Trametinib after disease reactivation under dabrafenib in Erdheim-Chester disease with both BRAF and KRAS mutations

Thierry M. Nordmann, Freimut D. Juengling, Mike Recher, Christoph T. Berger, Daniel Kalbermatten, Andreas Wicki, Aino Paasinen-Sohns, Gieri Cathomas, Alexandar Tzankov and Thomas Daikeler

Key Points

  • Development of treatment resistance through further somatic mutations may occur in Erdheim-Chester disease during BRAF inhibition.

  • Combinatorial BRAF/MEK inhibition may be beneficial in treatment-resistant ECD harboring a BRAFV600E and further MAPK-activating mutations.


Major advances have been made in understanding the pathogenesis of Erdheim-Chester disease (ECD) leading to novel treatment strategies. Targeted therapies such as BRAF inhibition have shown a significant impact on disease management, emphasizing the importance of the activated mitogen-associated protein kinase pathway in this disease. However, incomplete responsiveness, potentially limiting adverse effects, and the occurrence of treatment resistance to BRAF inhibition observed in other BRAF-mutant malignancies imply the importance of therapeutic strategies beyond BRAF inhibition. We report a patient with ECD who carried the BRAFV600E mutation and developed treatment resistance under BRAF inhibition despite initial treatment response. Genetic analyses of a newly developing ECD lesion revealed a somatic KRASQ61H mutation without the presence of BRAFV600E. Accordingly, the addition of MEK-inhibiting trametinib to BRAF-inhibiting dabrafenib was able to overcome acquired partial treatment resistance. This is the first report of treatment resistance as a result of a secondary MAPK pathway–activating mutation during BRAF inhibition in ECD. This case contributes to the ongoing efforts of simultaneous BRAF/MEK inhibition as a promising strategy in ECD.

  • Submitted September 17, 2016.
  • Accepted November 29, 2016.
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