Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 52
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Cancer Discov ; 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029534

RESUMO

BRAF V600 mutations occur in a wide range of tumor types and RAF inhibition has become standard in several of these cancers. Despite this progress, BRAF V600 mutations have historically been considered a clear demonstration of tumor lineage context-dependent oncogene addiction, based predominantly on the insensitivity of RAF inhibition in colorectal cancer. However, the true broader activity of RAF inhibition pan-cancer remains incompletely understood. To address this, we conducted a multi-cohort 'basket' study of the BRAF inhibitor vemurafenib in non-melanoma BRAF V600 mutation-positive solid tumors. In total, 172 patients with 26 unique cancer types were treated, achieving an overall response rate of 33% and median duration of response of 13 months. Responses were observed in 13 unique cancer types, including historically treatment-refractory tumors such as cholangiocarcinoma, sarcoma, glioma, neuroendocrine carcinoma, and salivary gland carcinomas. Collectively, these data demonstrate that single-agent BRAF inhibition has broader clinical activity than previously recognized.

2.
Neuro Oncol ; 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31950179

RESUMO

BACKGROUND: Erdheim-Chester disease (ECD) is a rare histiocytic neoplasm characterized by recurrent alterations in the mitogen-activating protein kinase (MAPK) pathway. The existing literature about the neuro-oncological spectrum of ECD is limited. METHODS: We present retrospective clinical, radiographic, pathologic, molecular, and treatment data from 30 patients with ECD neurohistiocytic involvement treated at a tertiary center. RESULTS: Median age was 52 (range: 7-77) years and 20 (67%) patients were male. Presenting symptoms included ataxia in 19 (63%), dysarthria in 14 (47%), diabetes insipidus in 12 (40%), cognitive impairment in 10 (33%), and bulbar affect in 9 (30%) patients. Neurosurgical biopsy specimens in 8 patients demonstrated varied morphologic findings often uncharacteristic of typical ECD lesions. Molecular analysis revealed mutations in BRAF (18 patients), MAP2K1 (5), RAS isoforms (2), and two fusions involving BRAF and ALK. Conventional therapies (corticosteroids, immunosuppresants, interferon-alpha [IFN-α], cytotoxic chemotherapy) led to partial radiographic response in 8/40 (20%) by MRI with no complete responses, partial metabolic response in 4/16 (25%) and complete metabolic response in 1/16 (6%) by FDG-PET scan. In comparison, targeted (kinase inhibitor) therapies yielded partial radiographic response in 10/27 (37%) and complete radiographic response in 14/27 (52%) by MRI, and partial metabolic response in 6/25 (24%) and complete metabolic response in 17/25 (68%) by FDG-PET scan. CONCLUSIONS: These data highlight underrecognized symptomatology, heterogenous neuropathology, and robust responses to targeted therapies across the mutational spectrum in ECD patients with neurological involvement, particularly when conventional therapies have failed.

5.
Nat Med ; 25(12): 1839-1842, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31768065

RESUMO

Histiocytoses are clonal hematopoietic disorders frequently driven by mutations mapping to the BRAF and MEK1 and MEK2 kinases. Currently, however, the developmental origins of histiocytoses in patients are not well understood, and clinically meaningful therapeutic targets outside of BRAF and MEK are undefined. In this study, we uncovered activating mutations in CSF1R and rearrangements in RET and ALK that conferred dramatic responses to selective inhibition of RET (selpercatinib) and crizotinib, respectively, in patients with histiocytosis.


Assuntos
Quinase do Linfoma Anaplásico/genética , Histiocitose/genética , Proteínas Proto-Oncogênicas c-ret/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Adolescente , Adulto , Aminopiridinas/farmacologia , Benzotiazóis/farmacologia , Criança , Pré-Escolar , Feminino , Genoma Humano , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Histiocitose/tratamento farmacológico , Histiocitose/patologia , Humanos , Lactente , Masculino , Mutação , Ácidos Picolínicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Receptores Proteína Tirosina Quinases/genética , Gêmeos Monozigóticos , Sequenciamento Completo do Exoma , Adulto Jovem
6.
Clin Case Rep ; 7(10): 1989-1993, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31624624

RESUMO

Our rechallenge of cobimetinib in an Erdheim-Chester Disease (ECD) patient for the rare adverse effect, "dropped head syndrome," with a previously unexplored cobimetinib regimen was successful. Similar to other experiences with targeted agents in ECD, dosing of cobimetinib may vary to mitigate toxicity without impairing efficacy.

