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

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posted on 22.11.2019 by Dominiek Smeets, Ian S. Miller, Darran P. O'Connor, Sudipto Das, Bruce Moran, Bram Boeckx, Timo Gaiser, Johannes Betge, Ana Barat, Rut Klinger, Nicole CT van Grieken, Chiara Cremolini, Hans Prenen, Massimiliano Mazzone, Jeroen Depreeuw, Orna Bacon, Bozena Fender, Joseph Brady, Bryan T. Hennessy, Deborah A. McNamara, Elaine W. Kay, Henk M. Verheul, Neerincx Maarten, William M. Gallagher, Verena Murphy, Jochen HM Prehn, Miriam Koopman, Cornelis JA Punt, Fotios Loupakis, Matthias PA Ebert, Bauke Ylstra, Diether Lambrechts, Annette Byrne

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.

Funding

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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The original article is available at www.nature.com

Published Citation

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.

Publication Date

05/10/2018

Publisher

Nature Publishing Group

PubMed ID

30291241

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