Development of a cfDNA 5mC/5hmC-based Biomarker Panel to Predict Targeted Therapy Efficacy in mCRC
Purpose
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.
Condition
- CRC (Colorectal Cancer)
Eligibility
- Eligible Ages
- Over 18 Years
- Eligible Sex
- All
- Accepts 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.
Study Design
- Phase
- Study Type
- Observational
- Observational Model
- Case-Control
- Time Perspective
- Retrospective
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
| Discovery Cohort - Long PFS Group (Responder) | Patients with metastatic colorectal cancer (mCRC) who received EGFR- or VEGF-targeted therapy and achieved a progression-free survival (PFS) ≥ 12 months, classified as clinical responders. Pre-treatment plasma cfDNA samples were analyzed by genome-wide 5mC/5hmC sequencing to identify epigenetic determinants associated with durable treatment response. |
|
| Discovery Cohort - Short PFS Group (Non-Responder) | Patients with mCRC who received EGFR- or VEGF-targeted therapy and showed progression-free survival (PFS) < 12 months, classified as non-responders. Pre-treatment cfDNA samples were analyzed using genome-wide 5mC/5hmC sequencing and compared with long-PFS responders to identify differential methylation and hydroxymethylation patterns associated with resistance. |
|
| Training Cohort - Long PFS Group (Responder) | Independent mCRC cohort with PFS ≥ 12 months following EGFR- or VEGF-targeted therapy. Candidate cfDNA 5mC/5hmC markers identified in the discovery phase were validated using targeted sequencing (EpiDRIVE assay) to construct the predictive epigenetic biomarker panel. |
|
| Training Cohort - Short PFS Group (Non-Responder) | Independent mCRC patients with PFS < 12 months after targeted therapy. Targeted sequencing using the EpiDRIVE assay was conducted to refine and optimize the predictive model by comparing short- vs long-PFS cases. |
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| Validation Cohort - Long PFS Group (Responder) | Separate validation cohort of mCRC patients achieving PFS ≥ 12 months under EGFR- or VEGF-targeted therapy. qPCR-based EpiDRIVE assay was used to confirm predictive accuracy of the cfDNA 5mC/5hmC biomarker panel in identifying durable responders. |
|
| Validation Cohort - Short PFS Group (Non-Responder) | Independent validation cohort of mCRC patients with PFS < 12 months after targeted therapy. cfDNA was analyzed using the qPCR-based EpiDRIVE assay to assess model specificity and distinguish non-responders from long-term responders. |
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Recruiting Locations
Duarte, California 91016
More Details
- Status
- Recruiting
- Sponsor
- City of Hope Medical Center
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.