Exosome-derived Extrahepatic Metastasis Detection By Liquid Biopsy In Colorectal Cancer Liver Metastases

Overview

Colorectal cancer is the third most common malignancy worldwide, and prognosis largely depends on how effectively metastatic disease is managed. The liver is the most frequent and prognostically important site of metastasis, and patients responding well to chemotherapy may become candidates for curative hepatic resection. However, the presence of extrahepatic metastasis (EHM) critically influences treatment eligibility and survival. Although clinical scores such as the Fong and Beppu systems include EHM as a determinant, its detection by imaging remains limited, especially for small or occult lesions. Accurate identification of EHM is also essential when considering liver transplantation for unresectable colorectal liver metastases (CRLM), where EHM remains an exclusion criterion. The EXELION Study aims to develop a non-invasive diagnostic model using serum exosomal microRNAs (miRNAs) to detect both hepatic and extrahepatic metastases in patients with CRLM. By integrating circulating miRNA profiling with machine learning-based analysis, this study seeks to supplement imaging diagnostics, improve treatment stratification, and enhance clinical decision-making for metastatic colorectal cancer.

Detailed description

Despite improvements in diagnostic imaging-such as CT, MRI, and PET-CT-the sensitivity of EHM detection remains limited, particularly for small or occult lesions in the lung, peritoneum, or lymph nodes. As a result, patients may be inappropriately excluded from curative surgery or exposed to non-beneficial interventions. Thus, there is a pressing need for novel, non-invasive biomarkers capable of detecting EHM with higher accuracy than imaging alone.

MicroRNAs (miRNAs), especially those encapsulated within exosomes, have emerged as stable and reproducible biomarkers reflecting tumor dynamics. Recent studies have shown that circulating miRNA signatures are associated with liver metastasis, therapeutic response, and recurrence risk in CRC. However, their utility for detecting extrahepatic metastasis has not yet been validated in clinical cohorts.

In this research effort, the investigators will leverage small RNA sequencing and machine learning to develop a predictive model for the presence of hepatic and extrahepatic metastases in patients with CRLM. The research plan will consist of three phases:

1. A discovery phase, identifying candidate miRNAs associated with the presence of EHM using next-generation sequencing (NGS) or microarray-based profiling of serum exosomal miRNAs. 2. A model development phase, establishing a quantitative reverse transcription PCR (RT-qPCR) assay and training a predictive algorithm. 3. A validation phase, independently testing the predictive accuracy of the model in an external cohort.

This diagnostic framework is provisionally termed "EXELION" (Exosome-derived Extrahepatic Metastasis Detection by LIquid Biopsy in Colorectal Cancer Liver Metastases). At the end of this study, the EXELION assay is expected to serve as a non-invasive tool to assist clinical decision-making by accurately predicting the presence of extrahepatic metastasis in patients with CRLM.

Interventions

• Other EXELION
  A panel of exosomal microRNA, whose expression level is tested in serum or plasma

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

Eligibility criteria

Inclusion criteria

• Adults (≥18 years old)
• Histologically- or cytologically-confirmed colorectal cancer that is metastatic
• Availability of pre-treatment plasma samples
• Written informed consent provided
• Sufficient clinical and imaging data to determine presence/absence of extrahepatic metastasis

Exclusion criteria

• Prior malignancies within 5 years
• Poor sample quality or hemolysis
• Inability to provide informed consent

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

Healthy volunteers: No

Study design

Observational model

Case-control

Study locations

United States · 1 center

• City of Hope Medical Center — Duarte

Publications

• Adam R, Piedvache C, Chiche L, Adam JP, Salame E, Bucur P, Cherqui D, Scatton O, Granger V, Ducreux M, Cillo U, Cauchy F, Mabrut JY, Verslype C, Coubeau L, Hardwigsen J, Boleslawski E, Muscari F, Jeddou H, Pezet D, Heyd B, Lucidi V, Geboes K, Lerut J, Majno P, Grimaldi L, Levi F, Lewin M, Gelli M; Collaborative TransMet group. Liver transplantation plus chemotherapy versus chemotherapy alone in pa PMID 39306468
• Giuliante F, Vigano L, De Rose AM, Mirza DF, Lapointe R, Kaiser G, Barroso E, Ferrero A, Isoniemi H, Lopez-Ben S, Popescu I, Ouellet JF, Hubert C, Regimbeau JM, Lin JK, Skipenko OG, Ardito F, Adam R. Liver-First Approach for Synchronous Colorectal Metastases: Analysis of 7360 Patients from the LiverMetSurvey Registry. Ann Surg Oncol. 2021 Dec;28(13):8198-8208. doi: 10.1245/s10434-021-10220-w. Epub PMID 34212254
• Carpizo DR, D'Angelica M. Liver resection for metastatic colorectal cancer in the presence of extrahepatic disease. Lancet Oncol. 2009 Aug;10(8):801-9. doi: 10.1016/S1470-2045(09)70081-6. PMID 19647200
• Leung U, Gonen M, Allen PJ, Kingham TP, DeMatteo RP, Jarnagin WR, D'Angelica MI. Colorectal Cancer Liver Metastases and Concurrent Extrahepatic Disease Treated With Resection. Ann Surg. 2017 Jan;265(1):158-165. doi: 10.1097/SLA.0000000000001624. PMID 28009741
• Bojmar L, Zambirinis CP, Hernandez JM, Chakraborty J, Shaashua L, Kim J, Johnson KE, Hanna S, Askan G, Burman J, Ravichandran H, Zheng J, Jolissaint JS, Srouji R, Song Y, Choubey A, Kim HS, Cioffi M, van Beek E, Sigel C, Jessurun J, Velasco Riestra P, Blomstrand H, Jonsson C, Jonsson A, Lauritzen P, Buehring W, Ararso Y, Hernandez D, Vinagolu-Baur JP, Friedman M, Glidden C, Firmenich L, Lieberman PMID 38942992
• Katipally RR, Martinez CA, Pugh SA, Bridgewater JA, Primrose JN, Domingo E, Maughan TS, Talamonti MS, Posner MC, Weichselbaum RR, Pitroda SP; with the S:CORT Consortium. Integrated Clinical-Molecular Classification of Colorectal Liver Metastases: A Biomarker Analysis of the Phase 3 New EPOC Randomized Clinical Trial. JAMA Oncol. 2023 Sep 1;9(9):1245-1254. doi: 10.1001/jamaoncol.2023.2535. PMID 37471075
• Mekenkamp LJ, Haan JC, Koopman M, Vink-Borger ME, Israeli D, Teerenstra S, Ylstra B, Meijer GA, Punt CJ, Nagtegaal ID. Chromosome 20p11 gains are associated with liver-specific metastasis in patients with colorectal cancer. Gut. 2013 Jan;62(1):94-101. doi: 10.1136/gutjnl-2011-301587. Epub 2012 Jan 20. PMID 22267596
• Mahuron KM, Hernandez MC, Wong P, Fan D, Ituarte PHG, Raoof M, Singh G, Fong Y, Melstrom LG. Liver Resection With Extrahepatic Disease: A Population-Based Analysis of Thoughtful Selection. J Surg Oncol. 2025 Mar;131(3):443-449. doi: 10.1002/jso.27944. Epub 2024 Oct 28. PMID 39466980

Identifiers

NCT: NCT07224724 · 23228/EXELION

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