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

City of Hope

Status: Enrolling

Conditions: CRC (Colorectal Cancer)

Treatments: Diagnostic Test: cfDNA 5mC/5hmC Sequencing (EpiCORE Discovery Phase); Diagnostic Test: EpiCORE Assay (Targeted Sequencing / qPCR Validation)

Study type: Observational

Funder types: Other

Identifiers

NCT07224815

23228/EpiCORE

Details and patient eligibility

About

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.

Full 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.

Enrollment: 600 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

600 participants in 6 patient groups

Discovery Cohort - PFS ≥ 12 Months (Responder)

Description:

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.

Treatment:

Diagnostic Test: cfDNA 5mC/5hmC Sequencing (EpiCORE Discovery Phase)

Discovery Cohort - PFS < 12 Months (Non-Responder)

Description:

Patients with progression-free survival \< 12 months after first-line chemotherapy. Compared with responders to identify epigenetic features associated with resistance.

Treatment:

Diagnostic Test: cfDNA 5mC/5hmC Sequencing (EpiCORE Discovery Phase)

Training Cohort - PFS ≥ 12 Months (Responder)

Description:

Independent mCRC cohort with long PFS (≥12M). Targeted sequencing (EpiCORE assay) to refine predictive markers.

Treatment:

Diagnostic Test: EpiCORE Assay (Targeted Sequencing / qPCR Validation)

Training Cohort - PFS < 12 Months (Non-Responder)

Description:

Independent mCRC cohort with short PFS (\<12M). Targeted sequencing to validate resistance-associated markers.

Treatment:

Diagnostic Test: EpiCORE Assay (Targeted Sequencing / qPCR Validation)

Validation Cohort - PFS ≥ 12 Months (Responder)

Description:

Independent validation cohort analyzed with qPCR-based EpiCORE assay to confirm biomarker predictive accuracy.

Treatment:

Diagnostic Test: EpiCORE Assay (Targeted Sequencing / qPCR Validation)

Validation Cohort - PFS < 12 Months (Non-Responder)

Description:

Independent validation cohort with poor PFS analyzed to assess specificity and model performance.

Treatment:

Diagnostic Test: EpiCORE Assay (Targeted Sequencing / qPCR Validation)