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. Author manuscript; available in PMC: 2025 Mar 3.
Published in final edited form as: Clin Cancer Res. 2024 Sep 3;30(17):3812–3823. doi: 10.1158/1078-0432.CCR-23-3981

Tumor-agnostic genomic and clinical analysis of BRAF fusions identify actionable targets

Monica F Chen 1,2,*, Soo-Ryum Yang 3,*, Jessica J Tao 4, Antoine Desilets 1, Eli L Diamond 5, Clare Wilhelm 1, Ezra Rosen 1,2, Yixiao Gong 6, Kerry Mullaney 6, Jean Torrisi 7, Robert J Young 7, Romel Somwar 3, Helena A Yu 1,2, Mark G Kris 1,2, Gregory J Riely 1,2, Maria E Arcila 3, Marc Ladanyi 3, Mark TA Donoghue 6, Neal Rosen 8, Rona Yaeger 1,2, Alexander Drilon 1,2, Yonina R Murciano-Goroff 1,2,*, Michael Offin 1,2,*
PMCID: PMC11371517  NIHMSID: NIHMS2006693  PMID: 38922339

Abstract

Background:

Even though BRAF fusions are increasingly detected in standard multigene next-generation sequencing panels, few reports have explored their structure and impact on clinical course.

Patients and methods:

We collected data from patients with BRAF fusion-positive cancers identified through a genotyping protocol of 97,024 samples. Fusions were characterized and reviewed for oncogenic potential (in-frame status, non-BRAF partner gene, intact BRAF kinase domain).

Results:

We found 241 BRAF fusion-positive tumors from 212 patients with 82 unique 5’ fusion partners spanning 52 histologies. 39 fusion partners were not previously reported, and 61 were identified once. BRAF fusion incidence was enriched in pilocytic astrocytomas, gangliomas, low-grade neuroepithelial tumors, and acinar cell carcinoma of the pancreas. 24 patients spanning multiple histologies were treated with MAPK-directed therapies of which 20 were evaluable for RECIST. Best response was partial response (N=2), stable disease (N=11), and progressive disease (N=7). The median time on therapy was 1 month with MEK plus BRAF inhibitors ([N=11], range 0-18 months) and 8 months for MEK inhibitors ([N=14], range 1-26 months). 9 patients remained on treatment for longer than 6 months [pilocytic astrocytomas (N=6), Erdheim-Chester disease (N=1), extraventricular neurocytoma (N=1), melanoma (N=1)]. Fifteen patients had acquired BRAF fusions.

Conclusions:

BRAF fusions are found across histologies and represent an emerging actionable target. BRAF fusions have a diverse set of fusion partners. Durable responses to MAPK therapies were seen, particularly in pilocytic astrocytomas. Acquired BRAF fusions were identified after targeted therapy underscoring the importance of post-progression biopsies to optimize treatment at relapse in these patients.

Keywords: BRAF fusion, pilocytic astrocytoma, MAPK targeted therapy, acquired resistance, EGFR targeted therapy

Introduction

The BRAF gene located on chromosome 7q34 encodes a serine/threonine protein kinase that plays a key role in the mitogen-activated protein kinase (MAPK) signaling pathway(1). Approximately 4-15% of cancers harbor activating BRAF alterations, with enrichment in melanoma, colorectal, thyroid, and lung cancers(1).

There are three categories of BRAF alterations. Class I BRAF V600 mutations are the most common, are RAS-independent, and signal as kinase monomers with high kinase activity(2). Class II alterations work as dimers, are RAS-independent, and have intermediate to high kinase activity(2). Class III alterations work in a RAS-dependent, heterodimer-dependent fashion and have low BRAF kinase activity(1,3,4). In a >100,000 tumor analysis, the prevalence for BRAF alterations were: class I (2% of cancers, 62% of BRAF alterations), class II (1% of cancers, 17% of BRAF alterations), and class III (1% of cancers, 18% of BRAF alterations)(1).

