Secondary histiocytic sarcoma with BRAF V600E mutation responsive to MAPK‐targeted therapy presenting with recurrence with mTOR mutation responsive to mTOR‐targeted therapy

Abstract In-operable low grade gliomas (LGG) in the pediatric population continue to present a treatment dilemma. Due to the low-grade nature of these tumors, and variable response to chemotherapy / radiation, the choice of adjuvant treatment is difficult. Overall survival is directly related to the degree of surgical resection, adding complexity to these inoperable tumors. Current chemotherapeutic regimen for these inoperable tumors includes vincristine (VCR) and carboplatin (Carbo). With advancements in the molecular characterization of gliomas, the role of targeted therapy has come into question. We present a 2-year-old female with biopsy proven Pilocytic Astrocytoma (positive BRAF-V600E mutation) involving the hypothalamic/optic chiasm region. She presented with ataxic gait, bi-temporal hemianopia, obstructive hydrocephalus and central hypothyroidism, which progressed to altered consciousness, and right hemiparesis due to location/mass effect of the tumor. She was initially treated with chemotherapy (VCR/Carbo) but her tumor progressed at 6 weeks of treatment. As her tumor was positive for BRAF-V600E mutation, she was started on Dabrafenib monotherapy, resulting in dramatic improvement in her clinical symptoms (able to stand, improved vision), and a 60% reduction in tumor size at 3-months. At 6-months, follow up MRI showed slight increase in the solid portion of the tumor, with no clinical symptoms. We plan to add MEK inhibitor (Trametinib) and continue with Dabrafenib. Our experience and literature review suggests that LGG with BRAF-V600E mutations may benefit from upfront targeted therapy. Prospective clinical trials comparing the efficacy of BRAF inhibitors versus standard chemotherapy in LGG with BRAF mutations are urgently needed.

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Histiocytic sarcoma arising from thyroid gland with BRAF V600E mutation

Pathology ◽

10.1016/j.pathol.2020.04.012 ◽

2020 ◽

Vol 52 (5) ◽

pp. 603-605

Author(s):

Rong Ge ◽

Yuqing Chang ◽

Yongli Gan ◽

Haidong Zhu ◽

Chuangfeng Liu

Keyword(s):

Thyroid Gland ◽

Braf V600e Mutation ◽

Histiocytic Sarcoma ◽

Braf V600e

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Secondary histiocytic sarcoma with BRAF V600E mutation after T‐cell acute lymphoblastic leukemia in a very young child with dramatic response to dabrafenib and trametinib

Pediatric Blood & Cancer ◽

10.1002/pbc.28200 ◽

2020 ◽

Vol 67 (5) ◽

Author(s):

Vinayak Venkataraman ◽

Lucas R. Massoth ◽

Ryan J. Sullivan ◽

Alison M. Friedmann

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Young Child ◽

Lymphoblastic Leukemia ◽

Braf V600e Mutation ◽

Histiocytic Sarcoma ◽

Braf V600e ◽

Cell Acute Lymphoblastic Leukemia

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Low-grade gliomas with the V600E mutation in the BRAF gene in children: clinical features and treatment options

Pediatric Hematology/Oncology and Immunopathology ◽

10.24287/1726-1708-2020-19-4-58-65 ◽

2020 ◽

Vol 19 (4) ◽

pp. 58-65

Author(s):

L. I. Papusha ◽

E. F. Valiakhmetova ◽

A. E. Druy ◽

L. A. Yasko ◽

K. A. Voronin ◽

...

Keyword(s):

