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.

Details

Title
Copy number load predicts outcome of metastatic colorectal cancer patients receiving bevacizumab combination therapy
Author
Smeets, Dominiek 1 ; Miller, Ian S 2   VIAFID ORCID Logo  ; Darran P O’Connor 3   VIAFID ORCID Logo  ; Das, Sudipto 3 ; Moran, Bruce 4   VIAFID ORCID Logo  ; Boeckx, Bram 1 ; Gaiser, Timo 5 ; Betge, Johannes 6   VIAFID ORCID Logo  ; Barat, Ana 2 ; Klinger, Rut 4 ; Nicole C T van Grieken 7 ; Cremolini, Chiara 8 ; Prenen, Hans 9   VIAFID ORCID Logo  ; Mazzone, Massimiliano 10 ; Depreeuw, Jeroen 11 ; Bacon, Orna 2 ; Fender, Bozena 12 ; Brady, Joseph 13 ; Hennessy, Bryan T 14 ; McNamara, Deborah A 14 ; Kay, Elaine 15 ; Verheul, Henk M 16 ; Neerincx Maarten 16 ; Gallagher, William M 17 ; Murphy, Verena 18 ; Prehn, Jochen H M 2 ; Koopman, Miriam 19 ; Punt, Cornelis J A 20 ; Loupakis, Fotios 21 ; Ebert, Matthias P A 6 ; Ylstra, Bauke 7   VIAFID ORCID Logo  ; Lambrechts, Diether 1 ; Byrne, Annette T 22 

 VIB Center for Cancer Biology, Leuven, Belgium; Department of Human Genetics, University of Leuven (KULeuven), Leuven, Belgium 
 Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland 
 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 
 UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland 
 Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany 
 Department of Medicine II, University Hospital Mannheim, Heidelberg University, Mannheim, Germany 
 Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands 
 Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Istituto Toscano Tumori, Pisa, Italy 
 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 
Pages
1-16
Publication year
2018
Publication date
Oct 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2116607873
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.