Development of a cfDNA 5mC/5hmC-based Biomarker Panel to Predict Targeted Therapy Efficacy in mCRC

Официальное название

Development of a cfDNA 5mC/5hmC-based Epigenetic Biomarker Panel to Identify Determinants of Response In VEGF/EGFR-targeted Therapy for Metastatic Colorectal Cancer

Обзор

The EpiDRIVE study aims to identify cfDNA-based epigenetic determinants of response in metastatic colorectal cancer (mCRC) patients treated with EGFR- or VEGF-targeted therapy. By integrating 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) profiling, this study seeks to develop a predictive biomarker panel capable of differentiating responders from non-responders to targeted therapy.

Подробное описание

Metastatic colorectal cancer (mCRC) remains one of the leading causes of cancer-related death. Although targeted agents such as anti-EGFR (cetuximab, panitumumab) and anti-VEGF (bevacizumab) therapies have improved survival, treatment response varies widely even among molecularly defined subgroups.

Traditional biomarkers, including RAS/BRAF mutation and tumor sidedness, fail to accurately predict therapeutic efficacy.

Recent studies highlight the potential of cell-free DNA (cfDNA) methylation (5mC) and hydroxymethylation (5hmC) as sensitive, non-invasive indicators of tumor biology and treatment dynamics.

The EpiDRIVE study integrates cfDNA 5mC/5hmC sequencing and targeted validation to discover and verify epigenetic determinants of therapeutic response.

Discovery phase: Whole-genome 5mC/5hmC profiling to identify differentially modified regions between responders and non-responders.

Training phase: Targeted sequencing to establish a predictive cfDNA epigenetic panel (EpiDRIVE panel).

Validation phase: qPCR-based validation of selected markers in an independent cohort to confirm predictive accuracy.

This study aims to provide a non-invasive biomarker framework to predict and monitor efficacy of EGFR- and VEGF-targeted therapies in mCRC, ultimately guiding personalized treatment selection.

Вмешательства

• Диагностический тест cfDNA 5mC/5hmC Sequencing (EpiDRIVE Discovery Phase)
  High-throughput genome-wide sequencing of cfDNA methylation (5mC) and hydroxymethylation (5hmC) profiles from pre-treatment plasma samples in the discovery cohort to identify epigenetic determinants of targeted-therapy response (PFS ≥ 12 months vs \< 12 months).
• Диагностический тест EpiDRIVE Assay (Targeted Sequencing / qPCR Validation)
  Targeted sequencing or qPCR-based validation of cfDNA 5mC/5hmC markers identified from the discovery phase to develop and validate a predictive biomarker model discriminating patients with long vs short progression-free survival after EGFR-/VEGF-targeted therapy.

Первичные конечные точки

• Progression-Free Survival (PFS) according to cfDNA 5mC/5hmC biomarker profile [Срок оценки: Up to 36 months from therapy initiation]

Вторичные конечные точки (1)

• Overall Survival (OS) [Срок оценки: Up to 60 months from therapy initiation]

Критерии участия

Критерии включения

• Histologically confirmed metastatic colorectal adenocarcinoma (mCRC).
• Received EGFR-targeted therapy (cetuximab/panitumumab) or VEGF-targeted therapy (bevacizumab).
• Availability of pre-treatment plasma sample for cfDNA analysis.
• Documented radiologic response evaluation (RECIST 1.1).
• RAS/BRAF mutation status known.

Критерии исключения

• Inadequate cfDNA quality or low cfDNA yield.
• Non-adenocarcinoma histology.
• Concurrent or prior other active malignancy.
• Active inflammatory or autoimmune disease affecting cfDNA methylation profiles.

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

• 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 PMID 39820673
• Koroukian SM, Booker BD, Vu L, Schumacher FR, Rose J, Cooper GS, Selfridge JE, Markt SC. Receipt of Targeted Therapy and Survival Outcomes in Patients With Metastatic Colorectal Cancer. JAMA Netw Open. 2023 Jan 3;6(1):e2250030. doi: 10.1001/jamanetworkopen.2022.50030. PMID 36656585
• Tirendi S, Marengo B, Domenicotti C, Bassi AM, Almonti V, Vernazza S. Colorectal cancer and therapy response: a focus on the main mechanisms involved. Front Oncol. 2023 Jul 19;13:1208140. doi: 10.3389/fonc.2023.1208140. eCollection 2023. PMID 37538108
• Xie YH, Chen YX, Fang JY. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct Target Ther. 2020 Mar 20;5(1):22. doi: 10.1038/s41392-020-0116-z. PMID 32296018
• Cai Z, Zhang J, He Y, Xia L, Dong X, Chen G, Zhou Y, Hu X, Zhong S, Wang Y, Chen H, Xie D, Liu X, Liu J. Liquid biopsy by combining 5-hydroxymethylcytosine signatures of plasma cell-free DNA and protein biomarkers for diagnosis and prognosis of hepatocellular carcinoma. ESMO Open. 2021 Feb;6(1):100021. doi: 10.1016/j.esmoop.2020.100021. Epub 2021 Jan 25. PMID 33508734
• Zeng C, Stroup EK, Zhang Z, Chiu BC, Zhang W. Towards precision medicine: advances in 5-hydroxymethylcytosine cancer biomarker discovery in liquid biopsy. Cancer Commun (Lond). 2019 Mar 29;39(1):12. doi: 10.1186/s40880-019-0356-x. PMID 30922396
• West-Szymanski DC, Zhang Z, Cui XL, Kowitwanich K, Gao L, Deng Z, Dougherty U, Williams C, Merkle S, He C, Zhang W, Bissonnette M. 5-Hydroxymethylated Biomarkers in Cell-Free DNA Predict Occult Colorectal Cancer up to 36 Months Before Diagnosis in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. JCO Precis Oncol. 2024 Oct;8:e2400277. doi: 10.1200/PO.24.00277. Epub 2024 Oct 11. PMID 39393034
• West-Szymanski DC, Zhang Z, Cui XL, Kowitwanich K, Gao L, Deng Z, Dougherty U, Williams C, Merkle S, Moore M, He C, Bissonnette M, Zhang W. Machine learning identifies cell-free DNA 5-hydroxymethylation biomarkers that detect occult colorectal cancer in PLCO Screening Trial subjects. bioRxiv [Preprint]. 2024 Feb 26:2024.02.25.581955. doi: 10.1101/2024.02.25.581955. PMID 38464122

Идентификаторы

NCT: NCT07224841 · 23228/EpiDRIVE

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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