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Abstract
Increased copy number alterations (CNAs) indicative of chromosomal instability (CIN) have been associated with poor cancer outcome. Here, we study CNAs as potential biomarkers of bevacizumab (BVZ) response in metastatic colorectal cancer (mCRC). We cluster 409 mCRCs in three subclusters characterized by different degrees of CIN. Tumors belonging to intermediate-to-high instability clusters have improved outcome following chemotherapy plus BVZ versus chemotherapy alone. In contrast, low instability tumors, which amongst others consist of POLE-mutated and microsatellite-instable tumors, derive no further benefit from BVZ. This is confirmed in 81 mCRC tumors from the phase 2 MoMa study involving BVZ. CNA clusters overlap with CRC consensus molecular subtypes (CMS); CMS2/4 xenografts correspond to intermediate-to-high instability clusters and respond to FOLFOX chemotherapy plus mouse avastin (B20), while CMS1/3 xenografts match with low instability clusters and fail to respond. Overall, we identify copy number load as a novel potential predictive biomarker of BVZ combination therapy.
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1 VIB Center for Cancer Biology, Leuven, Belgium; Department of Human Genetics, University of Leuven (KULeuven), Leuven, Belgium
2 Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
3 Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland; UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland
4 UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland
5 Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany
6 Department of Medicine II, University Hospital Mannheim, Heidelberg University, Mannheim, Germany
7 Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
8 Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Istituto Toscano Tumori, Pisa, Italy
9 Department of Oncology, University Hospital Antwerp, Edegem, Belgium; Center for Oncological Research, Antwerp University, Edegem, Belgium
10 VIB Center for Cancer Biology, Leuven, Belgium; Department of Oncology, University of Leuven (KULeuven), Leuven, Belgium
11 VIB Center for Cancer Biology, Leuven, Belgium; Department of Human Genetics, University of Leuven (KULeuven), Leuven, Belgium; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
12 OncoMark Limited, NovaUCD, Dublin, Ireland
13 Veterinary Pathobiology, School of Veterinary Medicine, University College Dublin, Dublin, Ireland
14 Department of Surgery, Beaumont Hospital, Dublin, Ireland
15 Department of Pathology, Beaumont Hospital, Dublin, Ireland
16 Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
17 UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland; OncoMark Limited, NovaUCD, Dublin, Ireland
18 Cancer Trials Ireland, Dublin, Ireland
19 Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
20 Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
21 Oncologia Medica 1, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS, Padova, Italy
22 Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland; UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland