BRAF/MEK Dual Inhibitors Therapy in Progressive and Anaplastic Pleomorphic Xanthoastrocytoma: Case Series and Literature Review

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  • 1 St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, Missouri;
  • | 2 Texas College of Osteopathic Medicine, University of North Texas Health Science Center, Fort Worth, Texas;
  • | 3 Vivian L. Smith Department of Neurosurgery, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, Texas;
  • | 4 Department of Neurology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, Texas;
  • | 5 Department of Radiology, Louisiana State University Health Shreveport, Shreveport, Louisiana;
  • | 6 Chicago Medical School, Rosalind Franklin University of Medicine and Science, Chicago, Illinois;
  • | 7 Department of Pathology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, Texas;
  • | 8 Memorial Hermann-Texas Medical Center, Houston, Texas;
  • | 9 Department of Radiology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, Texas; and
  • | 10 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Recurrent and anaplastic pleomorphic xanthoastrocytoma (r&aPXA) is a rare primary brain tumor that is challenging to treat. Two-thirds of PXA tumors harbor a BRAF gene mutation. BRAF inhibitors have been shown to improve tumor control. However, resistance to BRAF inhibition develops in most cases. Concurrent therapy with MEK inhibitors may improve tumor control and patient survival. In this study, we identified 5 patients diagnosed with BRAF-mutated PXA who received BRAF and MEK inhibitors over a 10-year interval at our institution. Patient records were evaluated, including treatments, adverse effects (AEs), outcomes, pathology, next-generation sequencing, and MRI. The median age was 22 years (range, 14–66 years), 60% male, and 60% anaplastic PXA. Median overall survival was 72 months (range, 19–112 months); 1 patient died of tumor-related hemorrhage while off therapy, and the other 4 experienced long-term disease control (21, 72, 98, and 112 months, respectively). Dual BRAF/MEK inhibitors were well tolerated, with only grade 1–2 AEs, including rash, neutropenia, fatigue, abdominal discomfort, and diarrhea. No grade 3–5 AEs were detected. A literature review was also performed of patients diagnosed with BRAF-mutated PXA and treated with BRAF and/or MEK inhibitors through August 2021, with a total of 32 cases identified. The median age was 29 years (range, 8–57 years) and the median PFS and OS were 8.5 months (range, 2–35 months) and 35 months (range, 10–80 months), respectively. The most common AEs were grade 1–2 fatigue and skin rash. Results of this case series and literature review indicate that dual-drug therapy with BRAF and MEK inhibitors for r&aPXA with BRAF V600E mutation may delay tumor progression without unexpected AEs.

Pleomorphic xanthoastrocytoma (PXA) is a rare type of glioma that is more predominant in the pediatric population, with an average of 0.03 cases per 100,000 annually.1 Survival at 5 years is 80% overall, and 57% for anaplastic PXA (aPXA; WHO grade III).2 Older age at diagnosis is inversely associated with survival in both WHO grade II disease and aPXA.3 Gross total resection (GTR) predicts a longer time to recurrence, but does not change overall survival (OS) in aPXA.3,4 Radiotherapy (XRT) is commonly used for recurrent PXA and newly diagnosed aPXA after maximum safe resection. However, there is no consensus on adjuvant chemotherapy.5

The BRAF gene encodes a serine-threonine kinase protein downstream from RAS in the MAPK signaling cascade, also known as the RAS/RAF/MEK/ERK pathway.6 Mutations in BRAF result in oncogenic activation of this pathway, promoting tumor cell proliferation and survival.5 V600E is the most common mutation in the BRAF gene (50%–70%).7 BRAF V600E has been shown to be a valuable diagnostic marker in central and peripheral nervous system tumors, including PXA, ganglioglioma, and pilocytic astrocytoma.8

The FDA first approved the BRAF V600E inhibitor vemurafenib in 2011 for use in advanced melanoma.9 It has also shown encouraging results in BRAF V600E–mutated non–small cell lung cancer, papillary thyroid cancer, and central nervous system (CNS) neoplasms, including PXA.1012

Despite the encouraging response, resistance to BRAF inhibitors often emerges within months of starting treatment due to acquired reactivation of the MAPK pathway.13,14 Impeding MEK, which is downstream of BRAF, with an MEK inhibitor such as trametinib has demonstrated a dramatic and durable response in melanoma.15 Initiation of both inhibitors at the beginning of treatment may improve progression-free survival (PFS) and OS.

