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Translationale Forschung und Diagnostik beim Melanom

Translational research and diagnostics of melanoma

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Zusammenfassung

Während das maligne Melanom (MM) im frühen Stadium eine günstige Prognose aufweist, liegt die 5-Jahres-Überlebensrate bei Fernmetastasierung unter 10%. Aufgrund einer molekular definierten Typsierung des MM ist es erstmals gelungen, mithilfe spezifischer Inhibitoren der mutierten BRAF-Kinase (Vemurafinib, Dabrafenib) Biomarker-basierte zielgerichtete Therapien mit hoher Ansprechrate in der metastasierten Situation zu entwickeln. Daraus ergibt sich für die Pathologie die Notwendigkeit zur qualitätsgesicherten BRAF-Mutationsanalyse im klinischen Alltag. Andererseits erfordert das Neuauftreten plattenepithelialer Neoplasien (v. a. Keratoakanthome) unter der zielgerichteten Therapie sowie die relativ schnelle Resistenzentwicklung (meist <6 Monaten) weitergehende translationale Forschungsansätze. Dementsprechend konnten bereits am Signalweg der BRAF-(MAP-)Kinase orientierte Medikamente, wie z. B. MEK-Inhibitoren, erfolgreich eingesetzt werden. Die mögliche Bedeutung der molekularen Charakterisierung weiterer spezifischer Subtypen des MM (arkral, mukosal, uveal) anhand des jeweils typischen Mutationsspektrums (z. B. cKIT , NRAS , GNAQ) wird nachfolgend aufgezeigt.

Abstract

Although early stage malignant melanoma (MM) has a favorable prognosis five year survival rate is poor (<10%) in patients suffering from distant metastases. Due to molecular typing of MM recently high response rates were achieved in metastatic MM by using specific inhibitors directed against the mutated form of BRAF kinase, e.g. Vemurafinib and Dabrafinib. Therefore BRAF mutation analysis has become standard of care in advanced MM and pathologists are urged to provide a quality guaranteed molecular diagnostics. However, squamous neoplasias (e. g., keratoacanthomas) and recurrences of MM mostly within 6 months during targeted therapy point to the need of further translational research. Thus new drugs, such as MEK inhibitors, based on the MAP-kinase pathway downstream of BRAF have already effectively been used. Finally, the impact of molecular characteristics in different subtypes of MM (acral, mucosal, uveal) will be discussed with respect to their specific mutational spectrum (e.g. cKIT , NRAS , GNAQ).

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Literatur

  1. Anderson S, Bloom KJ, Vallera DU et al (2012) Multisite analytic performance studies of a real-time polymerase chain reaction assay for the detection of BRAF V600E mutations in formalin-fixed paraffin-embedded tissue specimens of malignant melanoma. Arch Pathol Lab Med [Epub ahead of print]

  2. Robert Koch-Institut (2012) Beiträge zur Gesundheitsberichterstattung des Bundes: Krebs in Deutschland 2007/2008. Häufigkeiten und Trends, 8. Ausgabe

  3. Capper D, Berghoff AS, Magerle M et al (2012) Immunhistochemical testing of BRAF V600E status in 1120 tumor tissue samples of patients with brain metastases. Acta Neuropathol 123:223–233

    Article  PubMed  CAS  Google Scholar 

  4. Carvajal RD, Antonescu CR, Wolchok JD et al (2011) KIT as a therapeutic target in metastatic melanoma. JAMA 305:2327–2334

    Article  PubMed  CAS  Google Scholar 

  5. Chapman PB, Hauschild A, Robert C et al (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507–2516

    Article  PubMed  CAS  Google Scholar 

  6. Chin L, Pomerantz J, Polsky D et al (1997) Cooperative effects of INK4a and ras in melanoma susceptibility in vivo. Genes Dev 11:2822

    Article  PubMed  CAS  Google Scholar 

  7. Dietel M, Enk A, Lehmann A et al. (2012) BRAF-Mutationstestung beim metastasierten malignen Melanom. Pathologe 33:352–356

    Article  PubMed  CAS  Google Scholar 

  8. Garraway LA, Chin L (2011) Molecular Biology of Cutaneous Melanoma. In: DeVita VT, Hellman S, Rosenberg SA (Hrsg) Cancer: Principles & Practice of Oncology, 9. Aufl. Kap. 118

