Dominiek Smeets, VIB Center for Cancer Biology, Belgium
Ian S. Miller, Royal College of Surgeons in IrelandFollow
Darran P. O'Connor, Royal College of Surgeons in IrelandFollow
Sudipto Das, Royal College of Surgeons in IrelandFollow
Bruce Moran, University College Dublin
Bram Boeckx, University of Leuven
Timo Gaiser, University of Heidelberg
Johannes Betge, University of Heidelberg
Ana Barat, Royal College of Surgeons in IrelandFollow
Rut Klinger, University of Heidelberg
Nicole CT van Grieken, Vrije Universiteit Amsterdam
Chiara Cremolini, University of Pisa
Hans Prenen, University Hospital Antwerp
Massimiliano Mazzone, University of Leuven
Jeroen Depreeuw, University of Leuven
Orna Bacon, Royal College of Surgeons in IrelandFollow
Bozena Fender, University College Dublin
Joseph Brady, University College Dublin
Bryan T. Hennessy, Royal College of Surgeons in IrelandFollow
Deborah A. McNamara, Royal College of Surgeons in IrelandFollow
Elaine W. Kay, Royal College of Surgeons in IrelandFollow
Henk M. Verheul, Vrije Universiteit Amsterdam
Neerincx Maarten, Vrije Universiteit Amsterdam
William M. Gallagher, University College Dublin
Verena Murphy, Cancer Trials Ireland
Jochen HM Prehn, Royal College of Surgeons in IrelandFollow
Miriam Koopman, Utrecht University
Cornelis JA Punt, Utrecht University
Fotios Loupakis, Istituto Oncologico Veneto
Matthias PA Ebert, Heidelberg University
Bauke Ylstra, Vrije Universiteit Amsterdam
Diether Lambrechts, VIB Center for Cancer Biology, Belgium
Annette Byrne, Royal College of Surgeons in IrelandFollow

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Metastatic Colorectal Cancer, Chromosomal Instability, Copy Number Alterations, Bevacizumab Combination Therapy.


The ANGIOPREDICT project was funded by the European Commission Framework Programme Seven (FP7) initiative under contract No. 278981 ‘ANGIOPREDICT’ Science Foundation Ireland under grant 13/CDA/2183. Irish Cancer Society Fellowship award CRF13DAS. Flemish Research Foundation ‘Kom op tegen kanker’ (grant 419.052.173). FWO-F (grant G070615N). State of Baden-Württemberg for “Center of Geriatric Biology and Oncology (ZOBEL)—Perspektivförderung” and “Biology of Frailty —Sonderlinie Medizin”.


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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.


Physics | Physiology


Smeets D, Miller IS, O'Connor DP, Das S, Moran B, Boeckx B, Gaiser T, Betge J, Barat A, Klinger R, van Grieken NCT, Cremolini C, Prenen H, Mazzone M, Depreeuw J, Bacon O, Fender B, Brady J, Hennessy BT, McNamara DA, Kay E, Verheul HM, Maarten N, Gallagher WM, Murphy V, Prehn JHM, Koopman M, Punt CJA, Loupakis F, Ebert MPA, Ylstra B, Lambrechts D, Byrne AT. Copy number load predicts outcome of metastatic colorectal cancer patients receiving bevacizumab combination therapy. Nature Communications. 2018;9(1):4112.

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