7.
Clin Cancer Res ; 25(18): 5537-5547, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31263031

RESUMO

PURPOSE: The genomic landscape of gliomas has been characterized and now contributes to disease classification, yet the relationship between molecular profile and disease progression and treatment response remain poorly understood.Experimental Design: We integrated prospective clinical sequencing of 1,004 primary and recurrent tumors from 923 glioma patients with clinical and treatment phenotypes. RESULTS: Thirteen percent of glioma patients harbored a pathogenic germline variant, including a subset associated with heritable genetic syndromes and variants mediating DNA repair dysfunctions (29% of the total) that were associated with somatic biallelic inactivation and mechanism-specific somatic phenotypes. In astrocytomas, genomic alterations in effectors of cell-cycle progression correlated with aggressive disease independent of IDH mutation status, arose preferentially in enhancing tumors (44% vs. 8%, P < 0.001), were associated with rapid disease progression following tumor recurrence (HR = 2.6, P = 0.02), and likely preceded the acquisition of alkylating therapy-associated somatic hypermutation. Thirty-two percent of patients harbored a potentially therapeutically actionable lesion, of whom 11% received targeted therapies. In BRAF-mutant gliomas, response to agents targeting the RAF/MEK/ERK signaling axis was influenced by the type of mutation, its clonality, and its cellular and genomic context. CONCLUSIONS: These data reveal genomic correlates of disease progression and treatment response in diverse types of glioma and highlight the potential utility of incorporating genomic information into the clinical decision-making for patients with glioma.

8.
Mol Cancer Ther ; 18(6): 1149-1157, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31015311

RESUMO

The BRAF V600E mutation and BRAF inhibitor responsiveness characterize ∼50% of patients with the non-Langerhans cell histiocytosis (non-LCH) Erdheim-Chester disease (ECD). We interrogated the non-LCH molecular landscape [ECD, n = 35; Rosai-Dorfman disease (RDD), n = 3; mixed ECD/RDD, n = 1] using BRAF V600E PCR and/or next-generation sequencing [tissue and cell-free DNA (cfDNA) of plasma and/or urine]. Of 34 evaluable patients, 17 (50%) had the BRAF V600E mutation. Of 31 patients evaluable for non-BRAF V600E alterations, 18 (58%) had ≥1 alteration and 12 putative non-BRAF V600E MAPK pathway alterations: atypical BRAF mutation; GNAS, MAP2K1, MAP2K2, NF1, and RAS mutations; RAF1 or ERBB2 amplifications; LMNA-NTRK1 (TRK inhibitor-sensitive) and CAPZA2-BRAF fusions. Four patients had JAK2, MPL ASXL1, U2AF1 alterations, which can correlate with myeloid neoplasms, a known ECD predisposition, and one developed myelofibrosis 13 months after cfDNA testing. Therefore, our multimodal comprehensive genomics reveals clinically relevant alterations and suggests that MAPK activation is a hallmark of non-LCH.

9.
Blood Adv ; 3(7): 934-938, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30917949

RESUMO

Erdheim-Chester disease (ECD) is an ultra-rare hematologic neoplasm characterized by somatic mutations of the MAPK pathway and by accumulation of lesional histiocytes within tissues. Clinical phenotypes and sites of disease involvement are heterogenous in ECD, and no tool exists for systematic and comprehensive assessment of ECD symptomatology. We describe a collaborative effort among ECD specialists, patient-reported outcome (PRO) methodologists, and ECD patients to develop the Erdheim-Chester Disease Symptom Scale (ECD-SS): a symptom inventory for clinical ECD care and evaluation of ECD therapies. Methodologically rigorous focus groups led to the identification of 63 ECD symptoms in 6 categories, incorporated into the ECD-SS with respect to both severity and frequency. Among 50 ECD patients participating in a prospective registry study completing the ECD-SS, 46 (92%) reported neurological/psychological symptoms, 29 (58%) reported pain, and at least one-half reported mood symptoms, memory problems, or fatigue. Symptoms were highly frequent or almost constant regardless of their severity. The ECD-SS is a rigorously developed, patient-centered tool that demonstrates the wide and previously unappreciated burden of symptomatology experienced by ECD patients. Further studies will refine the symptom inventory and define its psychometric properties and role in clinical care and investigation in the context of ECD.

