculescu VE, Kinzler KW, Vogelstein B, Papadopoulos N, Diaz LA Jr. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014 Feb 19;6(224):224ra24. doi: 10.1126/scitranslmed.3007094.
• Cavestro GM, Mannucci A, Balaguer F, Hampel H, Kupfer SS, Repici A, Sartore-Bianchi A, Seppala TT, Valentini V, Boland CR, Brand RE, Buffart TE, Burke CA, Caccialanza R, Cannizzaro R, Cascinu S, Cercek A, Crosbie EJ, Danese S, Dekker E, Daca-Alvarez M, Deni F, Dominguez-Valentin M, Eng C, Goel A, Guillem JG, Houwen BBSL, Kahi C, Kalady MF, Kastrinos F, Kuhn F, Laghi L, Latchford A, Liska D, Lynch P, Malesci A, Mauri G, Meldolesi E, Moller P, Monahan KJ, Moslein G, Murphy CC, Nass K, Ng K, Oliani C, Papaleo E, Patel SG, Puzzono M, Remo A, Ricciardiello L, Ripamonti CI, Siena S, Singh SK, Stadler ZK, Stanich PP, Syngal S, Turi S, Urso ED, Valle L, Vanni VS, Vilar E, Vitellaro M, You YN, Yurgelun MB, Zuppardo RA, Stoffel EM; Associazione Italiana Familiarita Ereditarieta Tumori; Collaborative Group of the Americas on Inherited Gastrointestinal Cancer; European Hereditary Tumour Group, and the International Society for Gastrointestinal Hereditary Tumours. Delphi Initiative for Early-Onset Colorectal Cancer (DIRECt) International Management Guidelines. Clin Gastroenterol Hepatol. 2023 Mar;21(3):581-603.e33. doi: 10.1016/j.cgh.2022.12.006. Epub 2022 Dec 20.
• Ahlquist DA, Sargent DJ, Loprinzi CL, Levin TR, Rex DK, Ahnen DJ, Knigge K, Lance MP, Burgart LJ, Hamilton SR, Allison JE, Lawson MJ, Devens ME, Harrington JJ, Hillman SL. Stool DNA and occult blood testing for screen detection of colorectal neoplasia. Ann Intern Med. 2008 Oct 7;149(7):441-50, W81. doi: 10.7326/0003-4819-149-7-200810070-00004.
• Aziz Z, Wagner S, Agyekum A, Pumpalova YS, Prest M, Lim F, Rustgi S, Kastrinos F, Grady WM, Hur C. Cost-Effectiveness of Liquid Biopsy for Colorectal Cancer Screening in Patients Who Are Unscreened. JAMA Netw Open. 2023 Nov 1;6(11):e2343392. doi: 10.1001/jamanetworkopen.2023.43392.
• Barnell EK, Kang Y, Wurtzler EM, Griffith M, Chaudhuri AA, Griffith OL; Geneoscopy Scientists. Noninvasive Detection of High-Risk Adenomas Using Stool-Derived Eukaryotic RNA Sequences as Biomarkers. Gastroenterology. 2019 Sep;157(3):884-887.e3. doi: 10.1053/j.gastro.2019.05.058. Epub 2019 May 30. No abstract available.
• Carethers JM. Stool-Based Screening Tests for Colorectal Cancer. JAMA. 2023 Mar 14;329(10):839-840. doi: 10.1001/jama.2023.0547.
• Chung DC, Gray DM 2nd, Singh H, Issaka RB, Raymond VM, Eagle C, Hu S, Chudova DI, Talasaz A, Greenson JK, Sinicrope FA, Gupta S, Grady WM. A Cell-free DNA Blood-Based Test for Colorectal Cancer Screening. N Engl J Med. 2024 Mar 14;390(11):973-983. doi: 10.1056/NEJMoa2304714.
• 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.
• Barnell EK, Wurtzler EM, La Rocca J, Fitzgerald T, Petrone J, Hao Y, Kang Y, Holmes FL, Lieberman DA. Multitarget Stool RNA Test for Colorectal Cancer Screening. JAMA. 2023 Nov 14;330(18):1760-1768. doi: 10.1001/jama.2023.22231.
• Xu C, Mannucci A, Esposito F, Oliveres H, Alonso-Orduna V, Yubero A, Fernandez-Martos C, Salud A, Gallego J, Martin-Richard M, Fernandez-Plana J, Guillot M, Aparicio J, Fakih M, Kopetz S, Feliu J, Maurel J, Goel A. An Exosome-Based Liquid Biopsy Predicts Depth of Response and Survival Outcomes to Cetuximab and Panitumumab in Metastatic Colorectal Cancer: The EXONERATE Study. Clin Cancer Res. 2025 Mar 17;31(6):1002-1015. doi: 10.1158/1078-0432.CCR-24-1934.
• Mannucci A, Balaguer F, Yamada Y, Nagasaka T, Toiyama Y, Okugawa Y, Marti-Gallostra M, Jimenez-Toscano M, Vidal-Tocino R, Jimenez F, Perea J, Quintero E, Boland CR, Cavestro GM, Goel A; SECOC-ENCODER Collaborators. An Exosome-Based Liquid Biopsy for the Detection of Early-Onset Colorectal Cancer: The ENCODER Multicenter Study. Gastroenterology. 2026 Feb;170(2):330-343. doi: 10.1053/j.gastro.2025.08.013. Epub 2025 Dec 9.
• Mannucci A, Goel A. Circulating Tumor DNA-Based Blood Test for Colorectal Cancer Screening. JAMA. 2025 Nov 11;334(18):1680-1681. doi: 10.1001/jama.2025.14109. No abstract available.