  9. Göppner D, Leverkus M (2011) Prognostic parameters for primary care of melanoma patients: what is really risky in melanoma? J Skin Cancer 13 (521947)

  10. Hauschild A, Grob JJ, Demidov LV et al (2012) Phase III, randomized, open-label, multicenter trial (BREAK-3) comparing the BRAF kinase inhibitor dabrafenib (GSK2118436) with dacarbazine (DTIC) in patients with BRAFV600E-mutated melanoma. J Clin Oncol 30 (suppl): abstr LBA8500

    Google Scholar 

  11. Hussussian CJ, Struewing JP, Goldstein AM et al (1994) Germline p16 mutations in familial melanoma. Nat Genet 8:15–21

    Article  PubMed  CAS  Google Scholar 

  12. Leyvraz S, Keilholz U (2012) Ocular melanoma: what’s new? Curr Opin Oncol 24:162–169

    Article  PubMed  CAS  Google Scholar 

  13. Lin WM, Baker AC, Beroukhim R et al (2008) Modeling genomic diversity and tumor dependency in malignant melanoma. Cancer Res 68:664–73

    Article  PubMed  CAS  Google Scholar 

  14. Nazarian R, Shi H, Wang Q et al (2010) Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468:973–977

    Article  PubMed  CAS  Google Scholar 

  15. Oberholzer PA, Kee D, Dziunycz P et al (2012) RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors. J Clin Oncol 30:316–321

    Article  PubMed  CAS  Google Scholar 

  16. Querings S, Altmüller J, Ansén S (2011) Benchmarking of mutation diagnostics in clinical lung cancer specimens. PLoS One 6:e19601

    Article  PubMed  CAS  Google Scholar 

  17. Robert C, Flaherty KT, Hersey P et al (2012) METRIC phase III study: Efficacy of trametinib (T), a potent and selective MEK inhibitor (MEKi), in progression-free survival (PFS) and overall survival (OS), compared with chemotherapy (C) in patients (pts) with BRAFV600E/K mutant advanced or metastatic melanoma (MM). J Clin Oncol 30 (suppl): abstr LBA8509

    Google Scholar 

  18. Siegel R, Ward E, Brawley O, Jemal A (2011) Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 61:212–236

    Article  PubMed  Google Scholar 

  19. Slingluff CL, Flaherty K, Rosenberg SA, Read RW (2011) Cutaneous Melanoma. In: DeVita VT, Hellman S, Rosenberg SA (Hrsg) Cancer: Principles & Practice of Oncology, 9. Aufl. Kap. 119

  20. Sosman JA, Kim KB, Schuchter L et al (2012) Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 366:707–714

    Article  PubMed  CAS  Google Scholar 

  21. Su F, Viros A, Milagre C et al (2012) RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 366:207–215

    Article  PubMed  CAS  Google Scholar 

  22. Weeraratna AT (2012) RAF around the edges – the paradox of BRAF inhibitors. N Engl J Med 366:271–273

    Article  PubMed  CAS  Google Scholar 

  23. Yancovitz M, Litterman A, Yoon J et al (o J) Intra- and inter-tumor heterogeneity BRAF V600E mutations in primary and metastatic melanoma. PLOSone 7:e29336

  24. Zimmer L, Hillen U, Livingstone E et al (2012) Atypical melanocytic proliferations and new primary melanomas in patients with advanced melanoma undergoing selective braf inhibition. J Clin Oncol 30:2375–2383

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Institut für Pathologie Nordhessen, Germaniastr. 7, 34119, Kassel, Deutschland

    J. Rüschoff & P. Middel

  2. Targos Molecular Pathology GmbH, Kassel, Deutschland

    M. Kleinschmidt

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  1. J. Rüschoff
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  2. M. Kleinschmidt
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  3. P. Middel
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Rüschoff, J., Kleinschmidt, M. & Middel, P. Translationale Forschung und Diagnostik beim Melanom. Pathologe 33 (Suppl 2), 291–295 (2012). https://doi.org/10.1007/s00292-012-1661-1

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