scholarly journals BRAF fusions in pediatric histiocytic neoplasms define distinct therapeutic responsiveness to RAF paradox breakers

2020 ◽  
Author(s):  
Payal Jain ◽  
Lea Surrey ◽  
Joshua Straka ◽  
Richard Womer ◽  
Marilyn Li ◽  
...  
Keyword(s):  
Braf V600e Mutation ◽  
Braf V600e ◽  
Gene Fusions ◽  
Braf Inhibitors ◽  
Braf Gene ◽  
Mek Inhibition ◽  
Hematopoietic Disorders ◽  
Stable Fusion

Pediatric histiocytic neoplasms are hematopoietic disorders frequently driven by the BRAF-V600E mutation. Here we identified two BRAF gene fusions (novel MTAP-BRAF and MS4A6A-BRAF) in two aggressive histiocytic neoplasms. In contrast to previously described BRAF fusions, MTAP-BRAF and MS4A6A-BRAF do not respond to the paradox breaker RAF inhibitor (RAFi) PLX8394 due to stable fusion dimerization mediated by the N-terminal fusion partners. This highlights a significant and clinically relevant shift from the current dogma that BRAF-fusions respond similarly to BRAF-inhibitors. As an alternative, we show suppression of fusion-driven oncogenic growth with the pan-RAFi LY3009120 and MEK inhibition.

scholarly journals Novel BRAF fusions in pediatric histiocytic neoplasms define distinct therapeutic responsiveness to RAF paradox breakers

2020 ◽  
Author(s):  
Payal Jain ◽  
Lea F. Surrey ◽  
Joshua Straka ◽  
Pierre Russo ◽  
Richard Womer ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Braf V600e ◽  
Fusion Partner ◽  
Gene Fusions ◽  
Braf Gene ◽  
Mitogen Activated Protein ◽  
Hematopoietic Disorders ◽  
Mechanistic Basis

Pediatric histiocytic neoplasms are clonal hematopoietic disorders driven by mutations activating the mitogen-activated protein kinase (MAPK) pathway, such as BRAF-V600E. In non-BRAFV600E cases, we investigated alternative MAPK mutations and found two novel BRAF gene fusions. We investigated the distinct responsiveness of novel BRAF fusions to RAFi therapies and explored the mechanistic basis of such differential responses compared to other BRAF fusions. Two histiocytic patient tumors were analyzed using the CHOP Comprehensive Next-Gen Sequencing Solid Tumor Panel and a targeted RNA-seq panel for 106 fusion partner genes. In the two M- and L-type histiocytic neoplasms assessed, we found novel and rare BRAF gene fusions, MTAP-BRAF and MS4A6A-BRAF, respectively. Both BRAF fusions activated the MAPK/ PI3K pathways and showed homo- and hetero-dimerization with BRAF and the respective N-terminal fusion partner. In contrast to common BRAF fusions, MTAP-BRAF and MS4A6A-BRAF did not respond to PLX8394 due to a lack of disruption of active fusion homo- and hetero-dimers, which was in turn due to the untargeted, stable dimerization mediated by the N-terminal fusion partners. Conversely, we observed robust suppression with LY3009120 that bound fusion dimers and kept them in an inactivate confirmation. MEKi were found to successfully suppress fusion driven signaling and oncogenic phenotypes. Our finding that PLX8394 does not disrupt MTAP-BRAF or MS4A6A-BRAF dimerization due to contribution of N-terminal partners defines a novel paradigm for the distinct mechanisms sought by BRAF fusions in response to RAFi therapy. Overall, this study highlights the unique and differential biology hijacked by BRAF fusions in response to RAFi and further warrants detailed mechanistic classification of BRAF fusions based on their responsiveness to targeted agents.

scholarly journals Low-Dose BRAF-Inhibitors in the Treatment of Histiocytic Disorders with the BRAF-V600E Mutation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5895-5895
Author(s):  
Gordon Ruan ◽  
Gaurav Goyal ◽  
Jithma P. Abeykoon ◽  
N. Nora Bennani ◽  
Karen Rech ◽  
...  
Keyword(s):  
Median Time ◽  
Low Dose ◽  
Braf Inhibitor ◽  
Brain Parenchyma ◽  
Advisory Board ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Braf Inhibitors ◽  
Starting Dose ◽  
Dose Reductions

Introduction: The landmark VE-BASKET trial demonstrated that Erdheim-Chester disease (ECD) patients with the BRAF-V600E mutation can be effectively treated with vemurafenib 1920 mg/day. However, all patients required dose reductions due to adverse effects. The efficacy of low dose BRAF-inhibitors is not well established in ECD. Further, as Langerhans cell histiocytosis (LCH) also harbors BRAF-V600E mutations in 50-60% of patients, BRAF-inhibitors may be effective in this disease as well. In this study, we evaluated the efficacy of low dose BRAF-inhibitors (vemurafenib and dabrafenib) in the treatment of ECD and LCH. Methods: We conducted a retrospective study of ECD and LCH patients who were seen at our institution from January 1998 to July 2018. All patients had a diagnosis of ECD and LCH determined by clinical criteria in conjunction with histopathologic findings. Based on the standard doses approved for malignant melanoma and ECD, patients were categorized into the low dose BRAF-inhibitor group if they were treated with vemurafenib < 960 mg/day or dabrafenib ≤ 150mg/day at any point in time. We used a simple response criteria that defined clinical progressive disease (PD) as worsening of symptoms attributed to ECD/LCH or radiologic PD as a progression or worsening of proven or suspected lesions due to ECD/LCH. The minimum duration for symptom improvement to be considered a response was set at 3 months. Results: A total of 89 ECD patients and 186 LCH patients were identified. Within the ECD cohort, 24 of 44 (55%) patients who were tested had the BRAF-V600E mutation. Eight patients were included in the low dose BRAF-inhibitor group. The median age at diagnosis was 57 years (range 37-74) and 5 (63%) were male. The most common areas of involvement included bone (88%), cardiovascular system (63%), kidneys (63%), and brain parenchyma (50%). The median time of follow up was 66 months (range 23-165) and the median time on low-dose BRAF-inhibitor was 10 months (range 1-27) [Table 1]. Three patients had a starting dose of vemurafenib 1920 mg/day, 4 had 960 mg/day, and 1 had 480 mg/day. All patients required dose reductions and 50% of the patients ultimately discontinued vemurafenib due to side effects. Side effects included fatigue, pruritus, nausea, facial swelling, blisters, papillomas, and/or subcutaneous nodules. Four patients were able to remain on low-dose vemurafenib for a median follow up time of 24.5 months (range 12-28) with ongoing response and no signs of clinical or radiologic PD. Within the LCH cohort, 18 of 31 tested (58%) patients had the BRAF-V600E mutation. Four patients were included in the low dose BRAF-inhibitor group. The median age at diagnosis of this cohort was 43 years (range 34-69) and 2 (50%) were male. Areas of involvement included bone (100%), brain parenchyma (hypothalamus/optic stalk and pons; 50%), and skin (25%). The median time of follow up was 31 months (range 21-46) and the median time on low-dose BRAF-inhibitor was 4 months (range 3-24) [Table 2]. Two patients had a starting dose of vemurafenib 960mg/day. The patients with brain parenchymal involvement had a starting dose of dabrafenib 150mg/day or 100mg/day. All patients taking vemurafenib 960mg/day required dose reductions and one patient discontinued treatment due to skin blistering in her feet. In the patients taking dabrafenib, no side effects have yet been reported. 3 patients had an ongoing response and did not have clinical or radiologic PD. Patient #10 however, had clinical and radiologic PD after being on vemurafenib 720mg/day for 22 months. Conclusion: Our study suggests a potential role for lower doses of BRAF-inhibitors in ECD and LCH patients harboring BRAF-V600E mutations. Dabrafenib was found to be particularly efficacious and well-tolerated in LCH involving the brain parenchyma. However, patients who undergo dose reductions should be closely monitored due to the risk of disease progression. Careful balance of toxicities and efficacy is needed for optimizing patient outcomes with targeted therapies. Disclosures Bennani: Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Seattle Genetics: Other: Advisory board. OffLabel Disclosure: Vemurafenib and dabrafenib for Langerhans cell histiocytosis. Vemurafenib dosage for Erdheim-Chester disease is less than the approved dose of 960mg every 12 hours.

