Analysis of cell free DNA to predict outcome to bevacizumab therapy in colorectal cancer patients
To predict outcome to combination bevacizumab (BVZ) therapy, we employed cell-free DNA (cfDNA) to determine chromosomal instability (CIN), nucleosome footprints (NF) and methylation profiles in metastatic colorectal cancer (mCRC) patients. Low-coverage whole-genome sequencing (LC-WGS) was performed on matched tumor and plasma samples, collected from 74 mCRC patients from the AC-ANGIOPREDICT Phase II trial (NCT01822444), and analysed for CIN and NFs. A validation cohort of plasma samples from the University Medical Center Mannheim (UMM) was similarly profiled. 61 AC-ANGIOPREDICT plasma samples collected before and following BVZ treatment were selected for targeted methylation sequencing. Using cfDNA CIN profiles, AC-ANGIOPREDICT samples were subtyped with 92.3% accuracy into low and high CIN clusters, with good concordance observed between matched plasma and tumor. Improved survival was observed in CIN-high patients. Plasma-based CIN clustering was validated in the UMM cohort. Methylation profiling identified differences in CIN-low vs. CIN high (AUC = 0.87). Moreover, significant methylation score decreases following BVZ was associated with improved outcome (p = 0.013). Analysis of CIN, NFs and methylation profiles from cfDNA in plasma samples facilitates stratification into CIN clusters which inform patient response to treatment.
Funding
Health Research Board (HRB) Investigator Led Project (ILP) grant agreement number: ILPPOR-2019-066
Higher Education Authority North-South Research Programme 2021 'RadCOL'
Kom Op Tegen Kanker (Stand up to Cancer, the Flemish Cancer Society)
Advancing a Precision Medicine Paradigm in metastatic Colorectal Cancer: Systems based patient stratification solutions
European Commission
Find out more...Predictive Genomic Biomarkers Methods for Combination Bevacizumab (Avastin) Therapy in Metastatic Colorectal Cancer
European Commission
Find out more...Leveraging chromosomal instability for improved diagnosis and treatment in bevacizumab resistant metastatic colorectal cancer
Science Foundation Ireland
Find out more...CIRCULATING TUMOR DNA AS AN EPIGENETIC BIOMARKER FOR TUMOR RESPONSE
European Research Council
Find out more...MICADO: Multiomic Integration of Cell-Free DNA Profiles for Better Disease Outcome
Research Foundation - Flanders
Find out more...History
Data Availability Statement
The sequencing data are deposited at the European Genome—Phenome Archive (https://ega-archive.org/) under accession code EGAS50000000131 and are available available from the corresponding author on reasonable request.Comments
The original article is available at https://www.nature.com/Published Citation
Venken T. et al. Analysis of cell free DNA to predict outcome to bevacizumab therapy in colorectal cancer patients. NPJ Genom Med. 2024;9(1):33.Publication Date
29 May 2024External DOI
PubMed ID
38811554Department/Unit
- Beaumont Hospital
- Centre for Systems Medicine
- Physiology and Medical Physics
- School of Pharmacy and Biomolecular Sciences
Publisher
Springer Nature in partnership with the Center of Excellence in Genomic Medicine Research at King Abdulaziz UniversityVersion
- Published Version (Version of Record)