This report presents 5 cases of recurrent and anaplastic PXA (r&aPXA) with BRAF V600E mutations. Each patient received BRAF and MEK inhibitors concurrently, with distinctive clinical and radiologic outcomes.

Methods

Medical records from 2010 to 2021 at Memorial Hermann-Texas Medical Center were reviewed after approval of the Committee for the Protection of Human Subjects (HSC-MS-17-0967). Five patients diagnosed with r&aPXA who received BRAF and MEK inhibitors were identified. The data evaluated included age, sex, treatment received, adverse effects (AEs), outcomes, laboratory results, pathology findings, next-generation sequencing (NGS) results, and MRI features. We retrospectively analyzed AEs according to the CTCAE, version 5.0.

Results

Median age at diagnosis was 22 years (range, 14–66 years), 60% of the cohort was male, and 60% had grade III PXA. Timelines of MRIs and various treatments received, including BRAF/MEK inhibitors, for each patient are depicted in supplemental eFigures 1–5, available with this article at JNCCN.org.

Case Series

Case 1

A 22-year-old female with a history of seizures was found to have an enhancing lesion in the left parietal-occipital lobe in January 2013 (Figure 1A, B). She underwent GTR in July 2013 with a diagnosis of PXA, WHO grade II (Figure 1C, D).

Figure 1.
Figure 1.

Case 1: Left temporo-occipital PXA, WHO grade II. Top and bottom rows show a series of coronal post-contrast T1 and T2 images, respectively and chronologically. (A, B) At diagnosis, a well-defined avidly enhancing cortically based mass was identified at the mesial aspect of the left occipital lobe (arrows). (C, D) Postoperative MRI in July 2013 showed GTR (arrows). (E, F) MRI in April 2018 showed the first tumor progression at the left temporo-occipital junction (arrows) with a second GTR performed in the same month. (G, H) In August 2018, tumor progression occurred again and was treated with LITT (arrows). (I, J) Increased enhancement was identified at the surgical bed of the left temporo-occipital junction in March 2019 (arrows). (K, L) MRI in May 2020 showed no residual enhancing tumor in the same location (circles). (M, N) MRI in September 2021 showed no new lesion (circles).

Abbreviations: GTR, gross total resection of enhancing mass; LITT, laser interstitial thermal therapy; PXA, pleomorphic xanthoastrocytoma; XRT, radiotherapy.

Citation: Journal of the National Comprehensive Cancer Network 20, 11; 10.6004/jnccn.2022.7046

Five years later, MRI revealed a new enhancing mass, which prompted a second GTR (Figure 1E, F) with pathologic diagnosis of recurrent PXA, WHO grade II, with Ki-67 of <5%. NGS by FoundationOne CDx showed BRAF  V600E mutation, CDKN2A/B loss, and MTAP loss. Epigenetic analysis showed no MGMT promoter methylation.

In August 2018, follow-up MRI showed tumor progression. The patient underwent laser interstitial thermal therapy (LITT) with biopsy, which showed PXA, WHO grade II (Figure 1G, H). In October 2018, she received fractionated XRT (50.4 Gy) and daily temozolomide (TMZ) with subsequent cyclic TMZ per the Stupp protocol.16 An MRI in December 2018 showed an enlarged enhancing mass, and follow-up MRI in March 2019 (Figure 1I, J) confirmed incremental progression after the patient began experiencing vision changes, dizziness, and ataxia.

