Early Onset Colorectal Cancer Detection

Official title

Development and Validation fo an Exosome-Based and Machine Learning Powered Liquid Biopsy for the Detection of Early-Onset Colorectal Cancer

Overview

Colorectal cancer (CRC) once predominantly affected older individuals, but in recent years has witnessed a progressive increase in incidence among young adults. Once rare, early-onset colorectal cancer (EOCRC, that is, a CRC diagnosed before the age of 50) now constitutes 10-15% of all newly diagnosed CRC cases and it stands as the first cause of cancer-related death in young men and the second for young women. This study aims to detect EOCRC with a non-invasive test, using a blood-based molecular assay based on microRNA (ribonucleic acid)

Detailed description

The rising incidence of early-onset colorectal cancer (EOCRC) is a pressing clinical issue unique to our times, and it is expected to grow with an anticipated further 90% increase in incidence by the decade's end. Challenges persist even after reducing the CRC screening age to 45: under-45s lack routine screening and compliance in the 45-50 age group remains low, partly due to invasiveness and discomfort of standard screening methods. Urgent action is warranted to develop affordable, sensitive, and feasible screening for timely detection and improved participation. A non-invasive, patient-friendly screening test, like a blood-based assay, could address these epidemiological concerns and also attract underserved populations.

This study involves the development and validation of a liquid biopsy, assessing circulating cell-free and exosomal microRNAs (cf-miRNA and exo-miRNA, respectively) for indirect sampling of tumor tissue in the bloodstream. The researchers intend to harness machine learning and bioinformatics to create an integrated panel (with both cf-miRNAs and exo-miRNAs) to enhance the inherently high sensitivity of cf-miRNAs with the distinctive specificity of exo-miRNAs. This combined approach will not only improve the performance of a diagnostic model but will also tap into the diverse tumor biology aspects of EOCRC.

The study's core goal is to develop cost-efficient, non-invasive, clinic-friendly biomarkers with high sensitivity and specificity, aiding EOCRC detection.

The researchers intend to do so in three phases:

1. To perform comprehensive small RNA-Seq from matched cf-miRNA, exo-miRNA, cancer-derived miRNA, and mucosa-derived miRNA. 2. To develop and train two miRNA detection panels (cf-miRNA and exo-miRNA, respectively) based on advanced machine-learning models and, then, combine these two using several machine-learning models to obtain a final detection biomarker. 3. To validate the findings in an independent cohort of EOCRC and controls.

In summary, this proposal promises to improve patient care and compliance, and, ultimately, reduce mortality from EOCRC.

Interventions

• Diagnostic test ENCODE
  A panel of microRNA, both cell-free and exosomes, whose expression level is tested from plasma samples from patients with early onset colorectal cancer and non-disease controls.

Primary outcome measures

• Sensitivity [Time frame: Through study completion, an average of 1 year]

Secondary outcome measures (2)

• Specificity [Time frame: Through study completion, an average of 1 year]
• Proportion of correct predictions (true positives and true negatives) among the total cases (i.e., accuracy) [Time frame: Through study completion, an average of 1 year]

Eligibility criteria

Inclusion criteria

• Stage I, II, III, IV colorectal cancer (TNM classification, 8th edition) diagnosed before the age of 50 (EOCRC cases)
• Received standard diagnostic and staging procedures as per local guidelines, and at least one sample was drawn before receiving any curative-intent treatment
• Colonoscopy-proven cancer-free status at the time of study inclusion (Non-disease controls)

Exclusion criteria

• Hereditary colorectal cancer syndromes (identified through genetic testing)
• Inflammatory bowel diseases
• Lack of written informed consent

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Observational model

Case-control

Study locations

Spain · 6 centers

• Barcelona University — Barcelona
• Colorectal Surgery, Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona U — Barcelona
• Surgery Department, Hospital del Mar, Barcelona, Spain — Barcelona
• Salamanca Biomedical Research Institute — Madrid
• University of Salamanca-SACYL-CSIC, Salamanca, Spain — Salamanca
• University of La Laguna — San Cristóbal de La Laguna

Japan · 5 centers

• Kawasaki University — Kawasaki
• Mie University — Mie
• National Cancer Center Hospital — Tokyo
• Tokyo Medical and Dental University — Tokyo
• Yamagata University — Yamagata

United States · 1 center

• City of Hope Medical Center — Duarte

Italy · 1 center

• IRCCS San Raffaele — Milan

Publications

• Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394-424. doi: 10.3322/caac.21492. Epub 2018 Sep 12. PMID 30207593
• Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4. PMID 33538338
• Patel SG, Karlitz JJ, Yen T, Lieu CH, Boland CR. The rising tide of early-onset colorectal cancer: a comprehensive review of epidemiology, clinical features, biology, risk factors, prevention, and early detection. Lancet Gastroenterol Hepatol. 2022 Mar;7(3):262-274. doi: 10.1016/S2468-1253(21)00426-X. Epub 2022 Jan 26. PMID 35090605
• Akimoto N, Ugai T, Zhong R, Hamada T, Fujiyoshi K, Giannakis M, Wu K, Cao Y, Ng K, Ogino S. Rising incidence of early-onset colorectal cancer - a call to action. Nat Rev Clin Oncol. 2021 Apr;18(4):230-243. doi: 10.1038/s41571-020-00445-1. Epub 2020 Nov 20. PMID 33219329
• Keum N, Giovannucci E. Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies. Nat Rev Gastroenterol Hepatol. 2019 Dec;16(12):713-732. doi: 10.1038/s41575-019-0189-8. Epub 2019 Aug 27. PMID 31455888
• 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 PMID 36549470
• Ullah F, Pillai AB, Omar N, Dima D, Harichand S. Early-Onset Colorectal Cancer: Current Insights. Cancers (Basel). 2023 Jun 15;15(12):3202. doi: 10.3390/cancers15123202. PMID 37370811
• Syed H, Sommovilla J, Burke CA, McGee S, Macaron C, Heald B, Lyu R, Schmit SL, Nair K, Kamath S, Krishnamurthi S, Khorana AA, Liska D. Referral, Uptake, and Outcome of Genetic Counseling and Testing in Patients With Early-Onset Colorectal Cancer. J Natl Compr Canc Netw. 2023 Nov;21(11):1156-1163.e5. doi: 10.6004/jnccn.2023.7057. PMID 37935108

Identifiers

NCT: NCT06342401 · 23228/ENCODE

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