Clinical, radiological, and genomic features of BRAF V600E-mutated adult glioblastoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2554-2554 ◽  
Author(s):  
Mary Jane Lim-Fat ◽  
Kun Wei Song ◽  
Patrick Y. Wen ◽  
David A. Reardon ◽  
Elizabeth Robins Gerstner ◽  
...  
Keyword(s):  
Array Cgh ◽  
Massachusetts General Hospital ◽  
Methylation Status ◽  
Copy Number Variants ◽  
Response Assessment ◽  
Braf V600e Mutation ◽  
Adult Patients ◽  
Braf V600e ◽  
Leptomeningeal Dissemination ◽  
Mek Inhibition

2554 Background: Although uncommon, detection of a BRAF V600E mutation in adult patients with glioblastoma has become relevant given the increased availability of NGS and encouraging therapeutic activity of BRAF/MEK inhibitors. The clinical course, radiological characteristics and genetic mutations in this patient population has, however, not been well described. Methods: Adult patients treated at Dana-Farber Cancer Institute or Massachusetts General Hospital with glioblastoma diagnosed from 2013-2019 and an identified BRAF V600E mutation on immunohistochemistry staining or institutional NGS platform were included. Patient demographics, treatments and outcomes were collected retrospectively. Molecular diagnostics (Oncopanel or SNaPSHOT) and cytogenetics (array CGH) were reviewed for relevant mutations or copy number variants (CNV). Qualitative MRI data was analyzed using Visually Accessible Rembrandt Images (VASARI) feature set. Response assessment was performed using the RANO criteria. Results: Nineteen glioblastoma patients had a BRAF V600E mutation (16 on NGS and 19 on IHC). The median age at diagnosis was 41 (22-69) years; 13/19 were female, 12/19 were Caucasian. Only 1/19 had an IDH mutation; 10 of the 17 with known methylation status had MGMT unmethylated tumors. The most frequent mutations on NGS or CNV on array-CGH were TERT (12/16), CDKN2A (10/16), EGFR (7/16), PIK3R1 (6/16) and CKDN2B (6/16). Most tumors were well circumscribed (12/19) and all were contrast-enhancing on MRI. While no patient had clear leptomeningeal involvement at diagnosis, 11/19 eventually developed subependymal or leptomeningeal dissemination. Six patients were treated with BRAF/MEK inhibition following progression after standard of care therapy, with 3/6 patients showing partial response and 2 showing stable disease as their best response. PFS after BRAF/MEK inhibition ranged from 1.9 to 19 months. Grade 1 skin rash was present in 1 patient, but no other adverse events were reported. Median OS for the patients with confirmed deaths (15/19) was 22.6 (14.5 – 39.0) months. Conclusions: Compared to the general glioblastoma population, adult patients with BRAF V600E mutations are younger, more frequently female, and have a higher median OS despite a much higher incidence of leptomeningeal dissemination. Outcome following BRAF/MEK targeted therapy was encouraging. Understanding the natural history and features of these tumors may help better screen patients for BRAF/MEK inhibition and identify novel therapeutic strategies.

scholarly journals LG-20CAUTION IN THE USE OF BRAF INHIBITORS IN CHILDHOOD BRAIN TUMORS WITH BRAF V600E MUTATION

2016 ◽  
Vol 18 (suppl 3) ◽  
pp. iii82.4-iii83 ◽  
Author(s):  
Helen Toledano ◽  
Orli Michaeli ◽  
Nitza Goldenberg-Cohen ◽  
Osnat Konen ◽  
Isaac Yaniv ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Braf Inhibitors ◽  
Childhood Brain Tumors

scholarly journals BRAF V600E mutation in hairy cell leukemia: from bench to bedside