TMZ was stopped in March 2019. The MEK inhibitor cobimetinib and the BRAF inhibitor vemurafenib were started in a planned staggered fashion in April 2019 and May 2019, respectively.

MRI 2 months later showed a decrease in enhancement along with the patient’s neurologic recovery (Figure 1K, L). At the time of writing in September 2021, the patient had continued on vemurafenib and cobimetinib for 28 and 29 months, respectively—except for short breaks (18 and 10 days, respectively) due to rash and neutropenia—without clinical or radiologic changes (Figure 1M, N). Results of pathology, NGS, and partial MRI were published previously by Dono et al.17

Case 2

A 14-year-old male from China was diagnosed with “rhabdoid meningioma” in June 2014 after craniotomy for a right temporal lobe lesion. He received XRT followed by multiple chemotherapy agents. In December 2015, he developed a scalp tumor that was resected, with pathology showing rhabdoid meningioma. He subsequently experienced tumor recurrence, which prompted further surgery and subsequent pharmacologic intervention (doxorubicin, ifosfamide, carboplatin, etoposide, cyclophosphamide, dactinomycin, vincristine).

In February 2017, he came to the United States seeking further therapy (Figure 2A–C). The previous surgical samples were evaluated by 2 independent neuropathologists, who determined that the specimens were anaplastic PXA, WHO grade III, with diffusely infiltrative rhabdoid morphology, positive for BRAF  V600E mutation, with Ki67 >90%. In March 2017, MRI of the spine showed evidence of leptomeningeal disease (LMD) (supplemental eFigure 6) prompting spinal XRT (39.6 Gy), and subsequently treatment with TMZ and the BRAF inhibitor vemurafenib, in March 2017. The MEK inhibitor trametinib was added 2 months later.

Figure 2.
Figure 2.

Case 2: Metastatic anaplastic PXA, WHO grade III. MRI images of original tumor and surgical cavity are not shown. Axial post-contrast T1W MRI at different time points since February 2017 at (A, D, G, J) the level of the lateral ventricles, (B, E, H, K) the posterior fossa, and (C, F, I, L) the parotid glands. The arrow in (A) indicates areas of enhancement corresponding to posttreatment changes with subsequent resolution over the following scans, corroborated by volume loss and compensatory enlargement of the adjacent ventricle (arrows in D, G, J). MRI in February 2017 showed multiple enhancing foci, including one at the right CPA (arrow in B). GK radiotherapy was performed targeting the CPA mass in January 2019. The CPA mass showed continued contrast enlargement and central necrosis (arrows in E and H), and the patient developed LMD (arrowhead in H) in October 2019. The LMD and parenchymal infiltrative PXA tumor showed a partial response to treatment, as shown in (K). Findings from MRI October 2019 showed extracranial metastases in the spine (see supplemental eFigure 6A, B), cervical lymph nodes (not shown), and right parotid gland (arrows in I). MRI in May 2020 showed rapid growth of the metastatic lesion to the right parotid gland (arrows in I and L) despite partial initial response to treatment (arrows in F). The arrowhead in (L) indicates the tumor encasement of the cervical segment of the right internal carotid artery. MRI from October 2019 to May 2020 showed rapidly growing scalp metastases (arrowheads in G and J) (see supplemental eFigure 6C–G), with progressive neoplastic ulceration and superinfection (asterisk in G and J). The relentless extracranial tumor progression can be appreciated by comparing the images from April 2018 with the scans from October 2019 and May 2020 (F–L).

Abbreviations: CPA, cerebellar pontine angle; GK, Gamma Knife; LMD, leptomeningeal carcinomatosis or disease; PXA, pleomorphic xanthoastrocytoma; T1W, T1 weighted.