Research developing BRAF-targeted therapies has led to multiple approvals of BRAF inhibitors used alone or in combination with a MEK or EGFR inhibitor(5-11). These drugs are effective in patients with class I mutations but benefits are not durable(9). Moreover, there are no BRAF-targeted options at resistance. Agents for Class II and III mutations represent an unmet need. BRAF fusions are class II alterations identified in 0.3% of cancers in the largest pan-cancer analysis to date (N=55)(12). In addition, there is growing evidence that BRAF fusions represent an acquired and potentially actionable mechanism of resistance to targeted therapies in multiple histologies including lung and colorectal cancer(13-16). Unlike BRAF V600 mutations, BRAF fusions activate the MAPK pathway by removing the auto-inhibitory N-terminal region which leads to constitutive dimerization of the BRAF protein which may lead to less reliance on the fusion partner(17). There is limited data on response to MAPK targeted therapies in patients with BRAF fusions, but these agents are in early clinical studies.(18-20) In preclinical models, BRAF fusions are insensitive to RAF inhibitors (i.e. vemurafenib) but sensitive to newer RAF inhibitors, BGB659 and PLX8394(21,22).

Here, we performed a clinical and genomic analysis of all BRAF fusions detected at Memorial Sloan Kettering Cancer Center (MSK) in a prospective genomic sequencing effort.

Materials and Methods

Patients

The study was approved by the MSK institutional review board and carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki). Utilizing a previously described center-wide next-generation sequencing (NGS) genotyping protocol (clinicaltrials.gov, NCT01775072) program of 97,024 sequenced samples between January 2014 and November 2022 (data lock) across a variety of malignancies, we collected data from adult and pediatric patients with BRAF fusion-positive cancers(23). All patients provided written informed consent. All cases underwent clinical data curation, including baseline demographic, tumor characteristics, and treatment histories. Patients treated with MAPK-pathway directed therapies were retrospectively evaluated using RECIST v1.1 (R.Y. and J.T.) and patients were retrospectively assessed for adverse events during treatment using CTCAE version 5.0 by a dedicated investigator (M.F.C.) (24).

Genomic Analyses

DNA-based hybrid capture tumor NGS (MSK-IMPACT)(23), circulating tumor DNA (ctDNA) targeted NGS (MSK-ACCESS)(25), and/or RNA anchored multiplex PCR tumor NGS (MSK-Fusion) were used (26) (27). Specifically, MSK-IMPACT targets all exons in BRAF and introns 7-10, while MSK-ACCESS targets BRAF exons 11-18 and introns 7-10. MSK-Fusion targets all exons in BRAF except for exons 6, 14, and 17. In brief, MSK-Fusion employs two sets of primers (gene specific and universal) that allow for the detection of fusion transcripts by targeting only one of the gene partners (e.g., BRAF), thus precluding the need for targeting the other fusion partner gene. This unique primer design enables partner-agnostic fusion detection and discovery of novel fusions involving the targeted gene (e.g, BRAF). In patients with multiple samples, the earliest sequenced sample with a BRAF fusion was included.

Fusions were manually reviewed by a diagnostic molecular pathologist (S.Y.) and considered potentially oncogenic if they predicted an in-frame protein fusion involving a non-BRAF partner gene and an intact BRAF kinase domain (exons 11-18; NM_004333). Fusions not previously reported in OncoKB (RRID:SCR_014782), COSMIC (RRID:SCR_002260), TCGA (RRID:SCR_003193), NIH gene (RRID:SCR_002473), Fusion GDB2, and PubMed (RRID:SCR_004846) were classified as novel(28-30). Fusions detected after treatment with targeted therapy with prior NGS sequencing where there was not a BRAF fusion identified were classified as acquired.

Tumor mutational burden (TMB) was defined as the total number of non-synonymous exonic mutations divided by the coding region analyzed. Microsatellite instability (MSI) was assessed via MSIsensor (RRID:SCR_006418)(31), a computational program that reports the percentage of unstable loci. Scores ≥10 were defined as high (MSI-H), 3-10 as indeterminate (MSI-I), and <3 as stable (MSS).

Statistical Analyses

Oncoprints were created using cBioPortal (https://www.cbioportal.org/, RRID:SCR_014555) as previously described for alterations with >5% frequency and alterations in the MAPK pathway (EGFR, KRAS, HRAS, NRAS, RAF1, and MAPK1)(32,33). Analyses were performed using the R programming language and environment (https://www.r-project.org, version 7.2.2022, RRID:SCR_001905, Vienna, Austria).

Data Availability Statement

We analyzed existing data from cBioPortal that are publicly available (https://www.cbioportal.org/study/summary?id=braf_msk_archer_2024 and https://www.cbioportal.org/study/summary?id=braf_msk_impact_2024). Additional data are available upon request from the corresponding author.

