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

Author

Listed:
  • Dominiek Smeets

    (VIB Center for Cancer Biology
    University of Leuven (KULeuven))

  • Ian S. Miller

    (Royal College of Surgeons in Ireland)

  • Darran P. O’Connor

    (Royal College of Surgeons in Ireland
    University College Dublin)

  • Sudipto Das

    (Royal College of Surgeons in Ireland
    University College Dublin)

  • Bruce Moran

    (University College Dublin)

  • Bram Boeckx

    (VIB Center for Cancer Biology
    University of Leuven (KULeuven))

  • 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
    Center for Oncological Research, Antwerp University)

  • Massimiliano Mazzone

    (VIB Center for Cancer Biology
    University of Leuven (KULeuven))

  • Jeroen Depreeuw

    (VIB Center for Cancer Biology
    University of Leuven (KULeuven)
    University Hospitals Leuven, KU Leuven)

  • 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
    OncoMark Limited, NovaUCD)

  • 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
    University of Leuven (KULeuven))

  • Annette T. Byrne

    (Royal College of Surgeons in Ireland
    University College Dublin)

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.

Suggested Citation

  • 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, 2018. "Copy number load predicts outcome of metastatic colorectal cancer patients receiving bevacizumab combination therapy," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06567-6
    DOI: 10.1038/s41467-018-06567-6
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