Citation: Journal of the National Comprehensive Cancer Network 20, 11; 10.6004/jnccn.2022.7046

While on the 3-drug treatment, the patient developed a new cerebellar mass in April 2018 (Figure 2D–F). Subsequent MRI confirmed tumor progression, and in September 2018 his chemotherapy was changed to the second-generation BRAF inhibitor dabrafenib + lomustine. He was stable for 9 months. In January 2019, he received Gamma Knife (GK) stereotactic radiosurgery to the cerebellar tumor and fractionated XRT to the right temporalis muscle lesion while continuing therapy with dabrafenib + lomustine.

In September 2019, the patient developed severe myelosuppression, resulting in hospitalization and discontinuation of dabrafenib and lomustine. His scalp tumors were visibly enlarging while off therapy. He experienced clinical deterioration with dysphagia and paraparesis, with MRI showing evidence of progression in October 2019 (Figure 2G–I).

In November 2019, encorafenib and binimetinib were initiated. Although MRI from December 2019 showed tumor progression, the majority of scalp soft tissue lesions were visibly stable (supplemental eFigure 6). The patient also reported significant improvement in nutrition and ambulation. Due to new bony metastases, nivolumab and ipilimumab were added in January 2020 while maintaining encorafenib and binimetinib.

While on this regimen for 4 months, with fatigue as the only AE, the patient experienced a slower tumor growth rate at extracranial sites (supplemental eFigure 6). His intracranial tumor remained stable (Figure 2J–L). In early July 2020, he developed partial paraplegia and dysphagia, with MRI evidence of cervical cord compression from an enlarging nonoperative cervical spinal mass. He was then transitioned to hospice and died shortly thereafter.

Case 3

A 28-year-old female presented in May 2012 for resection of a right frontal mass diagnosed as “glioblastoma multiforme (GBM)” with atypical features, positive for BRAF V600E mutation. She received XRT and TMZ per the Stupp protocol,16 and then enrolled in a clinical trial (ClinicalTrials.gov identifier: NCT01430351) in September 2012, undergoing treatment with TMZ, metformin, and mefloquine for 12 months. Follow-up MRI studies showed stable disease until 3 years later, and biopsy of the new enhancing mass in August 2015 was identified as “GBM” with BRAF V600E mutation. In September 2015 she entered a second clinical trial (NCT02034110) with the BRAF and MEK inhibitors dabrafenib and trametinib, respectively.

The patient remained stable for 4 more years (Figure 3A), until further tumor progression was confirmed by MRI in September 2019 while on both inhibitors (Figure 3B). She underwent a third surgery, with pathologic diagnosis of aPXA, WHO grade III, and Ki-67 of 32.6%. NGS showed BRAF V600E and RNF43 p.R389fs mutations (Figure 3C). While on both drugs, follow-up MRIs confirmed disease progression in December 2019 and January 2020.

Figure 3.
Figure 3.

Case 3: Right parietal anaplastic PXA, WHO grade III. Images of the initial tumor are not included. Series of axial post-contrast T1 at different time points are presented. The patient had stable MRIs for 48 months until September 2019 (arrow in A). MRI on November 4, 2019, showed enlarging areas of enhancement along the medial wall of the surgical cavity, extending into the posteromedial aspect of the right frontal lobe (arrows in B). GTR was achieved on November 5, 2019, with diagnosis of aPXA (arrows in C). MRI in January 2020 showed small area of enhancing tumor at the left splenium (arrow in D). Twelve days after discontinuation of BRAF/MEK inhibitors, MRI on April 28, 2020, showed a burst of growth in the bilateral splenium, the ventricles, the septum pellucidum, and the periventricular white matter (arrows in E). Follow-up MRI on May 22, 2020, showed near-complete resolution of the areas of enhancement (arrows in F). In June 2020, MRI showed an increase of previous enhancement at the body of the corpus callosum and a new nodular enhancement in the precentral cortex (arrows in G). LITT was performed in July 2020, showing stable postablation changes (arrow in H). Follow-up MRI in October 2020 showed increase enhancement in the periventricular white matter, corpus callosum and septum pellucidum (arrows in I). MRI in December 2020 showed an increase enhancement at the corpus callosum and the ependymal linings of the bilateral lateral ventricles (arrows in J). Decrease in size and intensity of enhancement at the corpus callosum and bilateral lateral ventricles was noticed on follow-up scan in March 2021 (arrows in K), with stable radiologic changes seen on her last scan in July 2021 (arrows in L).

