Since the discovery of the association between BRAF mutations and fusions in the development of childhood low-grade gliomas and the subsequent recognition that most childhood low-grade glial and glioneuronal tumors have aberrant signaling through the RAS/RAF/MAP kinase pathway, there has been a dramatic change in how these tumors are conceptualized. Many of the fusions and mutations present in these tumors are associated with molecular targets, which have agents in development or already in clinical use. Various agents, including MEK inhibitors, BRAF inhibitors, MTOR inhibitors and, in small subsets of patients NTRK inhibitors, have been used successfully to treat children with recurrent disease, after failure of conventional approaches such as surgery or chemotherapy. The relative benefits of chemotherapy as compared to molecular-targeted therapy for children with newly diagnosed gliomas and neuroglial tumors are under study. Already the combination of an MEK inhibitor and a BRAF inhibitor has been shown superior to conventional chemotherapy (carboplatin and vincristine) in newly diagnosed children with BRAF-V600E mutated low-grade gliomas and neuroglial tumors. However, the long-term effects of such molecular-targeted treatment are unknown. The potential use of molecular-targeted therapy in early treatment has made it mandatory that the molecular make-up of the majority of low-grade glial and glioneuronal tumors is known before initiation of therapy. The primary exception to this rule is in children with neurofibromatosis type 1 who, by definition, have NF1 loss; however, even in this population, gliomas arising in late childhood and adolescence or those not responding to conventional treatment may be candidates for biopsy, especially before entry on molecular-targeted therapy trials.

Dissemination in pediatric low-grade glioma may occur in about 4%-10% of patients according to retrospective cohort studies. Due to its low incidence, there is no consensus on treatment for these patients. According to the constitutional activation of the MAPK/ERK pathway in these tumors, MEK inhibitors such as trametinib have been used successfully in the relapsed setting. Skin toxicity is frequent in patients receiving trametinib, normally mild to moderate, but sometimes severe, needing to discontinue the drug, limiting the efficacy in the tumor. There is not much information in the literature regarding whether reducing the dose of trametinib is able to maintain efficacy while, at the same time, decreasing toxicity. Here, we present an adolescent, with severe skin toxicity, whose trametinib dose was reduced by 50% and efficacy on the tumor continued while skin toxicity significantly decreased.

Gliomas are the most common adult and pediatric primary brain tumors. Molecular studies have identified features that can enhance diagnosis and provide biomarkers. IDH1/2 mutation with ATRX and TP53 mutations defines diffuse astrocytomas, whereas IDH1/2 mutations with 1p19q loss defines oligodendroglioma. Focal amplifications of receptor tyrosine kinase genes, TERT promoter mutation, and loss of chromosomes 10 and 13 with trisomy of chromosome 7 are characteristic features of glioblastoma and can be used for diagnosis. BRAF gene fusions and mutations in low-grade gliomas and histone H3 mutations in high-grade gliomas also can be used for diagnostics.

BACKGROUND: Patients with histiocytic sarcoma occurring in the central nervous system (CNS) are rare and have a very poor prognosis. The increased use of molecular diagnostic approaches in solid tumors has brought more opportunities for the diagnosis and treatment of central nervous system histiocytic sarcoma (CNSHS).
METHODS: A 9-year-old girl was admitted to the hospital with pain in her head and neck, as well as vomiting. Imaging scans showed a prominent abnormality in the anterior falciform region, and histopathology revealed the presence of CD68 (+) and CD163 (+) cells, leading to a preliminary diagnosis of primary intracerebral CNSHS. Molecular profiling tests identified a new variant of ARHGAP45::BRAF fusion in this case, which has not been reported in any other tumor. The patient underwent surgical removal of the tumor and will require long-term monitoring.
CONCLUSIONS: The presence of the BRAF point mutation, predominantly BRAF p.V600E, has been documented in prior literature of CNSHS. This is the first case of pediatric histiocytic sarcoma in the anterior falciform region who has a unique ARHGAP45::BRAF fusion. The findings of our study indicate that a broader range of molecular assays should be employed in the diagnosis of CNSHS and opens up new possibilities for the treatment of the patient.

BACKGROUND: We aimed to develop machine learning models for prediction of molecular subgroups (low-risk group and intermediate/high-risk group) and molecular marker (KIAA1549-BRAF fusion) of pediatric low-grade gliomas (PLGGs) based on radiomic features extracted from multiparametric MRI.
METHODS: 61 patients with PLGGs were included in this retrospective study, which were divided into a training set and an internal validation set at a ratio of 2:1 based on the molecular subgroups or the molecular marker. The patients were classified into low-risk and intermediate/high-risk groups, BRAF fusion positive and negative groups, respectively. We extracted 5929 radiomic features from multiparametric MRI. Thereafter, we removed redundant features, trained random forest models on the training set for predicting the molecular subgroups or the molecular marker, and validated their performance on the internal validation set. The performance of the prediction model was verified by 3-fold cross-validation.
RESULTS: We constructed the classification model differentiating low-risk PLGGs from intermediate/high-risk PLGGs using 4 relevant features, with an AUC of 0.833 and an accuracy of 76.2% in the internal validation set. In the prediction model for predicting KIAA1549-BRAF fusion using 4 relevant features, an AUC of 0.818 and an accuracy of 81.0% were achieved in the internal validation set.
CONCLUSIONS: The current study demonstrates that MRI radiomics is able to predict molecular subgroups of PLGGs and KIAA1549-BRAF fusion with satisfying sensitivity.
BACKGROUND: This study was retrospectively registered at clinicaltrials.gov (NCT04217018).

