BRAF fusion

A repeated-measure generalized estimating equation demonstrated that targeted treatment was statistically significantly (1) more likely to result in a complete response (CR), partial response (PR) or stable disease (SD) (odds ratio &lsqb;OR]: 17.34, 95% CI: 2.19-137.00, p = 0.007), and (2) less likely to result in progression (OR: 0.08, 95% CI: 0.03-0.23, p < 0.0001). Histiocytic neoplasms represent an entity with underappreciated clinical and molecular diversity, poor responsiveness to conventional therapy and exquisite sensitivity to targeted therapy.

ADC values of tumor segmentations have differentiative signals that can be used for training machine learning classifiers for molecular biomarker identification of PLGNTs. ADC-based pretherapeutic differentiation of the BRAF status of PLGNTs has the potential to avoid invasive tumor biopsy and enable earlier initiation of targeted therapy.

P2, N=35, Active, not recruiting, National Cancer Institute (NCI)

P1, N=42, Recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Mar 2024 --> Mar 2025

These two fusion genes may be detected in resembling tumors, which contain giant cells, apart from malignant GCTB. The real-world data used herein provide a unique perspective on genomic alterations in clinicopathologically diagnosed malignant GCTB.

Conclusion Transfer learning and self-supervised cross-training improved classification performance and generalizability for noninvasive pLGG mutational status prediction in a limited data scenario.

Although they are rare, the therapeutic and diagnostic importance of these genomic events should not be underestimated, highlighting the need for quality-ensured molecular diagnostics in the management of cancer. Herein we review the existing literature on the role of fusion genes in pancreatic tumors and their clinical potential as effective biomarkers and therapeutic targets.

While CNV analysis of CSF samples from LGGs still has some limitations, it has the potential to serve as a valuable complementary tool. Furthermore, it can also be multiplexed with other aberrations, for example, to the BRAF V600 test, to provide important insights into the molecular characteristics of LGGs.

P1/2, N=168, Recruiting, Day One Biopharmaceuticals, Inc. | Phase classification: P1b/2 --> P1/2

The promising tovorafenib activity data, CNS-penetration properties, strong scientific rationale combined with the manageable tolerability and safety profile seen in patients with pLGG led to the SIOPe-BTG-LGG working group to nominate tovorafenib for comparison with SoC chemotherapy in this first-line phase 3 trial. The efficacy, safety, and functional response data generated from the trial may define a new SoC treatment for newly diagnosed pLGG.

Candidate oncogenic gene fusions involving BRAF, FGFR2 or NF1 as a fusion partner were identified. Molecular testing of LGSC may be used in clinical practice to reveal therapeutically significant targets.

Class 2/3 BRAFs are more present in Black male patients with co-mutations outside of the MAPK pathway, likely requiring additional oncogenic input for tumorigenesis. Improving access to NGS and trial enrollment will help the development of targeted therapies for non-V600 BRAF mutations.

Here we present the case of a young patient with a high-grade atypical Spitz tumor along with the diagnostic procedure and further management. We also review potential pitfalls in the literature that should alert clinicians to the more aggressive potential of the lesion, such as some BRAF fusions.

The study provided insights into MAPK-altered gliomas in Kuwait highlighting the differences among paediatric and adult patients and providing a framework for planning therapeutic polices.

Treatment with BVZ of progressive pediatric OPGs leads to a decrease of both total tumor volume and cystic volume for the majority of OPGs with emphasis on the first three months. NF1 and KIAA1549-BRAF fusion related OPGs showed a different (early) treatment effect regarding the tumor enhancing component on MRI, which did not correlate with tumor volume changes. Future research is necessary to further evaluate these findings and its relevance to clinical outcome parameters.

A particularly high fraction of adult tumours with histological features of PA do not match current PA methylation classes, indicating ambiguous histology and an urgent need for molecular profiling. Moreover, even in adult PAs with a match to a PA methylation class, the distribution of genetic drivers differs significantly from their paediatric counterparts (p<0.01).

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.

P1, N=114, Recruiting, MapKure, LLC | Phase classification: P1a/1b --> P1

No abstract available

Elevated pERK staining in tumor cells provided evidence of activated mitogen-activated protein kinase (MAPK) signaling. This report raises the possibility that gene fusion events may be involved in meningioma pathogenesis and warrant further investigation.

"cfDNA analysis may have a role to identify potential drivers of pathogenesis among cases that are unable to successfully undergo tissue molecular analysis. Further studies are underway to characterize other novel alterations that were discovered in the cfDNA analysis."

Regrettably, following the cessation of Trametinib, the patient's lesions rapidly progressed, and her disease worsened beyond the pre-treatment state. Taking into account the 10% PDL-1 positivity, immunotherapy with Pembrolizumab was commenced, resulting in partial improvement...Consequently, Cobimetinib was discontinued, and a continuously dosed MEK inhibitor, Binimetinib, was cautiously administered at a lower dose to mitigate the risk of cardiotoxicity... To our knowledge, this is the first clinical trial documenting MEK inhibition for a patient with xanthoma disseminatum harboring a BRAF fusion. Seeking to target downstream of BRAF, MEK inhibition demonstrated a dramatic response, with rapid relapse upon cessation, supporting a central oncogenic role for BRAF fusion. Further studies should explore alterations in the RAS-BRAF-ERK pathway in nLCH and consider clinical trials with MEK inhibitors.