Targeted Therapy ◽

Treatment Options ◽

Molecular Genetic ◽

Braf Inhibitor ◽

Complete Response ◽

Braf V600e Mutation ◽

Braf V600e ◽

Molecular Characteristics ◽

Low Grade ◽

Low Grade Gliomas

The main pathogenetic mechanism of the development of pediatric low grade gliomas (pLGGs) is genetic aberrations in BRAF gene. This study is supported by the Independent Ethics Committee and approved by the Academic Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology. We analyzed the clinical and molecular characteristics of 69 patients with LGGs. Molecular genetic testing for BRAF V600E mutation was performed by allele-specific real-time PCR and Sanger sequencing. BRAF V600E mutation was detected in 15 (21.7%) patients with LGG. The majority of BRAF-mutated cases of LGGs had the midline location: OPG – 7, subcortical ganglia – 1, brainstem – 2. The 2-year PFS was much worse in patients with BRAF V600E compared to patients without this mutation – 30% and 66.2%, respectively. The median time to progression for patients with BRAF V600E mutation was 9.5 months compared to 3.1 years for patients without indicated substitution. 5 patients with BRAF V600E-mutated LGGs who experienced progression after the conventional treatment, received targeted therapy (BRAF-inhibitor-3, BRAF + MEK inhibitors – 2) with good response (complete response – 2, partial response – 3). BRAF V600E mutation contributes to poor outcome in patients with LGGs Targeted therapy could be effective in this cohort of patients.

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A case report of metastatic giant sarcomatoid melanoma with BRAF V600E mutation: a complete response to targeted therapy

Oncotarget ◽

10.18632/oncotarget.27701 ◽

2020 ◽

Vol 11 (34) ◽

pp. 3256-3262

Author(s):

Matteo Torresetti ◽

Donatella Brancorsini ◽

Francesca Morgese ◽

Valeria Cognigni ◽

Alessandro Scalise ◽

...

Keyword(s):

Case Report ◽

Targeted Therapy ◽

Complete Response ◽

Braf V600e Mutation ◽

Braf V600e

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Clinical characteristics and treatment outcomes of 65 patients with BRAF-mutated non-small cell lung cancer (NSCLC).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e21745 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e21745-e21745

Author(s):

Yuxin Mu ◽

Ke Yang ◽

Xuezhi Hao ◽

Yan Wang ◽

Lin Wang ◽

...

Keyword(s):

Lung Cancer ◽

Targeted Therapy ◽

Small Cell ◽

Braf V600e Mutation ◽

Braf V600e ◽

Small Cell Lung ◽

First Line ◽

Braf Mutations ◽

Free Survival ◽

Stage Disease

e21745 Background: BRAF mutations are infrequently seen in non-small cell lung cancer (NSCLC) in Chinese population. We aimed to investigate the clinicopathologic characteristics and treatment outcomes of Chinese patients with NSCLC harboring BRAF mutations. Methods: We conducted a retrospective multicenter study in China of patients with NSCLC harboring BRAF mutations between Jan 2017 and Jul 2019. Results: A total of 65 patients treated in 22 centers were included, 54 harbored BRAF-V600E mutation and 11 had non-V600E mutations, including K601E, G469S, G469V, G469A, G596R, G466R and T599dup. No significant difference in age or gender was found between BRAF-V600E and non-V600E cases, while the majority of patients with non-V600E mutations were smokers (81.8%). Of the 18 patients with early-stage disease at diagnosis and underwent a resection, the median disease-free survival (DFS) was 43.2 months, 18.7 months and 10.1 months of stage I, II and IIIA patients (P = 0.07), respectively. In 46 patients with advanced-stage disease at data cutoff, disease control rate (DCR) and progression-free survival (PFS) of first-line anti-BRAF targeted therapy was superior than chemotherapy in patients harboring BRAF-V600E mutation (DCR, 100.0% vs. 70.0%, P = 0.027; median PFS, 9.8 months vs. 5.4 months, P = 0.149). Of 30 V600E-mutated patients who received anti-BRAF therapy during the course of disease, the median PFS of vemurafenib, dabrafenib, and dabrafenib plus trametinib was 7.8 months, 5.8 months and 6.0 months, respectively (P = 0.970). Median PFS were similar between V600E and non-V600E patients (5.4 months vs. 5.4 months, P = 0.825) to first-line chemotherapy. Nine patients were treated with checkpoint inhibitors, DCR and median PFS were 62.5% and 3.0 months (95%CI 2.9, 3.1), respectively. Conclusions: Our data demonstrated the clinical benefit of anti-BRAF targeted therapy in Chinese NSCLC patients harboring BRAF-V600E mutation. The value of immunotherapy and treatment selection among non-V600E population needs further study.[Table: see text]

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Result Analysis of BRAF V600E Gene Mutation Using Molecular and Immunohistochemistry Detection in Acral Malignant Melanoma

Asian Pacific Journal of Cancer Care ◽

10.31557/apjcc.2018.3.3.43 ◽

2018 ◽

Vol 3 (3) ◽

pp. 43 ◽

Cited By ~ 1

Author(s):