Abbreviations: aPXA, anaplastic pleomorphic xanthoastrocytoma; GTR, gross total resection of enhancing mass; LITT, laser interstitial thermal therapy; T1W, T1 weighted; XRT, radiotherapy.

aEncorafenib, binimetinib, nivolumab, ipilimumab.

Citation: Journal of the National Comprehensive Cancer Network 20, 11; 10.6004/jnccn.2022.7046

The patient then transferred her care to our institution with MRI study (Figure 3D). Two neuropathologists reviewed her 3 separate surgical specimens and confirmed that all were aPXA. She stopped dual inhibitors in April 2020 when she began a washout period in preparation for LITT and planned initiation of third-generation of inhibitors. She developed profound left leg weakness 12 days after stopping both drugs. Given new MRI evidence of profound tumor progression (Figure 3E), she was no longer a candidate for LITT. Encorafenib and binimetinib were started concurrently, and the patient reported significant improvement in 1 week, with reduction of enhancement by MRI (Figure 3F). She experienced acne rash and abdominal discomfort, as she had with previous BRAF/MEK inhibitors therapy.

Two months later, MRI in June 2020 showed new tumor expansion (Figure 3G), and she underwent LITT in July 2020 (Figure 3H) followed by addition of nivolumab and ipilimumab. The patient experienced improvement in her neurologic status. Three months later, MRI in October 2020 showed new tumor progression (Figure 3I), for which salvage XRT (35 Gy in 10 fractions) was implemented while continuing the 4-drug chemotherapy (encorafenib/binimetinib/nivolumab/ipilimumab).

Shortly after finishing XRT in November 2020 (Figure 3J), the patient developed worsening of left hemiparesis and changes on MRI concerning for tumor versus necrosis. She added bevacizumab, which resulted in clinical and radiologic improvement (Figure 3K). While on the 5-drug regimen, there was no evidence of radiologic progression for 7 months (Figure 3L). Unfortunately, she then deteriorated gradually with left hemiplegia, hemianesthesia fatigue, ageusia, and dysphagia. In late August 2021 she stopped chemotherapy and entered hospice, and died in September 2021.

Case 4

A 66-year-old male presented in August 2019 with headaches, vision change, and ataxia. MRI demonstrated a right temporal lobe mass involving the right cavernous sinus and internal carotid artery (Figure 4A). He underwent subtotal resection (STR) with pathologic diagnosis as PXA, WHO grade II, with BRAF V600E mutation and Ki-67 of 10% to 12% (Figure 4B). His symptoms improved, but he declined adjuvant therapy with BRAF and MEK inhibitors.

Figure 4.
Figure 4.

Case 4: Right temporal PXA, WHO grade II. Magnified coronal view T1 with contrast MRI except DWI MRI (J) and noncontrast CT head (H) are displayed. At the time of diagnosis in August 2019, a well-defined, centrally necrotic, avidly enhancing mass was seen centered at the medial aspect of the right temporal lobe (arrows in A). Residual versus recurrent disease within the right middle cranial fossa was observed on follow-up MRI in October 2019; areas of solid (arrows in B) and necrotic (arrowheads in B) residual tumor. In November 2019, MRI showed the first progression with enlargement of previous nodular enhancement at the right mesial temporal lobe (arrows in C). Vemurafenib + cobimetinib were started in December 2019 and then stopped in May 2020 by patient due to limited tolerance. MRI in February 2020 showed decreased size of the masses (arrow and arrowheads in D). MRI in May 2020 showed enlargement in the medial aspect of the right temporal lobe and ipsilateral supraclinoid region (arrow and arrowhead in E). MRI in October 2020 demonstrated significant enlargement of the lesion (arrow in F). Further increase in tumor size (arrows in G) and residual necrotic tumor (arrowhead in G), with extension to the cavernous sinus, was found on MRI in February 2021. CT without contrast on March 3, 2021, showed hyperdense signal consistent with hemorrhage in the right paraclinoid region (arrows in H). MRI on March 4, 2021, showed a new well-defined, centrally hemorrhagic lesion in the tumor area (arrowhead in I), enlargement of previous lesions (arrows in I), and ischemic changes at the right lateral and anterior aspect of the third ventricle (DWI MRI arrows in J).

