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 van Grieken, Chiara Cremolini, Hans Prenen, Massimiliano Mazzone, Jeroen Depreeuw, Orna Bacon, Bozena Fender, Joseph Brady, Bryan T Hennessy, Deborah A McNamaraElaine 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, Annette T Byrne

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)4112
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - Oct 5 2018

Keywords

  • Adenocarcinoma/drug therapy
  • Aged
  • Animals
  • Antineoplastic Agents, Immunological/therapeutic use
  • Bevacizumab/therapeutic use
  • Chromosomal Instability
  • Colorectal Neoplasms/drug therapy
  • DNA Copy Number Variations
  • Female
  • Humans
  • Male
  • Mice
  • Middle Aged
  • Retrospective Studies
  • Xenograft Model Antitumor Assays

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