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Basic science and translational research

1552 - Copy number alterations as predictive biomarkers for response to bevacizumab in metastatic colorectal cancer


09 Oct 2016


Basic science and translational research


Nicole van Grieken


Annals of Oncology (2016) 27 (6): 15-42. 10.1093/annonc/mdw363


N.C. van Grieken1, M. Cordes1, H.M. Verheul2, M. Neerincx2, C. Punt3, M. Koopman4, G.A. Meijer5, V. Murphy6, A. Barat7, J. Betge8, M. Ebert8, T. Gaiser9, B. Fender10, R. Klinger11, S. Das12, D. Smeets13, D. O'Connor12, D. Lambrechts13, A.T. Byrne7, B. Ylstra1

Author affiliations

  • 1 Department Of Pathology, VU University Medical Center, 1007 MB - Amsterdam/NL
  • 2 Department Of Medical Oncology, VU University Medical Center, Amsterdam/NL
  • 3 Medical Oncology, Academic Medical Center, University of Amsterdam, 1100 DD - Amsterdam/NL
  • 4 Medical Oncology, University Medical Center Utrecht, 3584 CX - Utrecht/NL
  • 5 Department Of Pathology, Het Nederlands Kanker Instituut Antoni van Leeuwenhoek (NKI-AVL), Amsterdam/NL
  • 6 Clinical Research, Irish Clinical Oncology Research Group ICORG, Dublin/IE
  • 7 Department Of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin/IE
  • 8 Department Of Medicine Ii, Universitätsklinikum Mannheim, 68167 - Mannheim/DE
  • 9 Institute Of Pathology, Universitätsklinikum Mannheim, Mannheim/DE
  • 10 Research And Development Department, OncoMark Limited, Dublin/IE
  • 11 Ucd Conway Institute, University College Dublin, Dublin/IE
  • 12 Department Of Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin/IE
  • 13 Vesalius Research Center, VIB and KU, Leuven/BE


Abstract 1552


Bevacizumab (BeV) is an angiogenesis inhibitor that is currently used in patients with metastatic colorectal cancer (mCRC). However, response on treatment is variable and predictive biomarkers are urgently needed. The aim of this study was to identify copy number alterations that are associated with response to bevacizumab.


Within the AngioPredict project tumor tissue samples from 182 mCRC patients treated with chemotherapy alone or chemotherapy plus BeV were retrospectively collected. The overall median progression-free survival (PFS) was 217 days. A second series of 103 patients who were treated with chemotherapy and BeV in the context of the CAIRO2 trial were included for validation purposes. Copy number data, obtained by next generation sequencing (NGS), were analyzed using a routine pipeline, generating regions called for gains or losses. A log-rank test using 10.000 permutations was performed to calculate the significance of DNA copy number correlations to PFS in each study arm. Then Kaplan-Meijer analysis was performed for individual candidate regions.


Out of 182 patients in the AngioPredict cohort, after quality assurance checks 157 cases remained for downstream analysis. Out of these 157 patients, 113 patients were treated with chemotherapy in combination with BeV and 44 were treated with chemotherapy alone (non-BeV). Frequency plots for copy number alterations matched with CRC profiles known from literature. Log-rank test revealed significant associations between copy number alterations and PFS in the BeV group (P = 0.002), but not in the non-BeV group. The predictive value of loss at chromosome 18q12.1-18q21.32 was confirmed in the CAIRO2 validation set.


NGS copy number sequencing revealed that loss of chromosome 18q12.1-18q21.32 is associated with prolonged PFS in patients treated with chemotherapy plus BeV and may serve as a candidate biomarker for response to BeV. Further studies are needed to confirm these results. The AngioPredict project was funded by the European Commission Framework Programme Seven (FP7) initiative under contract No. 278981 ‘AngioPredict’ (www. angiopredict.com).

Clinical trial identification

Legal entity responsible for the study

VU University Medical Center


European Commission Framework Programme Seven (FP7) initiative under contract No. 278981 ‘AngioPredict’


All authors have declared no conflicts of interest.

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