Blood ◽  
2016 ◽  
Vol 128 (15) ◽  
pp. 1918-1927 ◽  
Author(s):  
Brunangelo Falini ◽  
Maria Paola Martelli ◽  
Enrico Tiacci
Keyword(s):  
Hairy Cell Leukemia ◽  
Molecular Mechanisms ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Specific Gene ◽  
Hairy Cell ◽  
Braf Inhibitors ◽  
Cell Leukemia ◽  
Genetic Event ◽  
Mek Inhibitors

AbstractHairy cell leukemia (HCL) is a distinct clinicopathological entity whose underlying genetic lesion has remained a mystery for over half a century. The BRAF V600E mutation is now recognized as the causal genetic event of HCL because it is somatic, present in the entire tumor clone, detectable in almost all cases at diagnosis (encompassing the whole disease spectrum), and stable at relapse. BRAF V600E leads to the constitutive activation of the RAF-MEK-extracellular signal-regulated kinase (ERK) signaling pathway which represents the key event in the molecular pathogenesis of HCL. KLF2 and CDNK1B (p27) mutations may cooperate with BRAF V600E in promoting leukemic transformation. Sensitive molecular assays for detecting BRAF V600E allow HCL (highly responsive to purine analogs) to be better distinguished from HCL-like disorders, which are treated differently. In vitro preclinical studies on purified HCL cells proved that BRAF and MEK inhibitors can induce marked dephosphorylation of MEK/ERK, silencing of RAF-MEK-ERK pathway transcriptional output, loss of the HCL-specific gene expression profile signature, change of morphology from “hairy” to “smooth,” and eventually apoptosis. The overall response rate of refractory/relapsed HCL patients to the BRAF inhibitor vemurafenib approached 100%, with 35% to 40% complete remissions (CRs). The median relapse free-survival was about 19 months in patients who had achieved CR and 6 months in those who had obtained a partial response. Future therapeutic perspectives include: (1) combining BRAF inhibitors with MEK inhibitors or immunotherapy (anti-CD20 monoclonal antibody) to increase the percentage of CRs and (2) better understanding of the molecular mechanisms underlying resistance of HCL cells to BRAF inhibitors.

Prevalence of BRAF gene mutation in Thai sporadic colorectal cancer patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14051-e14051
Author(s):  
Krittiya Korphaisarn ◽  
Ekkapong Roothumnong ◽  
Akarin Nimmannit ◽  
Chanin Limwongse ◽  
Ananya Manuyakorn ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Gene Mutation ◽  
Braf Mutation ◽  
Prognostic Value ◽  
Braf V600e Mutation ◽  
Stage I ◽  
Braf V600e ◽  
Braf Gene ◽  
Primary Tumors ◽  
Caucasian Patients

e14051 Background: The role of BRAF gene mutation has been studied for its association with prognosis of colorectal cancer (CRC). The prevalence was reported 10-15% in Caucasian patients. However, there is no existing data in Thai patients. This study aimed to determine the prevalence of BRAF V600E mutation, association with various clinicopathological features and outcome in Thai sporadic CRC patients. Methods: DNA was extracted from randomly selected formalin-fixed paraffin-embedded tumor blocks of CRC patients with stage I-IV receiving surgery of the primary tumors at Siriraj Hospital between 2006 and 2007. BRAF V600E mutation was performed by two-round allele-specific PCR and analysis using high sensitivity DHPLC. The association between patient characteristics and BRAF status with overall survival (OS) and disease free survival (DFS) were explored by Kaplan-Meier estimation and log-rank test together with Cox’s proportional hazard regression. Results: BRAF V600E mutation was identified in 7 out of 188 patients (3.7%). Four patients were female. There were more likely to found in tumors on the left side (n=4) compared with right side (n=2) and rectum (n=1). All patients with mutation had stage I-III diseases; one with stage I and 3 with stage II and III each. Four had moderately differentiated tumors. Six patients had neither lymphovascular nor perineural invasion. Patients with mutation seemed to have better survival. In multivariate analysis, BRAF mutation did not have major prognostic value regarding DFS or OS. Conclusions: The prevalence of BRAF V600E mutation in Thai sporadic CRC was 3.7% which was lower than what reported in Caucasian patients. Further study with larger number of patients is warranted to determine whether BRAF mutation has significant prognostic value.

