Invasionsfaktoren uPA/PAI‐1 im Tumorgewebe bei Patientinnen mit primärem Mammakarzinom: Von Forschungsergebnissen zur klinischen Anwendung am Beispiel der NNBC 3-Europe-Studie

 

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Zusammenfassung

Nach der Risikoabschätzung entsprechend den Empfehlungen von St. Gallen 2007 werden mehr als 70 % der Patientinnen mit nodalnegativem Mammakarzinom anhand klinisch-pathologischer Prognosefaktoren der Gruppe mit mittlerem Rezidivrisiko zugeordnet. Nach St. Gallen besteht hier bei hormonrezeptorpositiven Karzinomen eine Therapieoption mit oder ohne adjuvante Chemotherapie, und es gilt, diejenigen Patientinnen zu identifizieren, denen aufgrund ihres niedrigen Risikos eine Chemotherapie erspart werden kann. Zur Identifizierung dieser Patientinnen eignet sich das uPA/PAI-1-System. Die Protease uPA (Plasminogen-Aktivator vom Urokinase-Typ) und deren Inhibitor PAI-1 (Plasminogen-Aktivator-Inhibitor-1) sind an einer Reihe von biologischen Prozessen, wie zelluläre Invasivität, Seneszenz und Angiogenese, beteiligt. Nach Erreichen des höchsten Evidenzniveaus (Level of Evidence, LoE-1) sind uPA und PAI‐1 als prognostische Biomarker beim nodalnegativen Mammakarzinom anerkannt. Hinsichtlich ihrer klinischen Wertigkeit zur Risikoabschätzung wurde der Kombination uPA/PAI-1 als Biomarker der Empfehlungsgrad „+“ von der AGO zugeordnet, d. h. sie können in der klinischen Routine zur Therapieentscheidung herangezogen werden. In der aktuell laufenden klinischen Studie NNBC 3-Europe sollen der prognostische und prädiktive Wert von uPA/PAI-1 und der Nutzen dieser Faktoren für die klinische Routine bestätigt werden. Inzwischen sind mehrere therapeutische Substanzen in klinischer Erprobung, die mit dem uPA/PAI-1-System selektiv interagieren. Die Prognosefaktoren uPA und PAI-1 stellen ein typisches Beispiel dar, wie Erkenntnisse aus der Grundlagenforschung in translationale Forschung einfließen, um später für den klinischen Alltag und zum Vorteil für den Patienten genutzt zu werden.

Abstract

According to established clinicopathological factors, approximately 70 % of breast cancer patients without axillary node involvement belong to the group of patients with an intermediate risk of recurrence. In such patients with endocrine responsive disease, the current guidelines suggest either adjuvant chemo-endocrine therapy or endocrine therapy alone. The challenge is therefore to identify those patients who will not need adjuvant chemotherapy due to their very low risk of recurrence. The plasminogen activator system is a complex system with multiple functions, e.g. cell invasion, angiogenesis and senescence, in a variety of solid tumors. Increased levels of the invasion factors uPA (urokinase-type plasminogen activator) and/or its inhibitor PAI-1 in primary breast cancer tissue have been correlated with a poor outcome. The clinical utility of uPA/PAI-1 has been proven at the highest level of evidence (LoE-1). In the evidence-based, annually updated AGO guidelines on breast cancer management, the German Working Group for Gynecological Oncology (AGO) recommended a combination of both biomarkers as risk-group-classification markers for routine clinical decisions. In addition to being clinically useful for prognostic assessment, the biomarkers may also serve as predictive factors predicting the response to adjuvant chemotherapy. Moreover, specific compounds that interact with the uPA/PAI-1 system are currently in phase II/III development for the treatment of several cancer entities. The ongoing NNBC 3-Europe trial is aimed at validating uPA/PAI-1 for clinical routine risk assessment and optimizing adjuvant chemotherapy in node-negative high-risk patients. The development and transfer of basic research data for uPA/PAI-1 into clinical practice in two evidence-based clinical trials represents an excellent example of successful translational research.

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Dr. Martina Vetter

Universitätsklinik und Poliklinik für Gynäkologie der Martin-Luther-Universität Halle-Wittenberg

Ernst-Grube-Straße 40

06120 Halle an der Saale

Email: martina.vetter@medizin.uni-halle.de