10.
Nature ; 567(7749): 521-524, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30867592

RESUMO

Histiocytic neoplasms are a heterogeneous group of clonal haematopoietic disorders that are marked by diverse mutations in the mitogen-activated protein kinase (MAPK) pathway1,2. For the 50% of patients with histiocytosis who have BRAFV600 mutations3-5, RAF inhibition is highly efficacious and has markedly altered the natural history of the disease6,7. However, no standard therapy exists for the remaining 50% of patients who lack BRAFV600 mutations. Although ERK dependence has been hypothesized to be a consistent feature across histiocytic neoplasms, this remains clinically unproven and many of the kinase mutations that are found in patients who lack BRAFV600 mutations have not previously been biologically characterized. Here we show ERK dependency in histiocytoses through a proof-of-concept clinical trial of cobimetinib, an oral inhibitor of MEK1 and MEK2, in patients with histiocytoses. Patients were enrolled regardless of their tumour genotype. In parallel, MAPK alterations that were identified in treated patients were characterized for their ability to activate ERK. In the 18 patients that we treated, the overall response rate was 89% (90% confidence interval of 73-100). Responses were durable, with no acquired resistance to date. At one year, 100% of responses were ongoing and 94% of patients remained progression-free. Cobimetinib treatment was efficacious regardless of genotype, and responses were observed in patients with ARAF, BRAF, RAF1, NRAS, KRAS, MEK1 (also known as MAP2K1) and MEK2 (also known as MAP2K2) mutations. Consistent with the observed responses, the characterization of the mutations that we identified in these patients confirmed that the MAPK-pathway mutations were activating. Collectively, these data demonstrate that histiocytic neoplasms are characterized by a notable dependence on MAPK signalling-and that they are consequently responsive to MEK inhibition. These results extend the benefits of molecularly targeted therapy to the entire spectrum of patients with histiocytosis.


Assuntos
Azetidinas/uso terapêutico , Transtornos Histiocíticos Malignos/tratamento farmacológico , Transtornos Histiocíticos Malignos/enzimologia , Histiocitose/tratamento farmacológico , Histiocitose/enzimologia , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Piperidinas/uso terapêutico , Azetidinas/farmacologia , Transtornos Histiocíticos Malignos/genética , Transtornos Histiocíticos Malignos/patologia , Histiocitose/genética , Histiocitose/patologia , Humanos , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 2/antagonistas & inibidores , MAP Quinase Quinase 2/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mutação , Piperidinas/farmacologia , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-raf/genética
12.
J Clin Invest ; 128(9): 3819-3825, 2018 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-29920189

RESUMO

Rearrangements involving the neurotrophic receptor kinase genes (NTRK1, NTRK2, and NTRK3; hereafter referred to as TRK) produce oncogenic fusions in a wide variety of cancers in adults and children. Although TRK fusions occur in fewer than 1% of all solid tumors, inhibition of TRK results in profound therapeutic responses, resulting in Breakthrough Therapy FDA approval of the TRK inhibitor larotrectinib for adult and pediatric patients with solid tumors, regardless of histology. In contrast to solid tumors, the frequency of TRK fusions and the clinical effects of targeting TRK in hematologic malignancies are unknown. Here, through an evaluation for TRK fusions across more than 7,000 patients with hematologic malignancies, we identified TRK fusions in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), histiocytosis, multiple myeloma, and dendritic cell neoplasms. Although TRK fusions occurred in only 0.1% of patients (8 of 7,311 patients), they conferred responsiveness to TRK inhibition in vitro and in vivo in a patient-derived xenograft and a corresponding AML patient with ETV6-NTRK2 fusion. These data identify that despite their individual rarity, collectively, TRK fusions are present in a wide variety of hematologic malignancies and predict clinically significant therapeutic responses to TRK inhibition.


