53PD - Copy number alterations as predictive biomarkers for response to bevacizumab in metastatic colorectal cancer

Date 09 October 2016
Event ESMO 2016 Congress
Session Basic science and translational research
Topics Anti-Cancer Agents & Biologic Therapy
Translational Research
Presenter Nicole van Grieken
Citation Annals of Oncology (2016) 27 (6): 15-42. 10.1093/annonc/mdw363
Authors 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
  • 1Department Of Pathology, VU University Medical Center, 1007 MB - Amsterdam/NL
  • 2Department Of Medical Oncology, VU University Medical Center, Amsterdam/NL
  • 3Medical Oncology, Academic Medical Center, University of Amsterdam, 1100 DD - Amsterdam/NL
  • 4Medical Oncology, University Medical Center Utrecht, 3584 CX - Utrecht/NL
  • 5Department Of Pathology, Het Nederlands Kanker Instituut Antoni van Leeuwenhoek (NKI-AVL), Amsterdam/NL
  • 6Clinical Research, Irish Clinical Oncology Research Group ICORG, Dublin/IE
  • 7Department Of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin/IE
  • 8Department Of Medicine Ii, Universitätsklinikum Mannheim, 68167 - Mannheim/DE
  • 9Institute Of Pathology, Universitätsklinikum Mannheim, Mannheim/DE
  • 10Research And Development Department, OncoMark Limited, Dublin/IE
  • 11Ucd Conway Institute, University College Dublin, Dublin/IE
  • 12Department Of Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin/IE
  • 13Vesalius Research Center, VIB and KU, Leuven/BE

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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

Funding

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

Disclosure

All authors have declared no conflicts of interest.