BRAF fusion

Although BRAF fusions are commonly observed in Spitz melanocytic neoplasms, the discovery of the RNF11::BRAF fusion in melanomas is unprecedented. Our case represents a triple wild-type, clinically aggressive melanoma of possibly non-Spitz lineage with an ultraviolet signature and a rare BRAF fusion, contributing to the expanding body of literature on BRAF-fused melanomas.

Congenital melanocytic nevi with BRAF fusion genes appear to have unique clinical features and may be associated with numerous satellite lesions. Marked desmoplasia is a histopathologic feature that can point towards an underlying BRAF fusion gene.

The BRAF fusion supports the diagnosis of Spitz melanoma, a genetically defined subset of Spitzoid melanoma. This case represents the first report of a TMEM106B::BRAF fusion in melanoma, emphasizing the critical role of molecular profiling in diagnosing and managing this malignancy, and suggesting a potential avenue for future therapeutic exploration.

P1/2, N=23, Terminated, SpringWorks Therapeutics, Inc. | Trial completion date: Jun 2027 --> Jan 2025 | Active, not recruiting --> Terminated | Trial primary completion date: Oct 2026 --> Jan 2025; Lack of tolerability of Brimarafenib when given in combination of Mirdametinib

Our radiogenomics study indicates that the intrinsic molecular characteristics of tumors correlate with distinct imaging subgroups in pLGG, paving the way for future multi-modal investigations that may enhance understanding of disease progression and targetability.

To the best of our knowledge, the EVI5::BRAF fusion has not yet been described in BRAF fusions in IFS. Nevertheless, further studies are needed to define the prognostic features of these emerging BRAF sarcomas, along with new anti-BRAF therapeutic approaches.

P1, N=110, Active, not recruiting, MapKure, LLC | Recruiting --> Active, not recruiting | Trial completion date: Jun 2025 --> Nov 2025 | Trial primary completion date: Jun 2025 --> Nov 2025

AI models may perform relatively well in predicting BRAF alterations in LGG using imaging data and appear to be capable of high sensitivities and specificities. However, future studies with larger sample sizes implementing different ML or DL algorithms are required to reduce imprecision.

P1/2, N=57, Active, not recruiting, Pediatric Brain Tumor Consortium | Recruiting --> Active, not recruiting

P2, N=26, Active, not recruiting, University Health Network, Toronto | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

She was then treated with a combination of selpercatinib and trametinib, which led to a likely partial response, despite the combination demonstrating side effects. This case report details the first known instance of NSCLC with a RET fusion developing resistance by means of a BRAF fusion, treated with combined RET and MEK inhibition.

P1/2, N=75, Recruiting, Pediatric Brain Tumor Consortium | Trial completion date: Jun 2029 --> Jun 2030 | Trial primary completion date: Aug 2026 --> Mar 2027

Next-generation sequencing has demonstrated significant value in identifying genetic fusions in pediatric PACC. In our case report, we identified both the classical SND1-BRAF fusion, commonly associated with PACC, and a previously unreported nonclassical BRAF-KMT2C fusion. These findings underscore the critical role of BRAF alterations as key drivers of oncogenesis in PACC. A multidisciplinary treatment strategy integrating surgery, chemotherapy, and radiation therapy offers a promising precedent for improving therapeutic outcomes and prolonging survival in pediatric PACC cases.

Genetic ancestry-associated differences exist across pediatric CNS tumor histological and molecular subtypes from PBTA and PNOC. Further investigation into genetic and socioeconomic factors contributing to these observed inequities is needed.

Positive margin status was associated with increased recurrence and reduced disease-free survival (DFS, p = 0.02). Moreover, it emphasizes the impact of multiplatform molecular testing in confirming the diagnosis. The lack of both local recurrence and metastatic potential outside VGLL3 amplifications requires further investigation.

The required post-marketing clinical trial (FIREFLY-2) was well underway at the time of accelerated approval. This represents the first FDA approval of a systemic therapy for the treatment of patients with pLGG with BRAF fusions or rearrangements.

A review of previously reported cases confirmed as Spitz melanoma with distant metastases (n = 7) revealed a broad age range (11-71 years, median 46 years), high mortality (5/7), frequent BRAF fusions (6/7), and recurrent TERT promotor mutations and CDKN2A/B deletions. This report adds valuable insights into our understanding of the clinical and genetic characteristics of Spitz melanoma with distant metastases.

During a limited 1.5-year follow-up period, neither a confirmed local recurrence nor a distant organ metastasis occurred in this case. We propose that BRAF fusion variations can occur in metastatic EOCC.

Gliomas are tumors arising in the central nervous system, frequently associated with Class I mutations and BRAF fusions. Further research into resistance mechanisms and long-term effects is necessary to optimize treatment strategies. Other therapies, such as everolimus and Selumetinib, also show potential and warrant further investigation.

Since BRAF activation occurs in BRAF fusion gene tumors and BRAF mutations, they could share a similar mechanism in tumorigenesis. This case suggests the further expansion of kinase-related spindle cell tumors.

Despite diverse therapeutic interventions targeting mitogen-activated protein kinase signaling and subsequent clinical trial enrollment, disease progression remained relentless, culminating in the patient's demise within 4 years of diagnosis. This report highlights the exceptional histopathological presentation associated with KIAA1549::BRAF fusion in prostatic adenocarcinoma, emphasizing the need for a deeper comprehension of its implications on disease behavior and therapeutic responsiveness in similar instances.