scholarly journals Frequency of BRAF V600E Mutation in the Mexican Population of Patients With Metastatic Melanoma

2018 ◽  
pp. 1-5
Author(s):  
Erika Ruiz-Garcia ◽  
Juan A. Matus-Santos ◽  
Jorge Alberto Guadarrama-Orozco ◽  
Miguel Angel Alvarez-Avitia ◽  
Jose Luis Aguilar-Ponce ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Braf Mutation ◽  
Large Scale ◽  
Braf V600e Mutation ◽  
Mexican Population ◽  
Braf V600e ◽  
Braf Gene ◽  
Braf Mutations ◽  
Nodular Melanoma ◽  
Pathologic Features

Purpose The BRAF V600E mutation has been described in melanomas occurring in the Caucasian, European, and Asian populations. However, in the Mexican population, the status and clinical significance of BRAF mutation has not been researched on a large scale. Methods Consecutive BRAF-tested Mexican patients with metastatic melanoma (n = 127) were analyzed for mutations in exon 15 of the BRAF gene in genomic DNA by real-time polymerase chain reaction technology for amplification and detection. The results were correlated with the clinical-pathologic features and the prognosis of the patients. Results The frequency of somatic mutation V600E within the BRAF gene was 54.6% (43 of 127 patients). Nodular melanoma was the most prevalent subtype in our population, with BRAF mutations in 37.2% (16 of 55 patients). In contrast, superficial spread had a frequency of 18.6% BRAF mutation (eight of 24). Other clinicopathologic features were assessed to correlate with the mutation status. Conclusion This study searched for the most prevalent BRAF V600E mutation type in melanoma in a heterogeneous population from Mexico. Nodular melanoma was found to be the most prevalent in metastatic presentation and the presence of BRAF V600E mutation, perhaps related to the mixed ancestry; in the north, ancestry is predominantly European and in the south, it is predominantly Asian. The outcomes of the mutation correlations were similar to those found in other populations.

scholarly journals Mutación BRAF V600E en pacientes con cáncer de tiroides. Fundación Clínica Valle del Lili: una serie de casos

2017 ◽  
Vol 3 (3) ◽  
pp. 45-49
Author(s):  
Guillermo Edinson Guzmán ◽  
Luz Ángela Casas ◽  
Julian David Orrego Celestino ◽  
Juliana Escobar ◽  
Lisa Rodríguez ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Gene Mutation ◽  
Medical Records ◽  
Vascular Invasion ◽  
Lymphatic Invasion ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Nodal Involvement ◽  
Extrathyroid Extension ◽  
Braf Gene

Objetivo: Describir las características clínicas y los hallazgos histopatológicos de los pacientes con diagnóstico de cáncer de tiroides y estudio de la mutación del Gen BRAF V600E.Métodos: Estudio descriptivo, retrospectivo, con información obtenida de las historias clínicas de los pacientes con diagnóstico de cáncer de tiroides atendidos durante 2014 y 2105 en la Fundación Clínica Valle del Lili con estudio para la mutación del gen BRAF V600E.Resultados: De los 344 pacientes con diagnóstico de cáncer de tiroides durante los años 2014 y 2015, se les realizó estudio de la mutación BRAF V600E a 24. La edad promedio fue de 47 años, con predominio en mujeres (87,5%), fueron positivos para la mutación 66% de los pacientes. En relación a las características histopatológicas, el 95,8% de los casos correspondían a cáncer papilar de tiroides, la mayoría de la variedad clásica. Los pacientes con la mutación BRAF V600E tenían mayor extensión extratiroidea, invasión linfática, invasión vascular y compromiso ganglionar, pero no se encontró relación con respecto a tamaño tumoral, multicentralidad, bilateralidad, tiroiditis de Hashimoto o presencia de metástasis.Conclusión: Este es el primer estudio en Colombia, que describe las características clínicas e histopatológicas de los pacientes con cáncer de tiroides en relación a la presencia de la mutacion del Gen BRAF.Abstract Objective: To describe the clinical and histopathological findings of patients diagnosed with thyroid cancer and BRAF V600E gene mutation study. Methods: A descriptive, retrospective study, with information obtained from the medical records of patients diagnosed with thyroid cancer seen during 2014 and 2105 in the Fundacion Clínica Valle del Lili with analysis of the BRAF V600E gene mutation. Results: Of the 344 patients diagnosed with thyroid cancer during the years 2014 and 2015, underwent study of the BRAF V600E to 24. The average age was 47 years, with prevalence in women (87.5%) were positive for mutation 66% of patients. Regarding the histopathologic features, 95.8% of the cases werepapillary thyroid cancer, most classic variety. Patients with BRAF V600E mutation were more extrathyroid extension, lymphatic invasion, vascular invasion and nodal involvement, but no relationship was found with respect to tumor size, multicentrality, bilateralism, Hashimoto’s thyroiditis or presence of metastasis. Conclusion: This is the first study in Colombia, describing the clinical and histopathologic of patients with thyroid cancer in relation to the presence of the BRAF gene mutation characteristics.-

