The Oncology Biomarker Discovery framework reveals cetuximab and bevacizumab response patterns in metastatic colorectal cancer

Alexander J. Ohnmacht, Arndt Stahler, Sebastian Stintzing, Dominik P. Modest, Julian W. Holch, C. Benedikt Westphalen, Linus Hölzel, Marisa K. Schübel, Ana Galhoz, Ali Farnoud, Minhaz Ud-Dean, Ursula Vehling-Kaiser, Thomas Decker, Markus Moehler, Matthias Heinig, Volker Heinemann () and Michael P. Menden ()
Additional contact information
Alexander J. Ohnmacht: Helmholtz Munich
Arndt Stahler: corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Cancer Immunology
Sebastian Stintzing: corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Cancer Immunology
Dominik P. Modest: corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Cancer Immunology
Julian W. Holch: partner sites Berlin and Munich, German Cancer Research Center (DKFZ)
C. Benedikt Westphalen: University Hospital, Ludwig-Maximilians University Munich
Linus Hölzel: Helmholtz Munich
Marisa K. Schübel: Helmholtz Munich
Ana Galhoz: Helmholtz Munich
Ali Farnoud: Helmholtz Munich
Minhaz Ud-Dean: Helmholtz Munich
Ursula Vehling-Kaiser: Oncological Practice
Thomas Decker: Oncological Practice
Markus Moehler: Johannes Gutenberg-University Clinic
Matthias Heinig: Helmholtz Munich
Volker Heinemann: University Hospital, Ludwig-Maximilians University Munich
Michael P. Menden: Helmholtz Munich

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41011-4

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