Abstract

Precision medicine has revolutionised cancer treatments; however, actionable biomarkers remain scarce. To address this, we develop the Oncology Biomarker Discovery (OncoBird) framework for analysing the molecular and biomarker landscape of randomised controlled clinical trials. OncoBird identifies biomarkers based on single genes or mutually exclusive genetic alterations in isolation or in the context of tumour subtypes, and finally, assesses predictive components by their treatment interactions. Here, we utilise the open-label, randomised phase III trial (FIRE-3, AIO KRK-0306) in metastatic colorectal carcinoma patients, who received either cetuximab or bevacizumab in combination with 5-fluorouracil, folinic acid and irinotecan (FOLFIRI). We systematically identify five biomarkers with predictive components, e.g., patients with tumours that carry chr20q amplifications or lack mutually exclusive ERK signalling mutations benefited from cetuximab compared to bevacizumab. In summary, OncoBird characterises the molecular landscape and outlines actionable biomarkers, which generalises to any molecularly characterised randomised controlled trial.

Identifying actionable biomarkers remains a challenge. Here, the authors develop a framework Oncology Biomarker Discovery (OncoBird), apply it to a phase III trial and investigate the molecular and biomarker landscape of metastatic colorectal carcinoma patients.

Details

Title
The Oncology Biomarker Discovery framework reveals cetuximab and bevacizumab response patterns in metastatic colorectal cancer
Author
Ohnmacht, Alexander J. 1 ; Stahler, Arndt 2 ; Stintzing, Sebastian 3   VIAFID ORCID Logo  ; Modest, Dominik P. 2   VIAFID ORCID Logo  ; Holch, Julian W. 4 ; Westphalen, C. Benedikt 5   VIAFID ORCID Logo  ; Hölzel, Linus 6 ; Schübel, Marisa K. 7 ; Galhoz, Ana 7 ; Farnoud, Ali 6 ; Ud-Dean, Minhaz 6 ; Vehling-Kaiser, Ursula 8 ; Decker, Thomas 9 ; Moehler, Markus 10 ; Heinig, Matthias 11 ; Heinemann, Volker 5 ; Menden, Michael P. 12   VIAFID ORCID Logo 

1  Helmholtz Munich, Computational Health Center, Neuherberg, Germany; Ludwig-Maximilians University Munich, Department of Biology, Martinsried, Germany (GRID:grid.5252.0) (ISNI:0000 0004 1936 973X) 
2  corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Cancer Immunology, Charité Universitätsmedizin, Berlin, Germany (GRID:grid.6363.0) (ISNI:0000 0001 2218 4662) 
3  corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Cancer Immunology, Charité Universitätsmedizin, Berlin, Germany (GRID:grid.6363.0) (ISNI:0000 0001 2218 4662); partner sites Berlin and Munich, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584) 
4  partner sites Berlin and Munich, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584); University Hospital, Ludwig-Maximilians University Munich, Department of Medicine III and Comprehensive Cancer Center Munich, Munich, Germany (GRID:grid.5252.0) (ISNI:0000 0004 1936 973X) 
5  University Hospital, Ludwig-Maximilians University Munich, Department of Medicine III and Comprehensive Cancer Center Munich, Munich, Germany (GRID:grid.5252.0) (ISNI:0000 0004 1936 973X) 
6  Helmholtz Munich, Computational Health Center, Neuherberg, Germany (GRID:grid.5252.0) 
7  Helmholtz Munich, Computational Health Center, Neuherberg, Germany (GRID:grid.5252.0); Ludwig-Maximilians University Munich, Department of Biology, Martinsried, Germany (GRID:grid.5252.0) (ISNI:0000 0004 1936 973X) 
8  Oncological Practice, Landshut, Germany (GRID:grid.5252.0) 
9  Oncological Practice, Ravensburg, Germany (GRID:grid.5252.0) 
10  Johannes Gutenberg-University Clinic, Department of Medicine I and Research Center for Immunotherapy (FZI), Mainz, Germany (GRID:grid.5802.f) (ISNI:0000 0001 1941 7111) 
11  Helmholtz Munich, Computational Health Center, Neuherberg, Germany (GRID:grid.5802.f) 
12  Helmholtz Munich, Computational Health Center, Neuherberg, Germany (GRID:grid.5252.0); Ludwig-Maximilians University Munich, Department of Biology, Martinsried, Germany (GRID:grid.5252.0) (ISNI:0000 0004 1936 973X); University of Melbourne, Department of Biochemistry and Pharmacology, Victoria, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X) 
Pages
5391
Publication year
2023
Publication date
2023
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-023-41011-4
ProQuest document ID
2860455516
Copyright
© The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.