Abbreviations: DWI, diffusion-weighted imaging; PXA, pleomorphic xanthoastrocytoma; T1W, T1 weighted; XRT, radiotherapy.

Citation: Journal of the National Comprehensive Cancer Network 20, 11; 10.6004/jnccn.2022.7046

In November 2019, he developed worsening vision and headaches. MRI revealed increased enhancement in the right temporal lobe (Figure 4C). Given the high risk of optic nerve injury, XRT was not advised, and he started cobimetinib + vemurafenib in December 2019 and January 2020, respectively. He showed radiologic and clinical improvement (Figure 4D), and continued the dual-inhibitor therapy with limited tolerance, including gastrointestinal discomfort and weight loss. He voluntarily stopped the dual inhibitors in April 2020.

One month after stopping dual-inhibitor treatment, MRI revealed increased enhancement (Figure 4E), for which fractionated XRT (50.4 Gy) was completed in June 2020. MRI in September 2020 and October 2020 (Figure 4F) revealed increased enhancement in the right temporal lobe, while the patient reported worsening vision and mild headaches. The patient declined initiating new therapy.

When MRI in February 2021 (Figure 4G) and March 2021 (Figure 4H) showed continued tumor progression, the patient ultimately agreed to start insurance preauthorization for a new generation of BRAF and MEK inhibitors. Unfortunately, before starting the therapy, he developed a tumor-related hemorrhage (Figure 4H, I) and subsequent cerebral ischemia (Figure 4J). The patient was transitioned to hospice and then died.

Case 5

A 20-year-old male with progressively deteriorating vision of the left eye, worsening headache, and nausea was found to have a right parietal-occipital tumor with brainstem compression and obstructive hydrocephalus in December 2019. He underwent urgent external ventricular drain placement, and bilateral ocular nerve sheath fenestration followed by an STR craniotomy (Figure 5A, B). Pathology showed aPXA, WHO grade III, positive for BRAF  V600E mutation and IDH1 wild-type, with a Ki67 of approximately 30%.

Figure 5.
Figure 5.

Case 5: Right occipital aPXA, WHO grade III with axial view post-contrast T1 images at different time points. At diagnosis in December 2019, a well-defined, heterogeneous centrally necrotic, avidly enhancing, and vascular mass is seen at the medial aspect of the right temporal lobe (arrows in A). Only STR was achieved due to its immediate proximity to eloquent area (arrows in B). Follow-up MRI in March 2020 showed reduction of right parietal occipital enhancement with resolved midline shift (arrows in C). MRI in June 2020 showed first progression with a solid enhancing mass at the right parieto-occipital lobe (arrows in D). MRI in July 2020 showed a decrease in size of the enhancing mass (arrows E). MRI in September 2020 showed a reduction of enhancing tumor (arrows F). A new tiny enhancing nodule located posteriorly to the surgical cavity was identified (arrowhead in F). MRI in November 2020 after GK XRT showed stable disease except mildly increased nodular enhancement along the lingual gyrus (arrowhead in G). Stable disease was observed in all subsequent MRIs, as shown in March 2021 and September 2021 (arrows and arrowhead in H, I).

