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Tumor genetics and individualized therapy

Tumorgenetik und personalisierte Therapie

  • Leitthema
  • Published:
Die Gynäkologie Aims and scope

Abstract

Efforts to translate information from sequencing-based tumor genetic characterization into treatment personalization are becoming widespread in the clinic. However, for them to be successful and consequently lead to improved treatment outcomes, familiarity with predictive biomarkers and the associated treatment landscape is mandatory. The purpose of this review is to provide a structured overview of established biomarkers and associated genetic alterations ranging from single-gene to complex biomarkers, as well as to summarize the presently available clinical evidence on their predictive value with respect to currently approved targeted therapies in advanced breast and gynecologic malignancies. Importantly, apart from predicting response, sequencing-derived biomarkers can also inform on the lack of benefit from or even resistance to certain targeted therapies. In addition to providing an overview on how tumor genetics can guide selection of targeted therapies within their approved indication, this review also provides biomarker examples and related evidence which could suggest their potential off-label use, particularly in situations where tumor sequencing reveals a potentially actionable alteration but no other satisfactory treatment options remain. Moreover, another practical consequence of tumor sequencing for clinicians is that it can also facilitate and expedite access of patients to innovative treatment options within clinical trials, as it can be used as a powerful tool for patient stratification, especially for genomically driven and biomarker-stratified trials. In conclusion, all of the above illustrate the transformative potential and impact that tumor molecular profiling is having on the clinical management of advanced breast and gynecologic malignancies.

Zusammenfassung

Die genetische Charakterisierung von Tumoren durch Sequencing nimmt zunehmend Eingang in die Klinik als personalisierte Medizin. Um aber diese Techniken erfolgreich für die Behandlung einsetzen zu können, sind gute Kenntnisse über prädiktive Biomarker und die daraus ableitbaren Behandlungsstrategien unumgänglich. In der vorliegenden Arbeit werden deshalb die Zusammenhänge zwischen genetischer Tumorcharakterisierung und etablierten prädiktiven Biomarkern dargestellt. Außerdem wird auf ihre prädiktive Bedeutung für bereits klinisch verwendete Targettherapien insbesondere bei fortgeschrittenen Mammakarzinomen und anderen gynäkologischen Malignomen eingegangen. Darüber hinaus können genetische Signaturen nicht nur als prädiktive Biomarker eingesetzt werden, sondern auch helfen, die Wirksamkeit neuer Therapien zu bewerten. Auch können sich aus dieser genetischen Diagnostik neue Behandlungsmöglichkeiten mit Medikamenten im „off-label use“ ergeben, wenn keine anderen etablierten Behandlungsverfahren mehr eingesetzt werden können. Eine genetische Tumorcharakterisierung kann Patienten auch den Zugang zu neuen Therapiestudien eröffnen, da die Tumorgenetik neue Wege der Stratifizierung insbesondere in Studien, die gezielt nach genetischen Befunden stratifizieren, ermöglicht. So bietet eine molekulargenetische Charakterisierung von Tumoren zahlreiche neue Ansätze für die Onkologie weg von einer ausschließlich organbezogenen Betrachtungsweise hin zu einer Tumorklassifizierung basierend auf genetischen Mustern. Damit wird das transformative Potenzial und der Einfluss des molekularen Profilings von Tumoren in Bezug auf die klinische Versorgung fortgeschrittener Mammakarzinome und anderer gynäkologischer Malignome veranschaulicht.

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  1. National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 69120, Heidelberg, Germany

    Mario Hlevnjak

  2. German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Mario Hlevnjak

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Correspondence to Mario Hlevnjak.

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M. Hlevnjak declares receiving speaker’s fee from Merck Sharp & Dohme (MSD).

For this article no studies with human participants or animals were performed by any of the authors. All studies mentioned were in accordance with the ethical standards indicated in each case.

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Thomas Strowitzki, Heidelberg

Klaus Diedrich, Lübeck

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Hlevnjak, M. Tumor genetics and individualized therapy. Gynäkologie 55, 424–431 (2022). https://doi.org/10.1007/s00129-022-04931-8

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