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Biomarkeranalytik aus Sicht des Pathologen

Grundlage für eine rationale, personalisierte Tumortherapie am Beispiel von Lungenkrebs

Biomarker analysis from a pathologist’s view

Founding the rationale for personalised treatment of lung cancer

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Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz Aims and scope

Zusammenfassung

In der Ära der genomischen Medizin und der Sequenzierung zahlreicher Krebsgenome hat sich unser Verständnis der molekularen Mechanismen der Krebsentstehung zusehends verbessert. Die Initiierung der Krebsentstehung über genetische und epigenetische Veränderungen (pathogenetische Läsionen) und die Tumorprogression durch sog. Treibermutationen wurden erkannt. Zudem hat die schnelle Entwicklung von niedermolekularen Inhibitoren und hochselektiven Biologika dazu geführt, dass onkogenen Signalen, die durch Alterationen im Krebsgenom entstehen, zielgerichtet begegnet werden kann. Hierdurch ist der Pathologe nun in der Lage, die tumorverursachenden Veränderungen im Krebsgenom als molekulare Biomarker zu diagnostizieren und die Selektion von Patienten in effektive und hochsensitive Therapiemodalitäten zu steuern. Wenn onkogene Treibermutationen intensiv präklinisch validiert werden und ein entsprechender diagnostischer Test zur Verfügung steht, ist es möglich, zu einem sehr frühen Zeitpunkt der klinischen Medikamentenentwicklung einen Proof-of-Concept (PoC) zu erbringen, der einen unmittelbaren persönlichen Nutzen für die Patienten in solchen Phase-I/II-Studien hat. Diese neue Vorgehensweise hat die klinischen Tests signifikant verändert und vermeidet zudem, dass die Wirksamkeit in großen klinischen Phase-III-Studien mit einer hohen Ausfallrate getestet werden muss. Daher fasst der vorliegende Beitrag neuste und paradigmatische Prozesse der Biomarkerdiagnostik am Beispiel von Lungenkrebs zusammen und definiert akademische und regulatorische Anforderungen der Biomarkeranalyse und selektiver personalisierter Therapien.

Abstract

The advent of genomic medicine and sequencing analysis of entire cancer genomes has rapidly improved our understanding of cancer genomics and has defined pathogenetic lesions initiating and driving cancer phenotypes in a causative manner. Moreover rapid development of small molecule inhibitors and highly selective biologicals provided effective tools to intervene with oncogenic signalling resulting from such lesions in the cancer genome. Thereby, the pathologist is now in the position to diagnose causative lesions in the cancer genome as molecular biomarkers directing the selection of patients for effective and highly selective therapies. If oncogenic driver lesions are vigorously validated preclinically and a useful diagnostic test is available, it is possible to provide a proof-of-concept at a very early stage of clinical drug development with the possibility of immediate personal benefit for participants in such phase I/II studies. This approach has significantly changed clinical testing and avoids testing proof for efficacy in large stage III clinical trials at a high failure rate. Therefore, our review summarises recent and paradigmatic progress in lung cancer biomarker diagnostics and defines academic and regulatory requirements for biomarker analysis and selective personalised therapies.

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Einhaltung ethischer Richtlinien

Interessenkonflikt. R. Büttner erhält Berater- und Referentenhonorar von den Firmen Roche, Novartis Boehringer Ingelheim, Lilly, AstraZeneca und Pfizer und Forschungsunterstützung von den Firmen Roche und Novartis. R. Büttner ist Gründer und Besitzer von Targos Molecular Diagnostics Ltd., Kassel und Köln, Deutschland. C. Heydt gibt an, dass kein Interessenkonflikt besteht. Dieser Beitrag beinhaltet keine Studien an Menschen oder Tieren.

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  1. Institut für Pathologie, Universitätsklinikum Köln und Centrum für Integrierte Onkologie, Universität zu Köln, Kerpener Str. 62, 50937, Köln, Deutschland

    R. Buettner & C. Heydt

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Correspondence to R. Buettner.

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Buettner, R., Heydt, C. Biomarkeranalytik aus Sicht des Pathologen. Bundesgesundheitsbl. 56, 1502–1508 (2013). https://doi.org/10.1007/s00103-013-1823-1

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