Predictive value of chromosome 18q11.2-q12.1 loss for benefit from bevacizumab in metastatic colorectal cancer: A post hoc analysis of the randomized phase III-trial AGITG-MAX

Erik van Dijk, Erik van Werkhoven, Rebecca Asher, Jennifer K. Mooi, David Espinoza, Hendrik F. van Essen, Harm van Tinteren, Nicole C.T. van Grieken, Cornelis J.A. Punt, Niall C. Tebbutt, Bauke Ylstra

Research output: Contribution to journalArticlepeer-review


The VEGF-A monoclonal antibody bevacizumab is currently recommended for first-line treatment of all metastatic colorectal cancer (mCRC) patients. Cost-benefit ratio and side-effects however necessitate patient selection. A large retrospective yet nonrandomized study showed that patients with loss of chromosome 18q11.2-q12.1 in the tumor and treated with bevacizumab have 3 months improved median progression-free (PFS) and overall survival (OS) benefit compared to patients without this loss and/or treatment modality. Implementation for loss of chromosome 18q11.2-q12.1 as a marker in clinical practice mandates evidence in a randomized controlled trial for bevacizumab. Of the trials with randomization of chemotherapy vs chemotherapy with bevacizumab, the AGITG-MAX trial was the only one with tumor materials available. Chromosome 18q11.2-q12.1 copy number status was measured for 256 AGITG-MAX trial patients and correlated with PFS according to a predefined analysis plan with marker-treatment interaction as the primary end-point. Chromosome 18q11.2-q12.1 losses were detected in 71% of patients (181/256) characteristic for mCRC. Consistent with the nonrandomized study, significant PFS benefit of bevacizumab was observed in patients with chromosome 18q11.2-q12.1 loss (P =.009), and not in patients without 18q loss (P =.67). Although significance for marker-treatment interaction was not reached (Pinteraction =.28), hazard ratio and 95% confidence interval of this randomized cohort (HRinteraction = 0.72; 95% CI = 0.39-1.32) shows striking overlap with the nonrandomized study cohorts (HRinteraction = 0.41; 95% CI = 0.32-0.8) supported by a nonsignificant Cochrane χ2 test (P =.11) for heterogeneity. We conclude that post hoc analysis of the AGITG-MAX RCT provides supportive evidence for chromosome 18q11.2-q12.1 as a predictive marker for bevacizumab in mCRC patients.

Original languageEnglish
Pages (from-to)1166-1174
Number of pages9
JournalInternational Journal of Cancer
Issue number7
Publication statusPublished - 1 Oct 2022


  • anti-VEGF monoclonal antibody
  • bevacizumab
  • chromosome 18q
  • metastatic colorectal cancer
  • predictive biomarker
  • randomized controlled trial
  • Chromosome Deletion
  • Colonic Neoplasms/genetics
  • Humans
  • Bevacizumab/therapeutic use
  • Colorectal Neoplasms/drug therapy
  • Antineoplastic Combined Chemotherapy Protocols/therapeutic use
  • Disease-Free Survival
  • Fluorouracil/therapeutic use
  • Rectal Neoplasms/drug therapy
  • Retrospective Studies
  • Chromosomes


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