Copy number load predicts outcome of metastatic colorectal cancer patients receiving bevacizumab combination therapy

Dominiek Smeets, Ian S. Miller, Darran P. O’Connor, Sudipto Das, Bruce Moran, Bram Boeckx, Timo Gaiser, Johannes Betge, Ana Barat, Rut Klinger, Nicole C. T. Grieken, Chiara Cremolini, Hans Prenen, Massimiliano Mazzone, Jeroen Depreeuw, Orna Bacon, Bozena Fender, Joseph Brady, Bryan T. Hennessy, Deborah A. McNamara, Elaine Kay, Henk M. Verheul, Neerincx Maarten, William M. Gallagher, Verena Murphy, Jochen H. M. Prehn, Miriam Koopman, Cornelis J. A. Punt, Fotios Loupakis, Matthias P. A. Ebert, Bauke Ylstra, Diether Lambrechts () and Annette T. Byrne
Additional contact information
Dominiek Smeets: VIB Center for Cancer Biology
Ian S. Miller: Royal College of Surgeons in Ireland
Darran P. O’Connor: Royal College of Surgeons in Ireland
Sudipto Das: Royal College of Surgeons in Ireland
Bruce Moran: University College Dublin
Bram Boeckx: VIB Center for Cancer Biology
Timo Gaiser: University Medical Center Mannheim, University of Heidelberg
Johannes Betge: University Hospital Mannheim, Heidelberg University
Ana Barat: Royal College of Surgeons in Ireland
Rut Klinger: University College Dublin
Nicole C. T. Grieken: Amsterdam UMC, Vrije Universiteit Amsterdam
Chiara Cremolini: University of Pisa, Istituto Toscano Tumori
Hans Prenen: University Hospital Antwerp
Massimiliano Mazzone: VIB Center for Cancer Biology
Jeroen Depreeuw: VIB Center for Cancer Biology
Orna Bacon: Royal College of Surgeons in Ireland
Bozena Fender: OncoMark Limited, NovaUCD
Joseph Brady: University College Dublin
Bryan T. Hennessy: Beaumont Hospital
Deborah A. McNamara: Beaumont Hospital
Elaine Kay: Beaumont Hospital
Henk M. Verheul: Amsterdam UMC, Vrije Universiteit Amsterdam
Neerincx Maarten: Amsterdam UMC, Vrije Universiteit Amsterdam
William M. Gallagher: University College Dublin
Verena Murphy: Cancer Trials Ireland
Jochen H. M. Prehn: Royal College of Surgeons in Ireland
Miriam Koopman: University Medical Center Utrecht, Utrecht University
Cornelis J. A. Punt: Amsterdam UMC, University of Amsterdam
Fotios Loupakis: Oncologia Medica 1, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS
Matthias P. A. Ebert: University Hospital Mannheim, Heidelberg University
Bauke Ylstra: Amsterdam UMC, Vrije Universiteit Amsterdam
Diether Lambrechts: VIB Center for Cancer Biology
Annette T. Byrne: Royal College of Surgeons in Ireland

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06567-6

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