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Title: 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.
Austin Authors: van Dijk, Erik;van Werkhoven, Erik;Asher, Rebecca;Mooi, Jennifer K ;Espinoza, David;van Essen, Hendrik F;van Tinteren, Harm;van Grieken, Nicole C T;Punt, Cornelis J A;Tebbutt, Niall C ;Ylstra, Bauke
Affiliation: Olivia Newton-John Cancer Research Institute
Medical Oncology
Department of Medicine, University of Melbourne, Melbourne, Australia
Peter MacCallum Cancer Institute, Melbourne, Australia
Department of Surgery, University of Melbourne, Melbourne, Australia
Department of Biostatistics, NHMRC Clinical Trials Centre, University of Sydney, Camperdown, Australia
Biometrics Department, Erasmus Medical Center, Rotterdam, The Netherlands
Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center, Amsterdam, The Netherlands
Trial and Datacenter, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
Department of Epidemiology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
Issue Date: 1-Oct-2022 2022-05-23
Publication information: International Journal of Cancer 2022; 151(7): 1166-1174
Abstract: 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.
DOI: 10.1002/ijc.34061
ORCID: 0000-0001-9479-3010
Journal: International Journal of Cancer
PubMed URL: 35489024
PubMed URL:
Type: Journal Article
Subjects: anti-VEGF monoclonal antibody
chromosome 18q
metastatic colorectal cancer
predictive biomarker
randomized controlled trial
Appears in Collections:Journal articles

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