Abbreviations: aPXA, anaplastic pleomorphic xanthoastrocytoma; GK, Gamma Knife; STR, subtotal resection; T1W, T1 weighted; XRT, radiotherapy

Citation: Journal of the National Comprehensive Cancer Network 20, 11; 10.6004/jnccn.2022.7046

He was treated with fractionated XRT and TMZ in January 2020 per the Stupp protocol.16 Follow-up MRI showed shrinkage of his tumor (Figure 5C). In June 2020, due to tumor progression (Figure 5D), TMZ was discontinued and BRAF and MEK inhibitors were initiated, with vemurafenib in June 2020 and cobimetinib in July 2020. MRI in July 2020 showed decreased tumor size and stable adjacent FLAIR changes (Figure 5E). All of his symptoms had resolved except left eye blindness and left hemianopia of his right eye. In September 2020, MRI showed an overall decrease of enhancement but a tiny nodular enhancement at the posterior periphery of the resection cavity (Figure 5F), prompting GK radiosurgery while continuing vemurafenib and cobimetinib. Two months after, in November 2020, MRI showed transient increase in enhancement of the GK treated area, which was likely GK treatment–related, and he continued with dual-inhibitor therapy without neurologic decline (Figure 5G).

At the time of this report in September 2021, he had been taking BRAF and MEK inhibitors for 15 and 14 months, respectively, with stable clinical and imaging results (Figure 5H, I). The only AE he experienced was facial erythema with sun exposure.

Adverse Effects

Dual BRAF and MEK inhibitors were well tolerated, with grade 1–2 AEs including transient skin rash, fatigue, abdominal discomfort, neutropenia, and diarrhea. All symptoms were reversible. Among the 5 patients in our cohort, 4 were able to tolerate dual therapy without significant AEs, except for fatigue and skin sensitivity to sun. No grade 3–4 AEs were detected (supplemental eTable 1).

Literature Review

Literature review through PubMed was performed for publications through August 2021 that included adult and pediatric patients diagnosed with BRAF-mutated r&aPXA who were treated with BRAF and/or MEK inhibitors. A total of 32 cases (including 7 from the BASKET study) were identified, as summarized in supplemental eTable 1. Median age was 29 years (range, 8–57 years), with 15 males and 17 females.

The number of prior surgeries (unknown in the BASKET study) were none in 2 patients, 1 in 6 patients, and 2 in 10 patients, whereas 7 patients had ≥3 resections. In all but 2 cases, XRT (details unknown) was used at least once, 13 (41%) patients had second XRT, 15 (47%) had initial chemotherapy, and 14 (44%) had salvage treatment. Median PFS was 8.5 months (range, 2–35 months) for the 25 cases without the BASKET study subjects from the literature review and 5.7 months for the BASKET study. Median OS was 35 months (range, 10–80 months) among the same 25 cases and not reached in the BASKET study. The most common AEs were grade 1–2 fatigue and skin rash.

Discussion

An increasing number of reports support the use of BRAF and MEK inhibitors in treating r&aPXA. Our literature search identified 32 cases, which were summarized along with our 5 patients (supplemental eTable 1).2,6,7,9,11,12,14,15,1830 Most had radiographically documented tumor progression while on standard of care (SoC) regimen before starting targeted therapy.

It is impossible to conclude superiority across described regimens based on case reports and retrospective reviews. However, promising clinical and radiologic outcomes are noted. Patients on BRAF inhibitor monotherapy in 32 published cases demonstrated up to 35 months (median, 7 months) of stable disease, 2 patients receiving adjunct MEK inhibitor at a later time experienced up to 21 months of stable disease, and those on dual concomitant therapy experienced up to 23 months (median, 11 months) of stable disease (supplemental eTable 1). The trend of drug usage developed over time, with dual inhibitors now being initiated relatively routinely. This shift in the treatment algorithm may correlate with improved outcomes and synergistic potential of dual BRAF and MEK inhibitors.