Hermin Aminah Usman ◽

Bethy S Hernowo ◽

Maringan Diapari Lumbantobing ◽

Reti Hindritiani

Keyword(s):

Targeted Therapy ◽

Malignant Melanoma ◽

Gene Mutation ◽

Sensitivity And Specificity ◽

Braf V600e Mutation ◽

Braf V600e ◽

Rt Pcr ◽

Paraffin Block ◽

Objective Detection ◽

Result Analysis

Background and Objective: Detection of BRAF V¬600E gene mutation in Malignant Melanoma (MM) is essential in offering anti BRAF targeted therapy for MM patients. Expression of BRAF V600E mutant protein detected using immunohistochemistry (IHC) is affordable, rapid, and reliable. This study aimed to measure the sensitivity and specificity of IHC compared to BRAFV 600E immunoexpression by molecular detection.Method: This study used a paraffin block of acral MM patients to analyze BRAF V600E mutation status using anti-BRAF V600E IHC compared to Real-Time Polymerase Chain Reaction (RT PCR) which is a gold standard.Result: In total, ninety-six samples were tested using IHC and RT-PCR. RT-PCR showed that 15 (15.6%) samples were positive for BRAF V600E mutation. The sensitivity and specificity for IHC were 73.3% and 87.6% respectively. Concordance value of IHC was 85.4%. There were 10 false positives and 4 false negatives. IHC staining may be applied as early detection of BRAFV600E mutation in MM patients that are going to receive anti BRAF targeted therapy.

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Concurrent driver mutations in non-small cell lung cancer (NSCLC) patients (p) on targeted therapy uncovered by comprehensive molecular profiling.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.11004 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 11004-11004

Author(s):

Collin M. Blakely ◽

Luping Lin ◽

Saurabh Asthana ◽

Nikoletta Sidiropoulos ◽

Tyrrell Nelson ◽

...

Keyword(s):

Targeted Therapy ◽

Braf Inhibitor ◽

Molecular Profiling ◽

Braf V600e Mutation ◽

Braf V600e ◽

Driver Mutations ◽

T790m Mutation ◽

Tki Resistance ◽

Egfr Tki ◽

Egfr T790m

11004 Background: NSCLC p with EGFR mutations respond initially to EGFR tyrosine kinase inhibitors (TKIs) but invariably develop acquired EGFR TKI resistance. Prior studies identified the EGFR T790M mutation and activation of MET, PI3K, AXL, HER2 and the MAPK pathway as drivers of acquired EGFR TKI resistance. To date, comprehensive molecular profiling to identify actionable modifiers of EGFR TKI response has not been conducted in NSCLC p on therapy. Methods: We performed next generation sequencing (NGS) using a 263-gene Nimblegen custom cancer panel on DNA isolated from primary patient lung adenocarcinoma FFPE specimens prior to initiating standard erlotinib treatment and upon the development of acquired erlotinib resistance after only 3 months of therapy. Results: In the pretreatment sample, we confirmed the presence of the EGFRL858R mutation in 95% of the sequencing reads and discovered a concurrent BRAF V600E mutation with a frequency of ~ 6%. NGS performed on the acquired erlotinib resistance sample revealed acquisition of the EGFR T790M mutation with a frequency of ~ 14%. Notably, the frequency of the BRAF V600E mutation increased 10-fold upon acquired erlotinib resistance from ~ 6% in the pretreatment tumor to ~ 60% in the recurrent tumor. We found that overexpression of BRAF V600E in H3255 human NSCLC, which harbor EGFR L858R (but not BRAF V600E) and are erlotinib sensitive, caused resistance to erlotinib treatment (10-fold increase in erlotinib IC50). BRAF V600E-mediated erlotinib resistance was reversed by treatment with the BRAF inhibitor vemurafenib. Additional functional studies are ongoing and the complete dataset will be presented. Conclusions: These results indicate that EGFR-mutant NSCLC can harbor additional oncogenic driver mutations in BRAF at low frequencies prior to therapy. EGFR TKI treatment can lead to expansion of BRAF V600E expressing tumor cells, resulting in acquired EGFR TKI resistance that can be reversed by BRAF inhibitor treatment. The data demonstrate the utility of routine molecular profiling of NSCLC p on targeted therapy and offer unprecedented insight into the genetic basis of therapeutic resistance.

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