Early Detection of Advanced Adenomas and Colorectal Cancer

Official title

A Liquid Biopsy Assay For The Non-Invasive Early Detection of Advanced Adenomas and Colorectal Cancer

Overview

This study aims to develop a highly sensitive, specific, and cost-effective blood assay for early detection of colorectal adenomas and cancer, using advanced machine learning and state-of-the-art biological analyses.

Detailed description

Colorectal cancer (CRC) is a significant global health concern, ranking third in diagnosis and second in mortality. Despite being potentially preventable, it remains a leading cause of cancer-related deaths. Traditional screening methods like fecal immunochemical testing (FIT) have shown benefits in reducing late-stage diagnoses but have not effectively prevented CRC incidence. This is because tests like FIT can effectively detect the cancers, but not the precursor lesions, called adenomas. On the other hand, endoscopy-first approaches offer higher sensitivity for such adenomas and, therefore, lower the risk of developing CRC but face challenges such as invasiveness, cost, and patient compliance.

Non-invasive tests are more appealing to patients than invasive tests and can increase participation rates. Biomarker studies have shown promise, but existing tests lack sensitivity for early-stage CRC and advanced adenomas (AAs). This is likely because they assume the same analyte can detect both CRC and AAs, which may not be accurate due to differences in analyte release and the biological changes that occur during the adenoma-carcinoma sequence.

This study proposes developing an innovative liquid biopsy test tailored for AAs and CRC to address this. An ideal screening test should be minimally invasive, highly sensitive, and cost-effective. This test would optimize patient compliance and resource allocation by detecting both conditions from a single blood draw. More specifically, circulating microRNA (miRNA) analysis shows promise: tests based on cell-free microRNA (cf-miRNA) have demonstrated high sensitivity, while those based on exosome-derived microRNA (exo-miRNA) offer high specificity. Therefore, combining both analytes in a single test could maximize sensitivity and specificity.

This study will develop a non-invasive blood test for AA and CRC in four phases:

1. Genome-wide profiling of cf-miRNA and exo-miRNA and selecting the best candidates for biomarker panels. 2. Utilizing machine learning to identify promising candidates and train algorithms for detecting AAs and CRC separately, based on results from quantitative polymerase chain reaction (qPCR) analysis. 3. Combining these algorithms to create detection signatures for both conditions. 4. Independently validating these signatures using diverse cohorts to ensure broad applicability and compare the effectiveness of the blood assay to standard care through retrospective and prospective studies.

This study aims to develop a highly sensitive, specific, and cost-effective liquid biopsy for early detection of AAs and CRC. Success could transform clinical practice by preventing CRC through early detection of pre-malignant lesions. Innovations include incorporating pre-malignant lesions into screening and combining cf-miRNA and exo-miRNA biomarkers for accuracy. This approach could reduce CRC mortality and incidence and pave the way for new clinical trials.

Interventions

• Diagnostic test DENEB
  A panel of circulating microRNA, whose expression level is tested in cell-free and exosome-derived samples.

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 number of cases (i.e., accuracy) [Time frame: Through study completion, an average of 1 year]

Eligibility criteria

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

• 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

United States · 2 centers

• City of Hope Medical Center — Monrovia
• University of California San Diego — San Diego

China · 1 center

• The First Affiliated Hospital of Dalian Medical University — Dalian

Italy · 1 center

• IRCCS San Raffaele — Milan

Japan · 1 center

• Mie University — Mie

Spain · 1 center

• Barcelona University — Barcelona

Publications

• 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. PMID 18838724
• 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. PMID 37971743
• 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. PMID 31154021
• 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. PMID 37870871
• 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 PMID 24553385
• Bosch LJW, de Wit M, Pham TV, Coupe VMH, Hiemstra AC, Piersma SR, Oudgenoeg G, Scheffer GL, Mongera S, Sive Droste JT, Oort FA, van Turenhout ST, Larbi IB, Louwagie J, van Criekinge W, van der Hulst RWM, Mulder CJJ, Carvalho B, Fijneman RJA, Jimenez CR, Meijer GA. Novel Stool-Based Protein Biomarkers for Improved Colorectal Cancer Screening: A Case-Control Study. Ann Intern Med. 2017 Dec 19;167(12 PMID 29159365
• Brenner H, Heisser T, Cardoso R, Hoffmeister M. Reduction in colorectal cancer incidence by screening endoscopy. Nat Rev Gastroenterol Hepatol. 2024 Feb;21(2):125-133. doi: 10.1038/s41575-023-00847-3. Epub 2023 Oct 4. PMID 37794234
• Carethers JM. Stool-Based Screening Tests for Colorectal Cancer. JAMA. 2023 Mar 14;329(10):839-840. doi: 10.1001/jama.2023.0547. PMID 36800187

Identifiers

NCT: NCT06342440 · 23228/AACRC

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