Analysis of Cell Free DNA to Predict Outcome to Bevacizumab Therapy in Colorectal Cancer Patients

Overview

Journal NPJ Genom Med

Specialty Genetics

Date 2024 May 29

PMID 38811554

Authors

Tom Venken

Ian S Miller

Ingrid Arijs

Valentina Thomas

Ana Barat

Johannes Betge

Tianzuo Zhan

Timo Gaiser

Matthias P Ebert

Alice C OFarrell

Jochen Prehn

Rut Klinger

Darran P OConnor

Brian Moulton

Verena Murphy

Garazi Serna

Paolo G Nuciforo

Ray McDermott

Brian Bird

Gregory Leonard

Liam Grogan

Anne Horgan

Nadine Schulte

Markus Moehler

Diether Lambrechts

Annette T Byrne

Affiliations

Soon will be listed here.

Abstract

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.

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