cfDNA 5mC/5hmC Biomarkers to Predict Chemotherapy Response in Metastatic Colorectal Cancer

Официальное название

Development of a cfDNA 5mC/5hmC-based Epigenetic Biomarker Panel to Predict Chemotherapy Efficacy in Metastatic Colorectal Cancer

Обзор

The EpiCORE study aims to identify cfDNA-based epigenetic markers predictive of response to first-line chemotherapy (FOLFOX or FOLFIRI) in metastatic colorectal cancer (mCRC). By integrating 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) profiling, this study seeks to establish a non-invasive biomarker panel capable of distinguishing responders from non-responders.

Подробное описание

Despite the introduction of multi-agent chemotherapy regimens such as FOLFOX (5-FU, leucovorin, oxaliplatin) and FOLFIRI (5-FU, leucovorin, irinotecan), treatment outcomes in metastatic colorectal cancer (mCRC) remain highly variable.

Current predictive biomarkers, such as RAS/BRAF mutation or microsatellite instability, fail to accurately forecast response to cytotoxic chemotherapy.

Emerging evidence suggests that cfDNA methylation (5mC) and hydroxymethylation (5hmC) patterns reflect tumor biology and drug sensitivity, offering a promising avenue for precision chemotherapy.

The EpiCORE study integrates genome-wide 5mC/5hmC sequencing and targeted validation assays to identify and confirm epigenetic determinants of chemotherapy efficacy.

Discovery phase: Genome-wide 5mC/5hmC profiling of cfDNA from patients treated with first-line FOLFOX or FOLFIRI to identify candidate regions associated with treatment response.

Training phase: Targeted sequencing and model construction based on candidate loci.

Validation phase: qPCR-based testing to confirm predictive accuracy of the finalized EpiCORE panel.

This study aims to establish a robust cfDNA biomarker framework for predicting and monitoring chemotherapy response in mCRC, contributing to individualized therapeutic decision-making.

Вмешательства

• Диагностический тест cfDNA 5mC/5hmC Sequencing (EpiCORE Discovery Phase)
  Genome-wide profiling of cfDNA methylation and hydroxymethylation from pre-treatment plasma to identify molecular determinants associated with chemotherapy efficacy (PFS ≥ 12M vs \< 12M).
• Диагностический тест EpiCORE Assay (Targeted Sequencing / qPCR Validation)
  Targeted validation of cfDNA 5mC/5hmC markers from discovery phase using sequencing and qPCR to build and validate a predictive model for first-line chemotherapy response.

Первичные конечные точки

• Progression-Free Survival (PFS) [Срок оценки: Up to 36 months from initiation of first-line chemotherapy]

Вторичные конечные точки (1)

• Overall Survival (OS): [Срок оценки: Up to 60 months from initiation of first-line chemotherapy]

Критерии участия

Критерии включения

• Histologically confirmed metastatic colorectal adenocarcinoma (mCRC).
• Received first-line chemotherapy (FOLFOX or FOLFIRI).
• Availability of pre-treatment serum or plasma samples for cfDNA 5mC/5hmC analysis.
• Documented radiologic or clinical response evaluation (RECIST 1.1 or PFS-based).
• RAS/BRAF mutation status available.

Критерии исключения

• Inadequate cfDNA yield or poor DNA quality.
• Non-adenocarcinoma histology.
• Active inflammatory or autoimmune disease that may alter cfDNA methylation.
• Concomitant malignancy requiring systemic therapy.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Случай-контроль

Центры проведения

США · 1 центр

• City of Hope Medical Center — Duarte

Публикации

• Nelson MA, Shetty S, Kulakodlu M, Harley C, Seal B. A comparison of mortality and costs associated with FOLFOX versus FOLFIRI in stage IV colorectal cancer. J Med Econ. 2011;14(2):179-86. doi: 10.3111/13696998.2011.556693. Epub 2011 Feb 14. PMID 21319948
• Bond MJG, Bolhuis K, Loosveld OJL, de Groot JWB, Droogendijk H, Helgason HH, Hendriks MP, Klaase JM, Kazemier G, Liem MSL, Rijken AM, Verhoef C, de Wilt JHW, de Jong KP, Gerhards MF, van Amerongen MJ, Engelbrecht MRW, van Lienden KP, Molenaar IQ, de Valk B, Haberkorn BCM, Kerver ED, Erdkamp F, van Alphen RJ, Mathijssen-van Stein D, Komurcu A, Lopez-Yurda M, Swijnenburg RJ, Punt CJA; Dutch Colorect PMID 37329889
• Bond MJG, Bolhuis K, Loosveld OJL, de Groot JWB, Droogendijk H, Helgason HH, Hendriks MP, Klaase JM, Kazemier G, Liem MSL, Rijken AM, Verhoef C, de Wilt JHW, de Jong KP, Gerhards MF, van Amerongen MJ, Engelbrecht MRW, van Lienden KP, Hermans JJ, Molenaar IQ, Grunhagen DJ, de Valk B, Haberkorn BCM, Kerver ED, Erdkamp F, van Alphen RJ, Mathijssen-van Stein D, Komurcu A, May AM, Swijnenburg RJ, Punt PMID 39570583
• Neugut AI, Lin A, Raab GT, Hillyer GC, Keller D, O'Neil DS, Accordino MK, Kiran RP, Wright J, Hershman DL. FOLFOX and FOLFIRI Use in Stage IV Colon Cancer: Analysis of SEER-Medicare Data. Clin Colorectal Cancer. 2019 Jun;18(2):133-140. doi: 10.1016/j.clcc.2019.01.005. Epub 2019 Jan 31. PMID 30878317
• Gibbons CE, Khan F. Dysphagia--a presenting symptom of forestier disease. J R Army Med Corps. 1996 Feb;142(1):32-3. doi: 10.1136/jramc-142-01-07. PMID 8667328
• Guler GD, Ning Y, Coruh C, Mognol GP, Phillips T, Nabiyouni M, Hazen K, Scott A, Volkmuth W, Levy S. Plasma cell-free DNA hydroxymethylation profiling reveals anti-PD-1 treatment response and resistance biology in non-small cell lung cancer. J Immunother Cancer. 2024 Jan 11;12(1):e008028. doi: 10.1136/jitc-2023-008028. PMID 38212123
• Ferrara R, Imbimbo M, Malouf R, Paget-Bailly S, Calais F, Marchal C, Westeel V. Single or combined immune checkpoint inhibitors compared to first-line platinum-based chemotherapy with or without bevacizumab for people with advanced non-small cell lung cancer. Cochrane Database Syst Rev. 2021 Apr 30;4(4):CD013257. doi: 10.1002/14651858.CD013257.pub3. PMID 33930176
• Baldassarre G, L de la Serna I, Vallette FM. Death-ision: the link between cellular resilience and cancer resistance to treatments. Mol Cancer. 2025 May 15;24(1):144. doi: 10.1186/s12943-025-02339-1. PMID 40375296

Идентификаторы

NCT: NCT07224815 · 23228/EpiCORE

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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