Prädiktive Mutationsdiagnostik bei Mammakarzinomen

Relevant mutations in predictive breast cancer pathology

Zusammenfassung

Während prädiktive Immunhistochemie beim Mammakarzinom seit langer Zeit ein zentrales Element der pathologischen Tumorklassifikation ist, hat die prädiktive Molekularpathologie, abgesehen von der In-situ-Hybridisierung zur Erfassung der HER2-Amplifikation, erst in den letzten Jahren durch die Zulassung von neuen Medikamenten zur gezielten Therapie in der metastasierten Situation an Bedeutung gewonnen. Für die Indizierung von PARP-Inhibitoren ist der Nachweis einer BRCA1- oder BRCA2-Mutation erforderlich. Wenn eine Mutation der katalytischen α‑Untereinheit der Phosphatidylinositol‑4,5‑bisphosphat-3-Kinase (PIK3CA) vorliegt, die bei bis zu 40 % der luminalen Mammakarzinome angetroffen werden kann, besteht die Option für eine spezifische Inhibition mit Alpelisib. Der HER2-codierte Rezeptor trägt nicht nur durch eine Amplifikation und Überexpression zur neoplastischen Transformation bei, sondern dies kann auch durch eine aktivierende Mutation in der Kinasedomäne bewirkt werden, wodurch eine Responsivität gegenüber Tyrosinkinaseinhibitoren vom Typ des Tucatinibs/Neratinibs gegeben ist. Bis zu 30 % aller metastasierten und endokrin behandelten luminalen Mammakarzinome erwerben eine aktivierende Mutation des Östrogenrezeptorgens ESR1, wodurch ein ligandenunabhängiger autokriner Wachstumsstimulationsmodus entsteht und Aromataseinhibitoren nicht mehr wirken können. Eine Larotrectinib-sensitive Mutation der Tropomyosinrezeptorkinase (NTRK) findet sich in bis zu 50 % der sekretorischen Mammakarzinome, während sie bei den übrigen histologischen Typen mit einer Frequenz von unter 1 % nachgewiesen werden kann. Zusammenfassend nimmt die prädiktive Molekularpathologie beim metastasierten Mammakarzinom eine zunehmend wichtige Stellung ein.

Abstract

Whereas predictive immunohistochemistry has represented a core element of breast cancer classification for decades, predictive molecular pathology, with the exception of in situ hybridization for assessment of HER2 amplification, has only recently gained importance because novel drugs have been approved for treatment of metastatic disease. For the use of PARP inhibitors, proof of BRCA1 or BRCA2 mutation is mandatory. When mutation of the catalytic subunit α of the phosphatidylinositol‑4.5‑bisphosphate 3‑kinase gene (PIK3CA) is present, which can be encountered in up to 40% of luminal breast cancers, the option for treatment with the specific inhibitor alpelisib arises. The HER2 -encoded growth factor receptor contributes to neoplastic transformation not only by amplification and overexpression but also by activating the mutation of the kinase domain, which is responsive to tyrosine kinase inhibitors of the tucatinib/neratinib type. Up to 30% of metastatic and endocrine treated luminal breast cancers acquire an activating mutation of the estrogen receptor gene ESR1, resulting in an autocrine and ligand-independent growth stimulation resistant to aromatase inhibitors. Larotrectinib-sensitive mutation of tropomyosinreceptor kinase is present in up to 50% of secretory breast cancers, whereas the other histologic subtypes display an incidence of below 1%. In conclusion, predictive molecular pathology has gained importance in metastatic breast cancer.

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Correspondence to Prof. Dr. Hans H. Kreipe.

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H. H. Kreipe und P. Sinn geben an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

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H. Kreipe, Hannover

W. Weichert, München

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Kreipe, H.H., Sinn, P. Prädiktive Mutationsdiagnostik bei Mammakarzinomen. Pathologe (2021). https://doi.org/10.1007/s00292-021-00929-6

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Schlüsselwörter

  • Östrogenrezeptoren
  • ESR1
  • ERBB2
  • BRCA1/2
  • PIK3CA

Keywords

  • Estrogen receptors
  • ESR1
  • ERBB2
  • BRCA1/2
  • PIK3CA