RESULTS

From January 2014 to November 2022, 97,024 samples from 69,337 different patients underwent NGS testing, with 212 harboring an oncogenic BRAF fusion (Supplemental Figure 1). Of these, 195 were de novo BRAF fusions and 17 were detected after targeted treatment. Of the 17 patients, fifteen had confirmed acquired BRAF fusions. Two patients did not have NGS testing prior to detection of the BRAF fusion.

De novo BRAF Fusions

Patient characteristics

Baseline demographics for all patients with de novo BRAF fusions are shown in Supplemental Table 1. The median age across all histologies was 53 years old (range: 1-89 years) and 53% were male. The prevalence of de novo BRAF fusions was <1% (195/69,337). BRAF fusions were noted in 52 different adult and pediatric tumor types with the rates differing by cancer type (Figure 1). The tumor type most enriched for BRAF fusions was pilocytic astrocytoma (N=29, prevalence 56%). BRAF fusions were found in ≥5% of patients with gangliogliomas, low- and high-grade neuroepithelial tumors, pleomorphic xanthoastrocytomas, fibrosarcomas, pancreatic neuroendocrine carcinomas, and acinar cell carcinoma of the pancreas. Of note, there were less than 20 patients with gangliomas, low- and high-grade neuroepithelial tumors, pleomorphic xanthoastrocytoma, pancreatic neuroendocrine carcinoma, and fibrosarcoma. The frequency of BRAF fusions in the remainder of histologies was ≤5%.

Figure 1.

Figure 1.

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Prevalence of de novo BRAF fusions by histology. Histologies with ≥5 BRAF fusions and/or histologies with >5% prevalence and at least 5 cases in the institutional cohort were included. (Created with BioRender.com)

Genomic analysis of de novo BRAF fusions

De novo BRAF fusions were detected by DNA-based tumor NGS (N=180), RNA-based tumor NGS (N=12), and ctDNA NGS (N=3). Among the de novo BRAF fusions, 75 unique 5’ fusion partners were identified of which 36 were novel (Figure 2A-B). The exon composition of the novel BRAF fusions is shown in Figure 2B and Supplemental Figure 2. A high proportion of 5’ partners were only identified once (‘non-recurrent’, N=54, 28%) (Figure 3A, orange box on x-axis). The most common upstream fusion partners were KIAA1549 (N=48, 25%), SND1 (N=20, 10%), AGK (N=12, 6%), MKRN1 (N=9, 5%), and TRIM24 (N=9, 5%) (Figure 3A). A full list of 5’ fusion partners can be found in Supplemental Table 2 and the structures of the most common isoforms in Supplemental Figure 3.

Figure 2.

Figure 2.

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BRAF fusion partners. A. Circos plot: inner track BRAF and fusion partner genes, outer track: chromosomes. B. Structures of novel BRAF fusions that had confirmatory RNA-sequencing and transcript IDs.

Figure 3.

Figure 3.

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Fusion partners by histology. A. 5’ gene fusion partners for de novo BRAF fusions. B. sunburst plot of 5’ gene fusion partners for de novo BRAF fusions. Histologies with at least 5 cases in the institutional cohort were included. Inner circle histology, outer circle 5’ gene fusion partner. CA: cancer; CRC: colorectal cancer; GBM: glioblastoma; NSCLC: non-small cell lung cancer.

Figure 3B shows the 5’ fusion partners stratified by histology for the tumor types with at least five patients. Almost all cases of pilocytic astrocytoma had BRAF-KIAA1549 (90%, N=26/29)(34). The most common 5’ fusion partners were SND1 (21%, N=6), TMPRSS2 (14%, N=4), and SLC45A3 (11%, N=3) in prostate adenocarcinoma, AGK (15%, N=4) and CDK5RAP2 (12%, N=3) in melanoma, TRIM24 (43%, N=6) and AGAP3 (21%, N=3) in colorectal cancer, and SND1 (56%, N=5) and TRIM24 (22%, N= 2) in pancreatic adenocarcinoma (Figure 3B).

Across all histologies, BRAF fusions were most commonly co-altered with TP53 mutations (22%), TERT mutations (18%), CDKN2A deletions (14%), and CDKN2B deletions (12%) (Supplemental Figure 4). Patients with pilocytic astrocytoma rarely had concurrent alterations (Supplemental Figure 5A), and no concurrent alterations occurred with >5% frequency in the pilocytic astrocytoma cohort. TERT mutations were frequently seen in melanomas (64%), thyroid cancers (73%), and gliomas (11%) (Supplemental Figure 5A-C). Colorectal cancers often had co-occurring mutations, those with >30% frequency included RNF43 (64%), TP53 (57%), KMT2D (43%), MSH3 (42%), ARID1A (36%), and INPPL1 (33%) (Supplemental Figure 5D). BRAF fusions were mutually exclusive with other MAPK pathway alterations in all histologies (Supplemental Figure 5E).