The detection of BRAF fusions and their many partners was enabled by the Afirma XA exome-enriched RNASeq panel. Although BRAF fusions occurred in only 0.2% of thyroid nodules, they were GSC-Suspicious and lacked typical BRAF/RAS mutations. Interestingly, expression signatures associated with malignancy varied by fusion partner.

OS+ is a reliable test to identify clinically relevant genomic alterations, cnLOH, and several hotspot mutations in pediatric FFPE solid tumor specimens. WGS/WES significantly increases the yield of actionable somatic mutations and cancer-predisposing germline variants. The cost, turnaround time, and tumor percentage in the specimen make OS+ followed by WES principal tests for pediatric solid tumor analysis at our institution.

P1/2, N=23, Active, not recruiting, SpringWorks Therapeutics, Inc. | Recruiting --> Active, not recruiting | N=136 --> 23

Two patients with BRAFv600E-mutated/CDKN2A deleted PXA-2, had progression following resection, and experienced stable/partial response at 9 months of dabrafenib use...Two patients who stopped trametinib due to side effects (significant acneiform rash/paronychia and intracranial bleeding) did not experience progression. Our experience with BRAF/MEK inhibitors' use was positive achieving response in all LGGs and provided sustained response with good quality of life for patients with HGG. Cost effectiveness analyses and patients' satisfaction comparisons with chemotherapy are needed to evaluate the routine use of these drugs in LMICs.

BRAF alterations, specifically BRAF mutations and BRAF fusions, facilitate resistance to EGFR-TKIs. Triple-targeted therapy is effective and safe for patients with EGFR-mutant NSCLC with acquired BRAF alterations, mainly among patients with BRAF class I mutations and potentially in patients with BRAF fusions.

Although most cases occur in adults, rare examples of LCS have been reported in children with variable clinical outcome. We present 2 childhood cases of Langerhans cell neoplasm with high grade sarcomatous features and OSBPL9::BRAF fusion and BRAF V600E mutation.

P1, N=114, Recruiting, MapKure, LLC | Trial primary completion date: Aug 2024 --> Jun 2025

Historical treatment options in pediatric low-grade gliomas have utilized surgery, radiation therapy and conventional chemotherapy. Recently greater insight into their biology has found that alterations in MAPK driven pathways are often the hallmark of tumorigenesis. Targeting these novel pathways has led to tumor control and shrinkage without the use of conventional chemotherapy. Caution should be taken however, since these treatment options are still novel, and we do not fully appreciate the long-term effects. Nonetheless a new era of targeted medicine is here.

Upon enrollment, the patient received two rounds of the radiolabeled somatostatin analogue lutetium-177 octreotate (177Lu-DOTATATE), which was well tolerated...The observed variation in SSTR2 expression between tumor lesions suggests that heterogeneous target expression may have been the reason for treatment failure in this patient's case. Further investigation within the LuDO-N trial will give a more comprehensive understanding of the correlation between SSTR2 expression levels and treatment outcomes, which will be important to advance treatment strategies based on MRT for children with high-risk NB.

P1/2, N=168, Active, not recruiting, Day One Biopharmaceuticals, Inc. | Recruiting --> Active, not recruiting

Conclusions The Archer® FUSIONPlex® custom panel detected fusion genes in 10% of driver gene-negative melanomas. Combining DNA- and RNA-based multiplex sequencing is useful to identify potentially targetable gene alterations.

There are significant differences in clinical manifestations, pathological characteristics, molecular variations, and prognosis between the pDLGG, CAG and pDHGG groups. The integrated diagnosis combining histology and molecular features is of great importance for the accurate diagnosis and treatment of pediatric gliomas.

Importantly, co-occurrence of rare fusions and EGFR classical activating mutations in patients pre-treated with anti-EGFR therapy suggests a potential resistance mechanism and consideration of upfront, dual mutation, targeted treatment to improve outcomes. Further clinical studies are needed to validate the best treatment options for these patients with rare fusions.

According to multivariate analysis, risk organ involvement was the strongest independent adverse prognostic factor (hazard ratio, 8.854; P < .001); BRAF or MAP2K1 mutation was not an independent prognostic factor. Most pediatric patients with LCH carry somatic mutations involving the MAPK pathway, correlating with clinical characteristics and outcomes for first-line chemotherapy.

KIAA1549::BRAF fusions are prevalent in PAs and can be reliably detected using both FISH and qRT-PCR assays. Cost considerations suggest qRT-PCR as a more economical option for fusion detection in routine clinical practice.

This study represents the largest molecularly defined cohort of non-oncocytic thyroid carcinomas with columnar cell morphology. These tumors represent a genetically and behaviorally heterogeneous group of neoplasms, some of which have RAS-like or follicular neoplasm-like genetics, some of which have BRAF-p.V600E-like or classic papillary thyroid carcinoma-like genetics, and some of which remain unclear. Noninvasive or minimally invasive tumors showed an indolent course compared to those with angioinvasion, gross extrathyroidal growth, or high-grade morphology. Consideration could be given to reclassification of this neoplasm outside of the subtyping of papillary thyroid carcinoma in light of its genetic diversity, distinct morphology, and clinical behavior more closely aligned with follicular thyroid neoplasms.

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

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