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

City of Hope

Status: Enrolling

Conditions: CRC (Colorectal Cancer)

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

Study type: Observational

Funder types: Other

Identifiers

NCT07224841

23228/EpiDRIVE

Details and patient eligibility

About

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.

Full 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.

Enrollment: 500 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

500 participants in 6 patient groups

Discovery Cohort - Long PFS Group (Responder)

Description:

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.

Treatment:

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

Discovery Cohort - Short PFS Group (Non-Responder)

Description:

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.

Treatment:

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

Training Cohort - Long PFS Group (Responder)

Description:

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.

Treatment:

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

Training Cohort - Short PFS Group (Non-Responder)

Description:

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.

Treatment:

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

Validation Cohort - Long PFS Group (Responder)

Description:

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.

Treatment:

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

Validation Cohort - Short PFS Group (Non-Responder)

Description:

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.

Treatment:

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