Treatment with MAPK Pathway Directed Therapies

Twenty-four patients with de novo BRAF fusions were treated with MAPK-pathway directed therapies spanning multiple histologies, lines of therapy, and treatment combinations. Their baseline characteristics are shown in Supplemental Table 3. The most frequent histology was pilocytic astrocytoma (21%, N=5). Multiple treatment approaches were used: 58% with a MEK inhibitor alone, 46% with a combination of a BRAF and MEK inhibitor, and 4% with an ERK inhibitor. The median prior lines of therapy were 2 (range 0-6).

There was a wide range of responses in this heterogeneous group (Figure 4A), with best response as partial response (PR, N=2), stable disease (SD, N=11), and progressive disease (PD, N=7) (Figure 4B). Best response by RECIST could not be evaluated in four patients. One patient did not have evaluable disease, 2 patients had clinical PD before first scan, and 1 patient stopped treatment due to toxicity before first scan. The median time on combination MEK and BRAF inhibitors (N=11) therapies was 1 month (range 0-18 months) and for MEK inhibitors (N=9) was 8 months (range 1-26 months). A patient with colon cancer treated with an ERK inhibitor was on treatment for 1 month.

Figure 4.

Figure 4.

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MAPK-pathway directed treatments. A. Swimmer’s plot of patients with de novo BRAF fusions treated with MAPK-pathway directed therapies. Dotted line is at 6 months from start of MAPK-pathway directed treatment. B. Waterfall plot of best change from baseline for 20 patients with follow-up target lesion measurements by RECIST v1.1.

Confirmed RECIST PRs were observed in 2 patients. A patient with Erdheim-Chester disease treated with cobimetinib achieved a 67% tumor reduction as best response with decreases in pulmonary nodules, pancreatic mass, and gastric masses. Despite 2 dose reductions due to rash and edema, the patient with Erdheim-Chester disease has remained on treatment for 22+ months. The second confirmed response was in a patient with high-grade neuroepithelial tumor treated with selumetinib who achieved a 52% tumor reduction of a primary temporal lobe lesion compared to baseline but progressed after 10 months on treatment.

Nine patients remained on treatment for >6 months, including all the patients with pilocytic astrocytomas (6/6). All patients with pilocytic astrocytomas were treated with a MEK inhibitor, 4 with selumetinib and 2 with trametinib. The median time on treatment was 11 months (range 6-26 months). Median follow-up time was 38 months (range 6-81 months). Four of the 6 patients with pilocytic astrocytoma had disease shrinkage with a MEK inhibitor.

Treatment-related adverse events of any grade occurred in 71% of patients receiving MAPK-pathway directed therapies, with 8 patients requiring dose holds, 4 patients requiring dose reductions, and 4 patients discontinuing treatment due to toxicity. The most common side-effect was rash (29%, N=7).

Acquired BRAF fusions

Fifteen patients acquired BRAF fusions following targeted therapy [EGFR-mutant lung adenocarcinoma (N=10), BRAF V600E-mutant lung adenocarcinoma (N=1), colorectal cancer (N=1), BRAF V600E-mutant papillary thyroid cancer (N=1), FGFR3 fusion-positive bladder cancer (N=1), NTRK1 fusion-positive lung adenocarcinoma (N=1)] (Figure 5A). The median age was 57 years (range 37-79 years), and most patients were female and never smokers (Supplemental Table 4). Of the patients with EGFR-mutant lung cancer, 8 had EGFR exon 19 deletions, 1 had an EGFR exon 21 L858R mutation, and 1 had an EGFR exon 18 G719C and EGFR exon 21 L861Q mutation. The oncoprint in Supplemental Figure 6 shows co-alterations with >5% frequency; TP53 was the most common.

Figure 5.

Figure 5.