Pilocytic astrocytoma (PA), a central nervous system (CNS) World Health Organization grade 1 tumor, is mainly seen in children or young adults aged 5-19. Surgical resection often provides excellent outcomes, but residual tumors may still remain. This low-grade tumor is well recognized for its classic radiological and morphological features; however, some unique molecular findings have been unveiled by the application of next-generation sequencing (NGS). Among the genetic abnormalities identified in this low-grade tumor, increasing evidence indicates that BRAF alterations, especially BRAF fusions, play an essential role in PA tumorigenesis. Among the several fusion partner genes identified in PAs, KIAA1549-BRAF fusion is notably the most common detectable genetic alteration, especially in the cerebellar PAs. Here, we report a case of a young adult patient with a large, right-sided posterior fossa cerebellar and cerebellopontine angle region mass consistent with a PA. Of note, NGS detected a novel GNAI3-BRAF fusion, which results in an in-frame fusion protein containing the kinase domain of BRAF. This finding expands the knowledge of BRAF fusions in the tumorigenesis of PAs, provides an additional molecular signature for diagnosis, and a target for future therapy.

UNASSIGNED: Non-small cell lung cancer (NSCLC) is one of the most common malignancies in the world. Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) indicated for NSCLC that effectively targets sensitive epidermal growth factor receptor mutation and exon20 T790M. Despite initially impressive outcomes, acquired resistance (AR) develops rapidly, typically within 9-13 months, and the mechanisms of resistance are not fully understood. Over the past years, EGFR-TKI and programmed cell death-ligand 1 (PD-L1) inhibitors have been widely used to treat for patients with advanced lung adenocarcinoma.
UNASSIGNED: Herein we report a middle-aged female who suffered from lung adenocarcinoma based on the pathological diagnosis. Epidermal growth factor receptor exon 19 deletion was detected by next-generation sequencing (NGS). After the patient underwent a series of treatments, including osimertinib, BTN2A1-BRAF fusion was identified. After assessing PD-L1 expression by immunohistochemistry (IHC), the patient was switched to duvalizumab, a PD-L1 inhibitor, but no significant improvements were observed. NGS and IHC assays were conducted to analyze the biopsy and blood samples obtained during treatment.
UNASSIGNED: This case substantiates that the acquisition of BTN2A1-BRAF fusion potentially serves as a mechanism of AR to osimertinib in NSCLC. Patients with sensitive epidermal growth factor receptor mutation derive minimal benefit from PD-L1 inhibitors irrespective of the degree of PD-L1 expression in the tumor tissue in IHC. Our case provides a new train of thought for treating this patient population.

BRAF gene has been identified as an oncogenic driver and a potential target in various malignancies. BRAF fusions are one subtype of BRAF alterations with a rare frequency. Here, we first report a previously treated advanced lung adenocarcinoma patient with de novo SND1-BRAF fusion who achieves partial response to the MAK inhibitor trametinib. We also provide a literature review on targeted therapies for BRAF fusions.

BRAF fusions are rare driver oncogenes in non-small cell lung cancer (NSCLC). Similar with BRAF V600E mutation, it could also activate the MAPK signaling pathway. There are a few case reports which had indicated the potential response to BRAF inhibitors and its important role as de novo driver mutation. In addition, the co-occurring MET amplification has been defined as a poor prognostic factor in patients with epidermal growth factor receptor (EGFR) mutant NSCLC. Currently, there are ongoing clinical trials which investigate the MET amplification as a therapeutic target in patients with EGFR mutant NSCLC and acquired resistance to osimertinib, which imply that the MET amplification also had a therapeutic significance. However, the co-occurring MET amplification had not been studied in patients with BRAF fusion before. A 67-year-old man was diagnosed with metastatic poorly-differentiated adenocarcinoma. He received first-line therapy with the combination of pembrolizumab and chemotherapy because the genomic test revealed wild-type EGFR, and negativity of ALK and ROS1 by immunohistochemical stain. Upon disease progression, the next-generation sequencing revealed co-occurring KIAA1549-BRAF fusion and MET amplification. Subsequent dabrafenib, trametinib, and capmatinib combination therapy showed a remarkable treatment effect. The combination therapy targeting the co-occurring driver mutations is a potential effective treatment for NSCLC patients. Further prospective study is still warranted to investigate the role of co-occurring driver mutations and the relevant treatment strategy.

Osimertinib has become a standard of care in the first-line treatment of advanced-stage non-small-cell lung cancer (NSCLC) harboring exon 19 and 21 activating mutations in the EGFR gene. Nevertheless, the 18.9-month median progression-free survival emphasizes the fact that resistance to osimertinib therapy is inevitable. Acquired resistance mechanisms to osimertinib in EGFR-driven NSCLC include MET amplification, EGFR C797S mutation, neuroendocrine differentiation, small-cell lung carcinoma histologic transformation, PD-L1 and KRAS amplifications and ESR1-AKAP12 and MKRN1-BRAF translocations, as well as BRAF V600 mutation. This last one represents 3% of the acquired resistance mechanisms to osimertinib. In this review, we discuss the rationale for EGFR/BRAF/MEK co-inhibition in the light of a clinical case of EGFR-mutant NSCLC developing a BRAF V600 mutation as an acquired resistance mechanism to osimertinib and responding to the association of osimertinib plus dabrafenib and trametinib. Additionally, we discuss the acquired resistance mechanisms to osimertinib plus dabrafenib and trametinib combination in that context.