scholarly journals BRAF Fusions in Histiocytic Disorders: Frequency and Clinical Characteristics

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2582-2582
Author(s):  
Saurabh Zanwar ◽  
Jithma P. Abeykoon ◽  
Aldo A. Acosta-Medina ◽  
Aishwarya Ravindran ◽  
Karen Rech ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Clinical Characteristics ◽  
Advisory Board ◽  
Langerhans Cell ◽  
Mitogen Activated Protein Kinase ◽  
Braf V600e ◽  
Juvenile Xanthogranuloma ◽  
Study Cohort ◽  
Gene Fusions ◽  
Braf Gene

Abstract Background: Activation of extracellular-signal regulated kinase (ERK) is almost universal in histiocytic disorders and is driven by genomic alterations in the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinases (PI3K) pathways. While BRAFV600E mutations are well described in histiocytic disorders, less is known about BRAF fusions. The goal of our study is to describe the frequency and clinical characteristics of patients harboring BRAF fusions. Methods: We included patients with a diagnosis of histiocytic disorder seen at our institution from November 2016-June 2021. Only those who had adequate BRAF testing were included. The following were considered adequate BRAF testing: 1) unequivocally positive BRAF V600E immunostain with or without molecular confirmation; 2) successful multigene next generation sequencing (mostly Tempus â or FoundationOne â) if BRAF V600Eimmunostain was equivocal or negative. We also searched the literature for similar cases and compared BRAF fusions found in histiocytic disorders to those found in solid tumors and other hematologic conditions. Results: One hundred and twenty-six patients were included in this study. BRAF fusions were detected in 7 (6%) patients. The median follow-up for these patients was 1.4 years (95% CI: 0.4-not reached). The frequency according to disease subtypes is as follows: Erdheim-Chester disease (ECD; 2/46 [4%]), Langerhans cell histiocytosis (LCH; 1/41 [2%]), adult or juvenile xanthogranuloma (AXG/JXG; 4/7 [57%]), and histiocytic or Langerhans cell sarcoma (HS/LCS; 0/9 [0%]). The median age at diagnosis for our study cohort was 34 years (range, 7-81 years) and 5 were females. The clinical characteristics and nature of BRAF fusions of our 7 patients plus additional 13 cases from the literature are shown in Table 1. For the final cohort of 20 patients with BRAF-fusions, the median age was 16 years (range, 0.5-81 years) and most (56%) were females. The distribution by histiocytic subtypes is as follows: AXG/JXG (45%), LCH (40%), ECD (10%), HS/LCS (5%). Two patients received cobimetinib as frontline treatment in our cohort and achieved partial responses. Of these two patients, one completed 12 cycles (12 months) of cobimetinib and had a sustained PR while the other patient received 2 cycles before having to hold therapy due to intolerable adverse effects despite dose reduction. From literature review, another patient (LR-12) received cobimetinib as second line treatment and achieved complete response. We found 15 unique BRAF gene fusions with 4 being recurrent. Except for AGAP3-BRAF, none of these BRAF fusions in histiocytosis has been reported in solid tumors or hematologic conditions to date. Conclusions: BRAF gene fusions occur rarely (&lt;5%) in histiocytic disorders. The only exception is AXG/JXG where more than half of the patients harbor BRAF gene fusions. These gene fusions are mostly distinct to histiocytosis and not found in solid tumors or other hematologic conditions. Figure 1 Figure 1. Disclosures Bennani: Purdue Pharma: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Vividion: Other: Advisory Board; Kymera: Other: Advisory Board; Verastem: Other: Advisory Board.