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Acquired BRAF fusions. A. Prevalence of acquired BRAF fusions by histology. B. Sunburst plot of 5’ gene fusion partners for acquired BRAF fusions. Inner circle histology, outer circle 5’ gene fusion partner. C. Treatment, histology, and time before detection of BRAF fusion (adjusted to time 0 for all patients). Center: Histology. Dark blue (time on targeted treatment), grey (time on non-targeted treatment). (A, Created with BioRender.com)

The most common 5’ fusion partner, AGK (N=3), was present in 25% of lung adenocarcinoma cases, of which 67% (N=2) were EGFR-mutant lung adenocarcinoma (Figure 5B). Both cases with TRIM24-BRAF fusions had EGFR-mutant lung adenocarcinoma. The remainder were non-recurrent 5’ fusion partners.

For patients with EGFR-mutant lung adenocarcinoma, the median time from start of targeted therapy to BRAF fusion detection was 23 months (range 9-37 months) (Figure 5C). Prior EGFR TKIs included osimertinib (N=9), afatinib (N=2), and erlotinib (N=3). Two patients were treated with multiple EGFR TKIs. Two patients were treated with trametinib in combination with an EGFR TKI at resistance. One patient remained on trametinib and erlotinib for 12 months with grade 1 rash as the only side-effect. Of note, this patient also harbored a de novo BRAF V600E mutation. Disease progression was noted after 2 months in a second patient on trametinib and erlotinib after 2 months. Neither patient experienced grade 3 nor higher toxicities.

Discussion

BRAF fusions constitute a potential actionable target. This series represents the largest and most molecularly diverse series of BRAF fusion-positive cancers reported. We found that BRAF fusions occurred in 0.3% of studied patients spanning 52 different histologies in de novo and acquired settings. BRAF fusions were enriched in pilocytic astrocytomas, gangliomas, low-grade neuroepithelial tumors, and acinar cell carcinoma of the pancreas.

Importantly, we show that BRAF fusions have an extraordinarily diverse set of fusion partners across cancer types. Patient-derived xenograft models show that BRAF fusion partners influence function, treatment response, and growth rates(35),(36). Therefore, the diversity of BRAF fusion partners provides challenges to developing targeted therapies.

Here we identify 82 different 5’ fusion partners, of which almost half (N=39, 48%) have not previously been reported. The most common 5’ fusion partners for both de novo and acquired BRAF fusions were KIAA1549 (23%), SND1 (9%), AGK (8%), and TRIM24 (5%); however, 29% were non-recurrent. This contrasts with other oncogenic fusions where one partner predominates and fuses with a receptor tyrosine kinase (e.g., EML4 for ALK, CD74 for ROS1, and CD74 for NRG1)(3,37,38). This might occur because unlike many other fusions, BRAF fusions do not require a coiled-coil domain within the 5’ gene partner to dimerize and initiate downstream phosphorylation(35). The genetic diversity of BRAF fusions highlights the need for partner-agnostic diagnostic strategies. The importance of partner-agnostic diagnostic strategies to identify all patients that may benefit from treatment has been previously shown in other fusions (i.e. NTRK, RET).(39,40) For instance, while ETV6-NTRK3 is the most common NTRK3 fusion in infantile fibrosarcoma, 20% of tumors were found to have non-ETV6-NTRK3 fusions in the clinical trials investigating larotrectinib.(39)

Despite remarkable diversity, BRAF fusion partners were enriched in some histologies. For instance, 90% of pilocytic astrocytomas with BRAF fusions were rearranged with KIAA1549 and 56% of pancreatic adenocarcinomas with BRAF fusions were rearranged with SND1. Histology differences are also seen with ALK fusions. EML4-ALK fusions account for 84% of ALK fusion variants in lung cancer but 30% of non-lung cancer tumors(37,41). Studies should consider the partner diversity of BRAF fusions and their role in histology and response to treatment. The large number of fusion partners highlights an additional diagnostic challenge which may limit recognition of activating fusions. Due to the frequent complexity of BRAF fusions, expert guidance is crucial in designing fusion partner-agnostic assays and interpreting results.