Assuntos
Neoplasias Hematológicas/genética , Fusão Oncogênica , Receptores Proteína Tirosina Quinases/genética , Adulto , Idoso , Animais , Criança , Feminino , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/enzimologia , Humanos , Lactente , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/genética , Camundongos , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Proteínas de Fusão Oncogênica/genética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-ets/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-ets/genética , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptor trkA/genética , Receptor trkB/antagonistas & inibidores , Receptor trkB/genética , Receptor trkC/genética , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
13.
Blood ; 131(26): 2877-2890, 2018 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-29720485

RESUMO

Rosai-Dorfman-Destombes disease (RDD) is a rare non-Langerhans cell histiocytosis characterized by accumulation of activated histiocytes within affected tissues. RDD, which now belongs to the R group of the 2016 revised histiocytosis classification, is a widely heterogeneous entity with a range of clinical phenotypes occurring in isolation or in association with autoimmune or malignant diseases. Recent studies have found NRAS, KRAS, MAP2K1, and ARAF mutations in lesional tissues, raising the possibility of a clonal origin in some forms of RDD. More than 1000 reports have been published in the English literature; however, there is a lack of consensus regarding approach for the clinical management of RDD. Although in most cases RDD can be observed or treated with local therapies, some patients with refractory or multifocal disease experience morbidity and mortality. Here we provide the first consensus multidisciplinary recommendations for the diagnosis and management of RDD. These recommendations were discussed at the 32nd Histiocyte Society Meeting by an international group of academic clinicians and pathologists with expertise in RDD. We include guidelines for clinical, laboratory, pathologic, and radiographic evaluation of patients with RDD together with treatment recommendations based on clinical experience and review of the literature.


Assuntos
Histiócitos/patologia , Histiocitose Sinusal/diagnóstico , Histiocitose Sinusal/terapia , Corticosteroides/uso terapêutico , Biópsia , Gerenciamento Clínico , Predisposição Genética para Doença , Histiócitos/metabolismo , Histiocitose Sinusal/genética , Histiocitose Sinusal/patologia , Humanos , Imunoterapia , Mutação , Guias de Prática Clínica como Assunto , Prognóstico , Radioterapia
14.
J Clin Oncol ; 36(17): 1702-1709, 2018 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-29683790

RESUMO

Purpose Carboxyamidotriazole orotate (CTO) is a novel oral inhibitor of non-voltage-dependent calcium channels with modulatory effects in multiple cell-signaling pathways and synergistic effects with temozolomide (TMZ) in glioblastoma (GBM) models. We conducted a phase IB study combining CTO with two standard TMZ schedules in GBM. Methods In cohort 1, patients with recurrent anaplastic gliomas or GBM received escalating doses of CTO (219 to 812.5 mg/m2 once daily or 600 mg fixed once-daily dose) combined with TMZ (150 mg/m2 5 days during each 28-day cycle). In cohort 2, patients with newly diagnosed GBM received escalating doses of CTO (219 to 481 mg/m2/d once daily) with radiotherapy and TMZ 75 mg/m2/d, followed by TMZ 150 mg to 200 mg/m2 5 days during each 28-day cycle. Results Forty-seven patients were enrolled. Treatment was well tolerated; toxicities included fatigue, constipation, nausea, and hypophosphatemia. Pharmacokinetics showed that CTO did not alter TMZ levels; therapeutic concentrations were achieved in tumor and brain. No dose-limiting toxicities were observed; the recommended phase II dose was 600 mg/d flat dose. Signals of activity in cohort 1 (n = 27) included partial (n = 6) and complete (n = 1) response, including in O6-methylguanine-DNA methyltransferase unmethylated and bevacizumab-refractory tumors. In cohort 2 (n = 15), median progression-free survival was 15 months and median overall survival was not reached (median follow-up, 28 months; 2-year overall survival, 62%). Gene sequencing disclosed a high rate of responses among EGFR-amplified tumors ( P = .005), with mechanisms of acquired resistance possibly involving mutations in mismatch-repair genes and/or downstream components TSC2, NF1, NF2, PTEN, and PIK3CA. Conclusion CTO can be combined safely with TMZ or chemoradiation in GBM and anaplastic gliomas, displaying favorable brain penetration and promising signals of activity in this difficult-to-treat population.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Glioma/tratamento farmacológico , Triazóis/administração & dosagem , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/efeitos adversos , Quimiorradioterapia , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Glioblastoma/patologia , Glioblastoma/radioterapia , Glioma/patologia , Glioma/radioterapia , Humanos , Masculino , Pessoa de Meia-Idade , Triazóis/efeitos adversos , Adulto Jovem
16.
J Palliat Med ; 21(4): 536-540, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29298104

