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Analysis of cell free DNA to predict outcome to bevacizumab therapy in colorectal cancer patients

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posted on 2024-10-24, 09:02 authored by Tom Venken, Ian Miller, Valentina Thomas, Ana Barat, Alice O'FarrellAlice O'Farrell, Jochen PrehnJochen Prehn, Darran O'ConnorDarran O'Connor, Liam GroganLiam Grogan, Annette ByrneAnnette Byrne

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

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Predictive Genomic Biomarkers Methods for Combination Bevacizumab (Avastin) Therapy in Metastatic Colorectal Cancer

European Commission

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Leveraging chromosomal instability for improved diagnosis and treatment in bevacizumab resistant metastatic colorectal cancer

Science Foundation Ireland

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CIRCULATING TUMOR DNA AS AN EPIGENETIC BIOMARKER FOR TUMOR RESPONSE

European Research Council

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MICADO: Multiomic Integration of Cell-Free DNA Profiles for Better Disease Outcome

Research Foundation - Flanders

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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 2024

PubMed ID

38811554

Department/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 University

Version

  • Published Version (Version of Record)