In this study, a variety of molecular diagnostic assays were used for BRAF fusion detection, including tissue-based DNA/RNA NGS and plasma-based ctDNA NGS assays. Given that the focus of this study was to explore the clinical landscape of oncogenic BRAF fusions, we did not interrogate the technical performance of each diagnostic assay. However, based on prior studies of other kinase fusions, it is reasonable to infer that tissue-based RNA sequencing likely represents the most sensitive and specific approach for BRAF fusion detection.(38) Since BRAF rearrangements at the genomic level generally occur within introns, it can be challenging for DNA-based NGS to capture these events unless the introns are sufficiently covered (i.e., limited sensitivity). Moreover, it is possible for DNA-based NGS to detect non-canonical BRAF rearrangements that may or may not lead to an oncogenic BRAF fusions (i.e., limited specificity). In both instances, RNA-based NGS may be used to provide a more sensitive and specific analysis by directly capturing oncogenic fusion transcripts at the mRNA level and bypassing technical issues related to DNA-based NGS. While ctDNA-based methods may allow for non-invasive detection of BRAF fusions, the limitations of DNA-based NGS are also relevant for ctDNA-based NGS assays given the shared usage of DNA. In addition, the performance of ctDNA-based NGS may be further limited by other issues inherent to liquid biopsies such as suboptimal sensitivity due to variable levels of circulating tumor DNA load.(42,43) Hence, the integration of multiple orthogonal and complementary NGS assays in tissue and liquid may be important for optimizing the detection of oncogenic BRAF fusions in the clinic.

There are limited data on clinical response of BRAF fusion-positive tumors to MAPK-pathway targeted therapies. Reports suggest that BRAF fusions may not be sensitive to first-generation BRAF inhibitors and can even cause paradoxical activation of the MAPK pathway(3,4). Trials of pan-RAF inhibitors have failed to show benefit in patients with class II and III alterations (e.g., NCT02296112)(44). A handful of trials looking at MAPK-pathway targeted therapies have enrolled patients with BRAF fusions as part of a non-V600E subgroup. The national trametinib platform trial NCI-MATCH enrolled 32 patients with BRAF non-V600 mutations or fusions(45); a single individual with a BRAF fusion did not respond.(45) Combined RAF and MEK inhibition to treat non-V600 BRAF altered cancers has also not been successful. Rustgi et al treated 8 patients with BRAF fusions with binimetinib plus encorafenib(46). On-treatment biopsies showed incomplete ERK pathway inhibition and no patients with BRAF fusions had tumor regression(46). In contrast, the Pediatric Brain Tumor Consortium conducted a phase II trial of selumetinib in patients with refractory/recurrent low-grade gliomas(18). Of the 18 patients with BRAF fusions, seven (39%) had a PR(18). While available therapies may be useful for some patients with BRAF fusions, discovery of more effective therapies remains a priority.

Here, we report outcomes on 24 patients with de novo BRAF fusions who were treated with MAPK-targeted therapies. We demonstrate that while there was variability of response, all patients with pilocytic astrocytoma remained on therapy for at least 6 months, and 6 patients with de novo BRAF fusions remained on therapy for 12 months: 3 patients with pilocytic astrocytoma treated with a MEK inhibitor, 1 with extraventricular neurocytoma treated with dabrafenib and trametinib, 1 with melanoma treated with encorafenib and binimetinib, and 1 with Erdheim-Chester disease treated with cobimetinib. While some patients had dramatic responses, the response rate in this retrospective cohort is low compared to targeted therapies in other fusion-positive cancers (i.e. ALK, ROS1, RET) where overall response rates are 60-80%(47-49). In addition, responses appear to be histology dependent, similar to dabrafenib and trametinib in BRAF V600E cancers(9).

Lastly, BRAF fusions are increasingly recognized as a recurrent (2-4%) mechanism of acquired resistance to targeted therapies against the MAPK pathway, particularly EGFR TKIs(13,14). To circumvent drug resistance, preclinical models suggest adding a second agent targeting the acquired alteration can be effective(19,50). Data demonstrating the efficacy of EGFR with BRAF and/or MEK inhibition is limited to a handful of case reports and subgroup analyses of prospective studies, and the optimal strategy is yet to be determined(19,20,50). Luo et al reported trial results of erlotinib and trametinib in patients with EGFR-mutant lung adenocarcinoma with acquired resistance to a prior EGFR TKI(19). Two of the 23 patients had tumor shrinkage, both of which had a BRAF fusion(19). The biomarker-matched ORCHARD (NCT03944772) trial includes a cohort with BRAF alterations who receive osimertinib and selumetinib(51). We identified 15 patients (10 with EGFR-mutant lung adenocarcinoma) with acquired BRAF fusions after treatment with targeted therapies. Two of the patients were treated with an EGFR TKI and MEK inhibitor at resistance. Of note, the patient with the longest time on treatment also harbored a BRAF V600E mutation. We also show that BRAF fusions emerged as an acquired mechanism of resistance in non-lung cancer histologies following therapies targeting other oncogenic drivers. These observations add to a growing literature that recognizes BRAF fusions as a recurrent mechanism of acquired resistance to TKIs and stresses the importance of routine genotyping post progression(52).