RESUMO

BACKGROUND: Cognitive function of patients with advanced cancer is frequently compromised. OBJECTIVE: To determine the extent that patients' cognitive screening scores was associated with their end-of-life (EoL) treatment preferences, advance care planning (ACP), and care. DESIGN: Patients were interviewed at baseline and administered a cognitive screen. Caregivers completed a postmortem assessment. SETTING/SUBJECTS: Patients with distant metastases and disease progression after first-line chemotherapy and their caregivers (n = 609) were recruited from outpatient clinics and completed baseline and postmortem assessments. MEASUREMENTS: In logistic regression models adjusting for patients' age, education level, and performance status, patients' scores on the Pfeiffer Short Portable Mental Status exam at baseline predicted ACP, treatments, and treatment preferences at baseline, and location of death and caregiver perceptions of the patients' death in a postmortem assessment. RESULTS: For each additional error, patients were less likely to consider the intensive care unit a bad place to die (adjusted odds ratio [AOR] = 0.81; confidence interval [95% CI]: 0.66-0.98; p = 0.03) and less likely to have an inpatient hospice stay (AOR = 0.63; 95% CI: 0.40-1.00; p = 0.05). After death (n = 318), caregivers were more likely to perceive that patients died at patients' preferred location (AOR = 1.38; 95% CI: 1.01-1.88; p = 0.04) and less likely to perceive that patients preferred to extend life over relieving discomfort (AOR = 0.63; 95% CI: 0.40-0.99; p = 0.05). CONCLUSIONS: Patient cognitive screening scores were associated with EoL outcomes. Rather than avoid patients who are cognitively impaired, oncologists should consider ACP with them.


Assuntos
Disfunção Cognitiva/etiologia , Neoplasias/complicações , Neoplasias/terapia , Cuidados Paliativos , Doente Terminal/psicologia , Planejamento Antecipado de Cuidados , Tomada de Decisões , Feminino , Humanos , Entrevistas como Assunto , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Preferência do Paciente , Estudos Prospectivos
17.
Mod Pathol ; 31(4): 581-597, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29192649

RESUMO

Erdheim-Chester disease is a rare, non-Langerhans cell histiocytosis histologically characterized by multi-systemic proliferation of mature histiocytes in a background of inflammatory stroma. The disease can involve virtually any organ system; most commonly the bones, skin, retroperitoneum, heart, orbit, lung, and brain are affected. Although a histiocytic proliferation is the histological hallmark of the disease, a wide range of morphological appearances have been described as part of case studies or small series. A comprehensive review of histopathological features in clinically and molecularly defined Erdheim-Chester disease has yet to be characterized. To address this issue and help guide clinical practice, we comprehensively analyzed the pathological spectrum of Erdheim-Chester disease in a clinically and molecularly defined cohort. We reviewed 73 biopsies from 42 patients showing involvement by histiocytosis from a variety of organ systems, including bone (16), retroperitoneum (11), skin (19), orbit (6), brain (5), lung (6), cardiac structures (2), epidural soft tissue (3), oral cavity (2), subcutaneous soft tissue (2), and testis (2). In eight patients, one or more bone marrow biopsies were performed due to clinical indication and an accompanying myeloid neoplasm was detected in six of them. Thirty-eight cases were investigated for genetic abnormalities. Somatic mutations involving BRAF (25/38), MAP2K1 (6/38), ARAF (2/38), MAP2K2 (1/38), KRAS (1/38), and NRAS (1/38) genes were detected. One of the cases with a MAP2K1 mutation also harbored a PIK3CA mutation. We have observed marked heterogeneity in histology and immunophenotype, identified site-specific features, overlap with other histiocytic and myeloid disorders and potential diagnostic pitfalls. We hope that broadening the spectrum of recognized pathologic manifestations of Erdheim-Chester disease will help practicing clinicians and pathologists to diagnose Erdheim-Chester disease early in the disease course and manage these patients effectively.


