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Nat Commun. 2018 Oct 5;9(1):4112. doi: 10.1038/s41467-018-06567-6.

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

Author information

1
VIB Center for Cancer Biology, VIB, Herestraat 49, 3000, Leuven, Belgium.
2
Department of Human Genetics, University of Leuven (KULeuven), Herestraat 49, 3000, Leuven, Belgium.
3
Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 31A York Street, Dublin, D2, Ireland.
4
Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, 123 St.Stephen's Green, Dublin, D2, Ireland.
5
UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, D4, Ireland.
6
Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
7
Department of Medicine II, University Hospital Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
8
Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
9
Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Istituto Toscano Tumori, Lungarno Antonio Pacinotti, 43, 56126, Pisa, Italy.
10
Department of Oncology, University Hospital Antwerp, Edegem, 2650, Belgium.
11
Center for Oncological Research, Antwerp University, 2650, Edegem, Belgium.
12
Department of Oncology, University of Leuven (KULeuven), Herestraat 49, 3000, Leuven, Belgium.
13
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University Hospitals Leuven, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
14
OncoMark Limited, NovaUCD, Belfield Innovation Park, Dublin, D4, Ireland.
15
Veterinary Pathobiology, School of Veterinary Medicine, University College Dublin, Stillorgan Rd, Belfield, Dublin, D4, Ireland.
16
Department of Surgery, Beaumont Hospital, Beaumont Rd, Beaumont, Dublin, D9, Ireland.
17
Department of Pathology, Beaumont Hospital, Beaumont Rd, Beaumont, Dublin, D9, Ireland.
18
Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
19
Cancer Trials Ireland, Innovation House, Old Finglas Road, Dublin, D9, Ireland.
20
Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
21
Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
22
Oncologia Medica 1, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS, Via Gattamelata, 64, 35128, Padova, Italy.
23
VIB Center for Cancer Biology, VIB, Herestraat 49, 3000, Leuven, Belgium. Diether.Lambrechts@kuleuven.vib.be.
24
Department of Human Genetics, University of Leuven (KULeuven), Herestraat 49, 3000, Leuven, Belgium. Diether.Lambrechts@kuleuven.vib.be.

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.

PMID:
30291241
PMCID:
PMC6173768
DOI:
10.1038/s41467-018-06567-6
[Indexed for MEDLINE]
Free PMC Article

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