Our study is limited by its retrospective single institution design, heterogenous population analyzed at various time points during their cancer care, and the small number of patients receiving each line of therapy and treatment type. Despite these limitations, this study remains among the largest cohorts of patients with BRAF fusions reported, provides important genomic data, and is one of the few to report outcomes of targeted therapy.

In summary, here we describe clinical outcomes as well as pathologic and genomic characteristics of patients with tumors harboring BRAF fusions. Increased adoption of routine NGS testing is expected to identify more patients with BRAF fusions. The large number of BRAF fusion partners contrasts with other oncogenic fusions, highlighting the importance of expert molecular pathology guidance in identifying and functionally characterizing oncogenic fusions. We found that BRAF fusions are a mechanism of acquired resistance not just to EGFR TKIs in lung cancer but also after other targeted therapies outside of lung cancer. This observation affirms the importance of sequencing tumor samples following progression to uncover precise targets for therapy. Our most recent experience in treating patients whose tumors developed acquired resistance following osimertinib shows that if a target is found and a matched targeted therapy is given, outcomes are improved(53). Our data documents responses in central nervous system tumors, Erdheim-Chester disease, and melanoma, making assessment for these alterations critical in these patients. New approaches targeting BRAF fusions, including BRAF dimer blockers, ERK inhibitors, and proteolysis targeting chimeras (PROTACs) are in clinical trial with the expectation that they may soon provide better treatments for patients with BRAF fusion-positive cancers.

Supplementary Material

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Translational Relevance.

BRAF fusions are increasingly detected in standard multigene next-generation sequencing panels and are the subject of active drug development, although no targeted therapies have yet been approved. Here, we report the largest study to date describing the structure and impact of BRAF fusions on clinical course. Responses to MAPK-directed therapies were low, but a signal was seen predominantly in pilocytic astrocytomas. Furthermore, we found that BRAF fusions are an acquired resistance mechanism in many cancers, emphasizing the need for post-progression sequencing.

Acknowledgements

Funding: This work was supported by the National Cancer Institute at the National Institutes of Health [grant number P30CA008748, P01CA129243, K12 CA184746] and a Squeri Grant for Drug Development.

Declarations of Interest:

MFC: T32-CA009207, ASCO Young Investigator Award; Stock Nordisk, Quest, Doximity, Figs; SY: consulting fees from Sanofi; honoraria from PRIME Education, LLC, and AstraZeneca; and travel funds from AstraZeneca, E.L.D discloses unpaid editorial support from Pfizer Inc and serves on an advisory board for Day One Biotherapeutics, Springworks Therapeutics, and Opna Bio; R.S. has received research support from Merus, Loxo Oncology and Elevation Oncology; M.L. has received advisory board compensation from Merck, Bristol Myers Squibb, Takeda, Bayer, Lilly Oncology, Janssen and Paige.AI. In addition, research grants unrelated to the current study were obtained from Merus, Loxo Oncology and Elevation Oncology; HY has received consulting fees from AstraZeneca, Daiichi Sankyo, Blueprint Medicines, Janssen, C4 Therapeutics, Cullinan Oncology, and Black Diamond Therapeutics; received travel, accommodation, and/or expenses from Lilly; other relationship with Astellas Pharma; received research funding from AstraZeneca, Astellas Pharma, Lilly, Novartis, Pfizer, Daiichi Sankyo, Cullinan Oncology, Janssen Oncology, Erasca, and Blueprint Medicines; GR reports grants from AACR during the conduct of the study and grants from Novartis, Mirati, Roche, Takeda, Lilly, Rain Therapeutics, and Verastem; N.R. reports grants and personal fees from AstraZeneca during the conduct of the study; personal fees and other support from MAPCure and Beigene, grants from Revolutionary Medicines, Pfizer-Colorado, and Boehringer Ingelheim, other support from Kura and Effector, and personal fees from Jubilant, Ikena, and Chugai outside the submitted work; a patent for a cream or lotion containing a standard RAF inhibitor to prevent the rashes induced by inhibitors of MEK, ERK, EGFR, and other inhibitors that inhibit ERK signaling in skin pending to Lutris; and work with biotech companies that is not relevant to the submitted work: Ribon (scientific advisory board and equity), ZaiLabs (scientific advisory board and equity), Concarlo (consulting), and Fortress (equity); R.Y. reports grants and personal fees from Mirati Therapeutics and Array BioPharma/Pfizer, grants from Daiichi Sankyo and Boehringer Ingelheim, and personal fees from Natera and Zai Lab; MGK: Consulting: Astrazeneca, Pfizer, Merus, BergenBio, Mirati, Sanofi Honoraria: WebMD; AD: Honoraria/Advisory Boards: 14ner/Elevation Oncology, Amgen, Abbvie, ArcherDX, AstraZeneca, Beigene, BergenBio, Blueprint Medicines, Chugai Pharmaceutical, EcoR1, EMD Serono, Entos, Exelixis, Helsinn, Hengrui Therapeutics, Ignyta/Genentech/Roche, Janssen, Loxo/Bayer/Lilly, Merus, Monopteros, MonteRosa, Novartis , Nuvalent, Pfizer, Prelude, Repare RX, Takeda/Ariad/Millenium, ,Treeline Bio, TP Therapeutics, Tyra Biosciences, Verastem; Associated Research Paid to Institution: Pfizer, Exelixis, GlaxoSmithKlein, Teva, Taiho, PharmaMar, Royalties: Wolters Kluwer; Other (Food/Beverage): Merck, Puma, Merus, Boehringer Ingelheim CME Honoraria: Answers in CME, Applied Pharmaceutical Science, Inc, AXIS, Clinical Care Options, EPG Health, Harborside Nexus, I3 Health, Imedex, Liberum, Medendi, Medscape, Med Learning, MJH Life Sciences, MORE Health, Ology, OncLive, Paradigm, Peerview Institute, PeerVoice, Physicians Education Resources, Remedica Ltd , Research to Practice, RV More, Targeted Oncology, TouchIME, WebMD; MDO reports consulting roles/honorarium with Novartis, Jazz, Pfizer, Targeted Oncology, OncLive, American Society for Radiation Oncology. Grant support from the Druckenmiller Foundation and LUNGevity Foundation. Uncompensated scientific advisory board member for the Mesothelioma Applied Research Foundation; YMG: travel, accommodation, and expenses from AstraZeneca and Loxo Oncology/ Eli Lilly. She acknowledges honoraria from Virology Education and Projects in Knowledge (for a CME program funded by an educational grant from Amgen). She acknowledges associated research funding to the institution from Mirati Therapeutics, Loxo Oncology at Eli Lilly, Elucida Oncology, Taiho Oncology, Hengrui USA, Ltd/ Jiangsu Hengrui Pharmaceuticals, Luzsana Biotechnology, Endeavor Biomedicines, and AbbVie. She is an employee of Memorial Sloan Kettering Cancer Center, which has an institutional interest in Elucida. She acknowledges royalties from Rutgers University Press and Wolters Kluwer. She acknowledges food/beverages from Endeavor Biomedicines. Y.R. Murciano-Goroff acknowledges receipt of training through an institutional K30 grant from the NIH (CTSA UL1TR00457). She has received funding from a Kristina M. Day Young Investigator Award from Conquer Cancer, the ASCO Foundation, endowed by Dr. Charles M. Baum and Carol A. Baum. She is also funded by the Fiona and Stanley Druckenmiller Center for Lung Cancer Research, the Andrew Sabin Family Foundation, the Society for MSK, and a Paul Calabresi Career Development Award for Clinical Oncology (NIH/NCI K12 CA184746) as well as through NIH/NCI R01 CA279264. The remaining authors report no disclosures.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1
NIHMS2006693-supplement-1.pdf (116.5KB, pdf)
2
NIHMS2006693-supplement-2.pdf (81.7KB, pdf)
3
NIHMS2006693-supplement-3.pdf (103.7KB, pdf)
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NIHMS2006693-supplement-4.pdf (73.8KB, pdf)
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NIHMS2006693-supplement-5.pdf (72.6KB, pdf)
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NIHMS2006693-supplement-6.pdf (418.3KB, pdf)
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NIHMS2006693-supplement-7.pdf (295.4KB, pdf)
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NIHMS2006693-supplement-8.pdf (220.4KB, pdf)
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NIHMS2006693-supplement-9.pdf (755.5KB, pdf)
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NIHMS2006693-supplement-10.pdf (240.3KB, pdf)

Data Availability Statement

We analyzed existing data from cBioPortal that are publicly available (https://www.cbioportal.org/study/summary?id=braf_msk_archer_2024 and https://www.cbioportal.org/study/summary?id=braf_msk_impact_2024). Additional data are available upon request from the corresponding author.

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