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- Title
Analysis of cell free DNA to predict outcome to bevacizumab therapy in colorectal cancer patients.
- Authors
Venken, Tom; Miller, Ian S.; Arijs, Ingrid; Thomas, Valentina; Barat, Ana; Betge, Johannes; Zhan, Tianzuo; Gaiser, Timo; Ebert, Matthias P.; O'Farrell, Alice C.; Prehn, Jochen; Klinger, Rut; O'Connor, Darran P.; Moulton, Brian; Murphy, Verena; Serna, Garazi; Nuciforo, Paolo G.; McDermott, Ray; Bird, Brian; Leonard, Gregory
- 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.
- Subjects
CELL-free DNA; BEVACIZUMAB; IRINOTECAN; COLORECTAL cancer; CELL analysis; CANCER patients; WHOLE genome sequencing
- Publication
NPJ Genomic Medicine, 2024, Vol 9, Issue 1, p1
- ISSN
2056-7944
- Publication type
Article
- DOI
10.1038/s41525-024-00415-x