The overall survival in FGFR1- and BRAF V600E-mutant DMGs was not statistically improved when compared with those that were wildtype. However, the possibility of targeted therapy argues for comprehensive sequencing of H3K27-altered gliomas.

This is the first Brazilian study that aimed to investigate possible genetic alterations in the BRAF gene in pilocytic astrocytomas, specifically in adults. Only 1 patient died, but due to operative complications and not the disease itself, suggesting a good evolution of these individuals.

In advanced non-small cell lung cancer (NSCLC), V-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation is highly malignant and has poor prognosis, and currently Dabrafenib in combination with Trametinib is approved for first-line treatment of patients with BRAF V600 mutation. With the development of gene detection, the detection of BRAF fusion is gradually increasing, but there is a lack of effective therapeutic strategies for BRAF fusion. In this paper, we review the clinical characteristics, mechanism of action, and clinical treatment of BRAF fusion to provide a basis for the treatment of BRAF fusion in NSCLC patients..

Everolimus is a well-tolerated therapy for progressive/recurrent pLGGs. Rare/novel KIAA1549::BRAF fusion breakpoints may define biomarkers for progressive disease and should be assessed in future clinical trials.

Our bi-institutional study shows radiomics-based ML models trained on ADC-extracted features differentiate BRAF fusion, V600E mutation, and other molecular subtypes of PLGNT with high diagnostic accuracies. We showed combining clinical variables and radiomics improves such models. *Clinical Relevance/Application: The success of treatment planning for PLGNT is conditioned on subtype identification, for which our machine learning models are demonstrated to be effective and reliable.

Although radiologists are not trained to diagnose PLGNT genetic markers, their analysis and description of MR images can significantly aid in genetic marker classification. Moreover, our model’s attention scores signify relevant text features such as location information and tumor pathological diagnosis, resulting in reliable and interpretable predictions. *Clinical Relevance/Application: Using radiology reports to predict PLGNT genetic markers can reveal important keywords, which are interpretable by radiologists.

Among the four imaging sequences in the dataset, T1CE was the best for separating BRAF fusion from V600E mutation. However, radiomic features extracted from FLAIR images outperformed other sequences at differentiating BRAF fusion and mutation from the other subtypes. *Clinical Relevance/Application: Identification of the molecular subtype of PLGNT is important for treatment planning.

In this large, real-world multiomic characterization of age-stratified molecular differences in pancreatic ductal adenocarcinoma, YOPC is associated with a distinct molecular landscape that has prognostic and therapeutic implications.

This is a rare case of an exophytic pilocytic astrocytoma in which the tumor’s atypical histologic and radiographic appearance increased the likelihood of diagnostic errors. This case illustrates the clinical importance of utilizing methylation array profiling and next-generation sequencing to confirm a diagnosis.

Objectives: PNOC001 sought to estimate progression-free survival (PFS) associated with everolimus for progressive/recurrent pediatric low-grade glioma (pLGG) and to determine if activated PI3K/AKT/mTOR pathway as measured by positive phosphorylated-ribosomal protein S6 (p-RPS6) was associated with response... Rare/novel KIAA1549-BRAF fusion breakpoints are more frequent in supratentorial midline pLGGs and define independent genomic risk factors for disease progression/recurrence. Our results indicate that future clinical trials must interrogate and define KIAA1549-BRAF fusion breakpoints for informative results and conclusions.

Tovorafenib demonstrated antitumor activity in recurrent/progressive BRAF-altered OPG and was generally well tolerated. Visual acuity remained stable for the majority with OPGs.

P2, N=26, Active, not recruiting, University Health Network, Toronto | Trial completion date: Dec 2023 --> Mar 2024 | Trial primary completion date: Dec 2023 --> Mar 2024 | Recruiting --> Active, not recruiting

F1R assay successfully detected oncogenic fusions with high concordance to orthogonal NGS-based tests. This study demonstrated the robustness of F1R and supports its use as a supplement to tissue DNA CGP in routine clinical practice. Additional work is required to clarify optimal clinical scenarios for fusion detection and enable GEP biomarkers for clinical use.

No abstract available

P1/2, N=105, Active, not recruiting, Children's Hospital Los Angeles | Phase classification: P2 --> P1/2

MEKi, selumetinib and trametinib, represent promising strategies in children with recurrent/progressive LGGs harboring MAPK alterations. In our small series, the treatment was effective and well tolerable in patients with localized disease and without other risk factors. The most common toxicities were CPK elevation and rash.

In recent years, the mutational landscape of thyroid tumors has been extensively described, and two molecular profiles have been identified: RAS-like (NRAS, HRAS, and KRAS mutations; EIF1AX mutations; BRAF K601E mutation; and PPARG and THADA fusions) and BRAF-like (including BRAF mutation and RET and BRAF fusions). The purpose of this review is to discuss the latest molecular findings in the context of indeterminate thyroid nodules, highlighting the role of molecular tests in patients' management.

Rare patients with BRAF fusions or rearrangements had decreased progression-free and overall survival following initial immunotherapy. Other BRAF, NRAS or NF1 mutations were not associated with significant differences in outcome.