CRC (Colorectal Cancer)
Conditions
Keywords
mCRC, Target therapy, 5mc/5hmc, 5-hydroxymethylation, Metastatic colorectal cancer, anti-EGFR therapy, anti-VEGF therapy, RAS/BRAF mutation, 5-methylcytosine
Brief summary
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.
Detailed description
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.
Interventions
DIAGNOSTIC_TESTcfDNA 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).
DIAGNOSTIC_TESTEpiDRIVE 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.
Sponsors
City of Hope Medical Center
Study design
Observational model
CASE_CONTROL
Time perspective
RETROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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.
Exclusion criteria
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) according to cfDNA 5mC/5hmC biomarker profile | Up to 36 months from therapy initiation | Progression-free survival (PFS) among patients with metastatic colorectal cancer (mCRC) receiving EGFR- or VEGF-targeted therapy, stratified by cfDNA 5mC/5hmC-based biomarker status. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to 60 months from therapy initiation | Time from initiation of EGFR- or VEGF-targeted therapy to death from any cause. Overall survival will be analyzed in relation to cfDNA 5mC/5hmC biomarker-defined groups (high vs low EpiDRIVE score) to assess whether epigenetic cfDNA profiles are associated with differences in survival outcomes. |
Countries
United States
Contacts
CONTACTAjay Goel, PhD
PRINCIPAL_INVESTIGATORAjay Goel, PhD
City of Hope Medical Center
Outcome results
None listed