cfDNA 5mC/5hmC Biomarkers to Predict Chemotherapy Response in Metastatic Colorectal Cancer
Purpose
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.
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 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.
Exclusion Criteria
- 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.
Study Design
- Phase
- Study Type
- Observational
- Observational Model
- Case-Control
- Time Perspective
- Retrospective
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
| Discovery Cohort - PFS ≥ 12 Months (Responder) | Patients with mCRC who achieved progression-free survival ≥ 12 months after first-line chemotherapy (FOLFOX or FOLFIRI). cfDNA 5mC/5hmC sequencing performed to identify epigenetic determinants of durable response. |
|
| Discovery Cohort - PFS < 12 Months (Non-Responder) | Patients with progression-free survival < 12 months after first-line chemotherapy. Compared with responders to identify epigenetic features associated with resistance. |
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| Training Cohort - PFS ≥ 12 Months (Responder) | Independent mCRC cohort with long PFS (≥12M). Targeted sequencing (EpiCORE assay) to refine predictive markers. |
|
| Training Cohort - PFS < 12 Months (Non-Responder) | Independent mCRC cohort with short PFS (<12M). Targeted sequencing to validate resistance-associated markers. |
|
| Validation Cohort - PFS ≥ 12 Months (Responder) | Independent validation cohort analyzed with qPCR-based EpiCORE assay to confirm biomarker predictive accuracy. |
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| Validation Cohort - PFS < 12 Months (Non-Responder) | Independent validation cohort with poor PFS analyzed to assess specificity and model performance. |
|
Recruiting Locations
Duarte, California 91010
More Details
- Status
- Recruiting
- Sponsor
- City of Hope Medical Center
Detailed Description
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.