• Mannucci A, Hernandez G, Uetake H, Yamada Y, Balaguer F, Baba H, Chen T, Chen J, Boland CR, Cavestro GM, Quintero E, Goel A. Prediction of long-term recurrence-free and overall survival in early-onset colorectal cancer: the ENCORE multi-centre study. NPJ Precis Oncol. 2025 Jun 21;9(1):202. doi: 10.1038/s41698-025-00978-7.
• Negro S, Perissinotto E, Mammi I, Crivellari G, Schiavi F, Cappello F, Spolverato G, Ferrari D, Rausa E, Vitellaro M, Fassan M, Cavestro GM, Mannucci A, Lonardi S, Bergamo F, Urso EDL. Emerging therapeutic strategies in Lynch syndrome-associated colorectal cancer and the role of MMR testing. Tumori. 2025 Jan 30:3008916241310706. doi: 10.1177/03008916241310706. Online ahead of print.
• Mannucci A, Goel A. Stool and blood biomarkers for colorectal cancer management: an update on screening and disease monitoring. Mol Cancer. 2024 Nov 19;23(1):259. doi: 10.1186/s12943-024-02174-w.
• Mannucci A, Goel A. Stool and Blood DNA Tests for Colorectal Cancer Screening. N Engl J Med. 2024 Jun 20;390(23):2224. doi: 10.1056/NEJMc2404924. No abstract available.
• Shiu PKT, DiStefano JK, Alahari SK, Enguita FJ, Feinberg MW, Sideris N, Bayraktar S, Castellano L, Buitrago DL, Caporali A, Mannucci A, Goel A. The Non-Coding RNA Journal Club: Highlights on Recent Papers-13. Noncoding RNA. 2023 Dec 14;9(6):76. doi: 10.3390/ncrna9060076.
• Russo M, Barchi A, Mannucci A, Puzzono M, Zuppardo RA, Biamonte P, Bencardino S, Leandro G, Cannizzaro R, Monica F, Zagari RM, Pasquale L, Goni E, Di Leo M, Ricciardiello L, Cavestro GM; Italian Society of Gastroenterology (AIGO), Italian Society of Digestive Endoscopy (SIED) and Italian Society of Gastroenterology and Digestive Endoscopy (SIGE). Increased Number of Colorectal Interval Cancers in Lynch Syndrome after the SARS-CoV-2 Pandemic: A Survey-Based Study. Dig Dis. 2023;41(2):227-232. doi: 10.1159/000524393. Epub 2022 Apr 25.
• Puzzono M, Mannucci A, Di Leo M, Zuppardo RA, Russo M, Ditonno I, Goni E, Notaristefano C, Azzolini F, Fanti L, Viale E, Elmore U, Pantaleo G, Cascinu S, Rosati R, Cavestro GM. Diet and Lifestyle Habits in Early-Onset Colorectal Cancer: A Pilot Case-Control Study. Dig Dis. 2022;40(6):710-718. doi: 10.1159/000521932. Epub 2022 Jan 27.
• Mannucci A, Zuppardo RA, Crippa S, Carrera P, Patricelli MG, Russo Raucci A, Calabrese F, Lazarevic D, Giannese F, Tonon G, Ferrari M, Testoni PA, Cavestro GM. MSH6 gene pathogenic variant identified in familial pancreatic cancer in the absence of colon cancer. Eur J Gastroenterol Hepatol. 2020 Mar;32(3):345-349. doi: 10.1097/MEG.0000000000001617.
• Cavestro GM, Zuppardo RA, Mannucci A. Early-onset colorectal cancer: trends and challenges. Lancet Gastroenterol Hepatol. 2019 Jul;4(7):491-492. doi: 10.1016/S2468-1253(19)30146-3. Epub 2019 May 16. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2024
• Primary Completion (Estimated): January 15, 2031
• Study Completion (Estimated): August 15, 2031

Study Registration Dates

• First Submitted: February 27, 2026
• First Submitted That Met QC Criteria: February 27, 2026
• First Posted (Actual): March 4, 2026

Study Record Updates

• Last Update Posted (Actual): March 4, 2026
• Last Update Submitted That Met QC Criteria: February 27, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Genetic Diseases, Inborn; Metabolic Diseases; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplastic Syndromes, Hereditary; DNA Repair-Deficiency Disorders; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Colonic Diseases; Colorectal Neoplasms; Colonic Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Lynch Syndrome II; Turcot syndrome; Lynch syndrome I (site-specific colonic cancer)
• Other Study ID Numbers: BEACON/2026

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Data collected for the study will be made available to others, including de-identified participant data, at publication, via a signed data access agreement and at the discretion of the investigators' approval of the proposed use of such data

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No