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

Author

Listed:
  • Alexander J. Ohnmacht

    (Helmholtz Munich
    Ludwig-Maximilians University 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
    partner sites Berlin and Munich, German Cancer Research Center (DKFZ))

  • 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)
    University Hospital, Ludwig-Maximilians University Munich)

  • C. Benedikt Westphalen

    (University Hospital, Ludwig-Maximilians University Munich)

  • Linus Hölzel

    (Helmholtz Munich)

  • Marisa K. Schübel

    (Helmholtz Munich
    Ludwig-Maximilians University Munich)

  • Ana Galhoz

    (Helmholtz Munich
    Ludwig-Maximilians University 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
    Ludwig-Maximilians University Munich
    University of Melbourne)

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.

Suggested Citation

  • 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-Dea, 2023. "The Oncology Biomarker Discovery framework reveals cetuximab and bevacizumab response patterns in metastatic colorectal cancer," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41011-4
    DOI: 10.1038/s41467-023-41011-4
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    References listed on IDEAS

    as
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    3. Stefan Wager & Susan Athey, 2018. "Estimation and Inference of Heterogeneous Treatment Effects using Random Forests," Journal of the American Statistical Association, Taylor & Francis Journals, vol. 113(523), pages 1228-1242, July.
    4. Susan Athey & Stefan Wager, 2021. "Policy Learning With Observational Data," Econometrica, Econometric Society, vol. 89(1), pages 133-161, January.
    5. Seibold Heidi & Zeileis Achim & Hothorn Torsten, 2016. "Model-Based Recursive Partitioning for Subgroup Analyses," The International Journal of Biostatistics, De Gruyter, vol. 12(1), pages 45-63, May.
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