BRAF Mutation Correlates With High-Risk Langerhans Cell Histiocytosis and Increased Resistance to First-Line Therapy.

Abstract

PURPOSE:

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with a broad spectrum of clinical manifestations and outcomes in children. The somatic BRAF(V600E) mutation occurs frequently, but clinical significance remains to be determined.

PATIENTS AND METHODS:

BRAF(V600E) mutation was investigated in a French LCH cohort. We analyzed associations between mutation status and clinical presentation, extent of disease, reactivation rate, response to therapy, and long-term permanent sequelae.

RESULTS:

Among 315 patients with successfully determined BRAF status, 173 (54.6%) carried a BRAF(V600E) mutation. Patients with BRAF(V600E) manifested more severe disease than did those with wild-type BRAF. Patients with BRAF(V600E) comprised 87.8% of patients (43 of 49) with multisystem LCH with risk organ involvement (liver, spleen, hematology), 68.6% of patients (35 of 51) with multisystem LCH without risk organ involvement, 43.9% of patients (86 of 196) with single-system LCH, and 42.1% of patients (8 of 19) with lung-involved LCH (P < .001). BRAF(V600E) mutation was also associated with organ involvement that could lead to permanent, irreversible damage, such as neurologic (75%) and pituitary (72.9%) injuries. Compared with patients with wild-type BRAF, patients with BRAF(V600E) more commonly displayed resistance to combined vinblastine and corticosteroid therapy (21.9% v 3.3%; P = .001), showed a higher reactivation rate (5-year reactivation rate, 42.8% v 28.1%; P = .006), and had more permanent, long-term consequences from disease or treatment (27.9% v 12.6%; P = .001).

CONCLUSION:

In children with LCH, BRAF(V600E) mutation was associated with high-risk features, permanent injury, and poor short-term response to chemotherapy. Further population-based studies should be undertaken to confirm our observations and to assess the impact of BRAF inhibitors for this subgroup of patients who may benefit from targeted therapy.

• Authors: Sébastien Héritier, Jean-François Emile, Mohamed-Aziz Barkaoui, Caroline Thomas, Sylvie Fraitag, Sabah Boudjemaa, Florence Renaud, Anne Moreau, Michel Peuchmaur, Catherine Chassagne-Clément, Frédérique Dijoud, Valérie Rigau, Despina Moshous, Anne Lambilliotte, Françoise Mazingue, Kamila Kebaili, Jean Miron, Eric Jeziorski, Geneviève Plat, Nathalie Aladjidi, Alina Ferster, Hélène Pacquement, Claire Galambrun, Laurence Brugières, Guy Leverger, Ludovic Mansuy, Catherine Paillard, Anne Deville, Corinne Armari-Alla, Anne Lutun, Marion Gillibert-Yvert, Jean-Louis Stephan, Fleur Cohen-Aubart, Julien Haroche, Isabelle Pellier, Frédéric Millot, Brigitte Lescoeur, Virginie Gandemer, Christine Bodemer, Roger Lacave, Zofia Hélias-Rodzewicz, Valérie Taly, Frédéric Geissmann, Jean Donadieu
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 34 Issue 25 Pg. 3023-30 (09 01 2016) ISSN: 1527-7755 [Electronic] United States
• PMID: 27382093 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 by American Society of Clinical Oncology.

Chemical References

• Adrenal Cortex Hormones
• Vinblastine
• BRAF protein, human
• Proto-Oncogene Proteins B-raf

Topics

• Adolescent
• Adrenal Cortex Hormones (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Child
• Child, Preschool
• Cohort Studies
• Drug Resistance, Neoplasm
• Female
• France (epidemiology)
• Histiocytosis, Langerhans-Cell (drug therapy, enzymology, epidemiology, genetics)
• Humans
• Infant
• Infant, Newborn
• Male
• Molecular Targeted Therapy
• Mutation
• Proto-Oncogene Proteins B-raf (antagonists & inhibitors, genetics)
• Registries
• Vinblastine (administration & dosage)