Assuntos
Doença de Erdheim-Chester/genética , Doença de Erdheim-Chester/patologia , Estudos de Coortes , Humanos
18.
JAMA Oncol ; 4(3): 384-388, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29188284

RESUMO

Importance: The histiocytic neoplasms Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) are highly enriched for BRAF V600 mutations and have been previously shown to be responsive to treatment with vemurafenib, an inhibitor of the BRAF V600 kinase. However, the long-term efficacy and safety of prolonged vemurafenib use in these patients are not defined. Here we analyze the final efficacy and safety data for vemurafenib in patients with ECD and LCH enrolled in the VE-BASKET study. Objective: To determine the efficacy and safety of vemurafenib in adults with ECD or LCH enrolled in the VE-BASKET study. Design, Setting, and Participants: The VE-BASKET study was an open-label, nonrandomized, multicohort study for patients with nonmelanoma cancers harboring the BRAF V600 mutation. Patients with BRAF V600-mutant ECD or LCH were enrolled in an "other solid tumor" cohort of the VE-BASKET study, and they were enrolled in the present study. Interventions: Patients received vemurafenib, 960 mg, twice daily continuously until disease progression, study withdrawal, or occurrence of intolerable adverse effects. Main Outcomes and Measures: The primary end point was confirmed objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Secondary end points included progression-free survival (PFS), overall survival (OS), metabolic response by modified positron-emission tomography (PET) Response Criteria in Solid Tumors (PERCIST) using 18F-fluorodeoxyglucose (FDG)-PET/computed tomography (CT), and safety. Results: A total of 26 patients from the VE-BASKET trial (22 with ECD, 4 with LCH) were included in the present study (14 women and 12 men; median age, 61 years; age range, 51-74 years). The confirmed ORR was 61.5% (95% CI, 40.6%-79.8%) in the overall cohort and 54.5% (95% CI, 32.2%-75.6%) in patients with ECD. All evaluable patients achieved stable disease or better. The median PFS and OS had not been reached in the overall cohort at study closure despite a median follow-up of 28.8 months; 2-year PFS was 86% (95% CI, 72%-100%), and 2-year OS was 96% (95% CI, 87%-100%). All 15 patients evaluated by FDG-PET/CT achieved a metabolic response, including 12 patients (80%) with a complete metabolic response. The most common adverse events (AEs) in the overall cohort included arthralgia, maculopapular rash, fatigue, alopecia, prolonged QT interval, skin papilloma, and hyperkeratosis. Hypertension and dermatologic AEs occurred at higher rates than those reported in metastatic melanoma. Conclusions and Relevance: In this study, vemurafenib had prolonged efficacy in patients with BRAF V600-mutant ECD and LCH and warrants consideration as a new standard of care for these patients.


Assuntos
Doença de Erdheim-Chester/tratamento farmacológico , Doença de Erdheim-Chester/genética , Histiocitose de Células de Langerhans/tratamento farmacológico , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas B-raf/genética , Vemurafenib/uso terapêutico , Idoso , Substituição de Aminoácidos/genética , Doença de Erdheim-Chester/diagnóstico , Doença de Erdheim-Chester/mortalidade , Feminino , Fluordesoxiglucose F18 , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Prognóstico , Análise de Sobrevida , Resultado do Tratamento , Valina/genética
19.
Pediatr Blood Cancer ; 65(1)2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28748614

RESUMO

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm characterized by constitutive activation of extracellular signal-regulated kinase (ERK). Genomic characterization has identified activating point mutations including mutually exclusive BRAFV600E and activating MAP2K1 mutations to be responsible for ERK activation in a majority of pediatric LCH patients. Here, we report the discovery of a novel BRAF kinase fusion, PACSIN2-BRAF, in a child with multisystem LCH. This is the second reported case of an activating BRAF kinase fusion and indicates a recurrent pathologic mechanism. Genomic evaluation for activating kinase fusions should be strongly considered in pediatric LCH patients lacking more common mutations.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , MAP Quinases Reguladas por Sinal Extracelular , Histiocitose de Células de Langerhans/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas B-raf/genética , Criança , Ativação Enzimática/genética , Humanos , Masculino
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA