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

被引：242

作者：

Heritier, Sebastien ^{[1
,2
,11
]}

Emile, Jean-Francois ^{[11
,12
]}

Barkaoui, Mohamed-Aziz ^{[1
]}

Thomas, Caroline ^{[13
]}

Fraitag, Sylvie ^{[3
]}

Boudjemaa, Sabah ^{[2
]}

Renaud, Florence ^{[14
]}

Moreau, Anne ^{[13
]}

Peuchmaur, Michel ^{[4
,5
]}

Chassagne-Clement, Catherine ^{[16
]}

Dijoud, Frederique ^{[17
]}

Rigau, Valerie ^{[19
]}

Moshous, Despina ^{[3
]}

Lambilliotte, Anne ^{[15
]}

Mazingue, Francoise ^{[15
]}

Kebaili, Kamila ^{[18
]}

Miron, Jean ^{[1
]}

Jeziorski, Eric ^{[20
]}

Plat, Genevieve ^{[21
]}

Aladjidi, Nathalie ^{[22
]}

Ferster, Alina ^{[35
]}

Pacquement, Helene ^{[6
]}

Galambrun, Claire ^{[23
]}

Brugieres, Laurence ^{[24
]}

Leverger, Guy ^{[2
,7
]}

Mansuy, Ludovic ^{[25
]}

Paillard, Catherine ^{[26
]}

Deville, Anne ^{[27
]}

Armari-Alla, Corinne ^{[28
]}

Lutun, Anne ^{[29
]}

Gillibert-Yvert, Marion ^{[30
]}

Stephan, Jean-Louis ^{[31
]}

Cohen-Aubart, Fleur ^{[8
]}

Haroche, Julien ^{[8
]}

Pellier, Isabelle ^{[32
]}

Millot, Frederic ^{[33
]}

Lescoeur, Brigitte ^{[4
]}

Gandemer, Virginie ^{[34
]}

Bodemer, Christine ^{[3
]}

Lacave, Roger ^{[9
]}

Helias-Rodzewicz, Zofia ^{[11
]}

Taly, Valerie ^{[10
]}

Geissmann, Frederic ^{[36
]}

Donadieu, Jean ^{[1
,2
,11
]}

机构：

[1] Trousseau Hosp, French Reference Ctr Langerhans Cell Histiocytosi, 26 Ave Dr Netter, F-75012 Paris, France

[2] Trousseau Hosp, AP HP, Paris, France

[3] Hop Necker Enfants Malad, AP HP, Paris, France

[4] Robert Debre Hosp, AP HP, Paris, France

[5] Univ Paris Diderot, Sorbonne Paris Cite, Paris, France

[6] Inst Curie Med Ctr, Paris, France

[7] Univ Paris 06, Paris, France

[8] Hop La Pitie Salpetriere, AP HP, Paris, France

[9] Tenon Hosp, AP HP, Paris, France

[10] Univ Paris Sorbonne Cite, INSERM, UMR S1147, CNRS,SNC 5014, Paris, France

[11] Univ Paris Saclay, Univ Versailles St Quentin Yvelines, Boulogne, France

[12] Ambroise Pare Hosp, AP HP, Boulogne, France

[13] CHU Nantes, Nantes, France

[14] Univ Lille, Ctr Hosp Reg Univ, Lille, France

[15] CHU Lille, Lille, France

[16] Ctr Leon Berard, Lyon, France

[17] Hosp Civils Lyon, Hop Femme Mere Enfant, Lyon, France

[18] Inst Hematooncol Pediat, Lyon, France

[19] Gui de Chauliac Hosp, Montpellier, France

[20] Hop Arnaud Villeneuve, Montpellier, France

[21] Ctr Hosp Univ Toulouse, Toulouse, France

[22] Ctr Hosp Univ Bordeaux, Bordeaux, France

[23] Hop La Timone, Marseille, France

[24] Inst Gustave Roussy, Villejuif, France

[25] Ctr Hosp Univ Nancy, Brabois Enfants Hosp, Vandoeuvre Les Nancy, France

[26] CHU Strasbourg, Strasbourg, France

[27] CHU Nice, Nice, France

[28] CHU Grenoble, Grenoble, France

[29] Ctr Hosp Univ Amiens, Amiens, France

[30] CHU Tours, Tours, France

[31] Ctr Hosp Univ St Etienne, St Etienne, France

[32] CHU Angers, Angers, France

[33] Ctr Hosp Univ Poitiers, Poitiers, France

[34] Ctr Hosp Univ Rennes, Rennes, France

[35] Univ Libre Bruxelles, Hop Univ Enfants Reine Fabiola, Brussels, Belgium

[36] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA

来源：

JOURNAL OF CLINICAL ONCOLOGY | 2016年 / 34卷 / 25期

关键词：

ERDHEIM-CHESTER DISEASE; HIGH PREVALENCE; FREE DNA; VEMURAFENIB; MAP2K1; INVOLVEMENT; GUIDELINES; DIAGNOSIS; EFFICACY;

D O I：

10.1200/JCO.2015.65.9508

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. (C) 2016 by American Society of Clinical Oncology

引用

页码：3023 / +

页数：10

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