Role of BRAF Mutations in Hematopoietic Malignancies and the Induction of Cytokine-Independence-Synergy with PI3K/Akt Pathway.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4291-4291
Author(s):  
Massimo Libra ◽  
Maria C. Mazzarino ◽  
Valli De Re ◽  
Linda S. Steelman ◽  
Steven L. Abrams ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Hematopoietic Cells ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Akt Pathway ◽  
Braf Gene ◽  
Braf Mutations ◽  
Hematopoietic Malignancies ◽  
Hematopoietic Cell Lines

Abstract Mutations in the Ras pathway have been detected in approximately 50% of hematopoietic malignancies. These mutations usually occur at KRAS, NRAS or upstream FLT3. Recent results from an Asian based leukemia study indicated that the BRAF gene is mutated in 4% of AMLs and 3% of NHL. We sought to determine whether the BRAF, KRAS, PI3K genes were mutated in various hematopoietic malignancies of European ancestry as differences in mutation frequencies for other genes has been reported among various ethnic groups. As controls for BRAF mutations, the structure of the BRAF gene was examined in melanoma biopsies from European patients with various stages of melanoma. 61% of the melanoma patients had the BRAF V600E mutation. In contrast, essentially no mutations were detected in the European based NHL and AML patients. The presence of CMV infection in NHL did not change the genetic status of BRAF. To determine the effects of the BRAF V600E mutation on the cytokine-dependency of hematopoietic cells, cDNAs encoding BRAF wild type (WT) and BRAF V600E mutation were ligated to the hormone binding domain of a mutated estrogen receptor (ER*) which responds to 4 hydroxyl tamoxifen (4HT). These modified cDNAs were inserted into retroviral vectors. BRAF V600E induced the morphological transformation of NIH-3T3 cells in a 4HT-dependent fashion. Prolonged expression of BRAF V600E induced anoikis, results consistent with our previous studies indicating that BRAF overexpression can induce cell cycle arrest and apoptosis. Three cytokine dependent hematopoietic cell lines (human TF-1, murine FL5.12 and FDC-P1) were infected with WT and V600E BRAF encoding retroviruses. Expression of WT or V600E BRAF did not efficiently abrogate cytokine dependence. To determine if expression of the PI3K/Akt pathway could synergize with BRAF to induce cytokine independence, WT and V600E BRAF transduced cells were infected with WT and activated PI3K (p110 catalytic subunit), active and inactive Akt and an empty retroviral vector as a control. Conditional (Akt:ER*Myr+) and constitutive (Akt−Myr+) and PI3K but not inactive (Akt:ER*Myr−) synergized at least 250-fold with activated V600E but not WT BRAF to abrogate cytokine-dependence. Conditional activation of BRAF V600E induced downstream MEK and ERK, which was associated with cell cycle progression and prevention of both caspase 3 activation and apoptosis. Prevention of apoptosis in the BRAF V600E and Akt transformed hematopoietic cells was highly sensitive to 3 different MEK inhibitors and apoptosis was synergistically enhanced when the cells were treated with MEK and the mTOR inhibitor rapamycin. Our results indicate that the BRAF gene is infrequently mutated in hematopoietic malignancies and that the BRAF V600E mutant does not efficiently abrogate the cytokine dependence of 3 hematopoietic cell lines. However activated V600E but not WT BRAF synergized with the activated PI3K/Akt pathway to induce cytokine independence which was MEK1 dependent. Our data suggest that the BRAF mutation may not be detected frequently in hematopoietic malignancies because it is relatively inefficient by itself in conferring a growth advantage to hematopoietic cells (e.g., cytokine-independence) which is often associated with the induction of leukemia.

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