TY - JOUR
T1 - Predictive value of chromosome 18q11.2-q12.1 loss for benefit from bevacizumab in metastatic colorectal cancer
T2 - A post hoc analysis of the randomized phase III-trial AGITG-MAX
AU - van Dijk, Erik
AU - van Werkhoven, Erik
AU - Asher, Rebecca
AU - Mooi, Jennifer K.
AU - Espinoza, David
AU - van Essen, Hendrik F.
AU - van Tinteren, Harm
AU - van Grieken, Nicole C. T.
AU - Punt, Cornelis J. A.
AU - Tebbutt, Niall C.
AU - Ylstra, Bauke
N1 - Funding Information: KWF Kankerbestrijding, Grant/Award Number: 2015-7882; The Sacha Swarttouw-Hijmans Foundation Publisher Copyright: © 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
PY - 2022/10/1
Y1 - 2022/10/1
N2 - 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.
AB - 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.
KW - anti-VEGF monoclonal antibody
KW - bevacizumab
KW - chromosome 18q
KW - metastatic colorectal cancer
KW - predictive biomarker
KW - randomized controlled trial
UR - http://www.scopus.com/inward/record.url?scp=85130614254&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/ijc.34061
DO - https://doi.org/10.1002/ijc.34061
M3 - Article
C2 - 35489024
SN - 0020-7136
VL - 151
SP - 1166
EP - 1174
JO - International journal of cancer
JF - International journal of cancer
IS - 7
ER -