Knowledge of the specific BRAF mutation is important for the proper selection of BRAF and MEK inhibitors. BRAF mutations have been grouped into 3 classes: class I comprises V600E mutations resulting in low RAS activity; class II includes BRAF fusions and non-V600E mutations, leading to increased ERK activation with decreased RAS activity; and class III have impaired and/or absent kinase activity. Class III mutations might not respond to BRAF inhibitors, making MEK inhibitors a more optimal option.13 Our cohort of 5 patients with class I mutation demonstrated the benefit of using dual BRAF and MEK therapy on PXA intracranial tumor control. Four patients experienced long-term disease control (21, 72, 98, and 112 months, respectively); 2 of them remain on dual therapy at the time of writing, and 1 died of systemic PXA progression while the intracranial PXA tumor remained stable (Case 2). The elderly patient (Case 4) experienced short-term disease stability for 5 months, but died of tumor progression and stroke complications while waiting for initiation of second-generation inhibitor therapy. The patient experiencing the longest period of stable disease (Case 3; 112 months) had a final episode of clinical deterioration while on the 5-drug therapy, and died shortly after stopping treatment (supplemental eFigure 3).

BRAF and MEK inhibitor regimen has potential utility not only in primary CNS tumor control but also as palliative treatment of aggressive systemic PXA. The patient in Case 2 had several metastatic lesions that significantly impacted his quality of life. BRAF- and MEK-targeted therapy allowed him a period of clinical improvement. Similarly, a recently published case demonstrated that encorafenib significantly reduced chest wall and spinal PXA metastases.30 Unfortunately, the patient developed disease at other sites while on therapy. Early initiation of dual-inhibitor therapy can also be an option for tumors located in eloquent areas of the brain. In Case 4, use of this strategy to treat a mass close to the optic nerve avoided or delayed potential AEs from XRT.

Interpretation of outcomes following BRAF- and MEK-targeted therapy can be complicated by pseudoprogression. Although its incidence remains low in low-grade astrocytic tumors, such as PXA WHO grade II, this phenomenon can mimic tumor progression in patients with GBM who have received XRT and TMZ.31 Two of our patients were noted to have MRI progression within a few months following treatment with the Stupp protocol and prior to initiation of BRAF and MEK inhibitors. Their subsequent improvement could be unrelated to the therapeutic benefit of the inhibitors. This is less likely, given that the patient in Case 1 was deteriorating while on TMZ and her immediate improvement clinically and by MRI would not be possible without the dual inhibitors. The significant worsening while off dual inhibitors for 12 days and subsequent dramatic improvement after starting a third generation of dual inhibitors, seen in Case 3, resulted from the absence and then readministration of BRAF and MEK inhibitors, respectively. Moreover, Pearson correlation analysis demonstrates no relationship between age and PFS or age and OS, respectively (supplemental eFigures 7 and 8). Although BRAF/MEK inhibitors play a major role, we cannot exclude that other therapies, including LITT, GK, salvage radiation, and chemotherapy, may contribute to the improved PFS and OS results.

Optimal medical intervention is a fine balance between benefit and potential harm. There is evidence that dual therapy can reduce cutaneous toxicity of BRAF inhinitor.27 Dual BRAF and MEK inhibitors were well tolerated in our patients, with only grade 1–2 AEs. Most symptoms subsided over time while continuing the dual therapy, except in Case 4, and no grade 3–5 AEs were detected. A limitation to our study is that the AEs were evaluated retrospectively from patients’ medical records, as outlined in supplemental eTable 1. It remains likely that some symptoms may have not been adequately documented.

Establishing evidence-based guidelines to maximize the value of BRAF and MEK inhibitors for PXA remains a challenge, but evidence is mounting to support the use of BRAF and MEK inhibitors concurrently. The up-front combination of inhibitors could be more effective than sequential use of MEK inhibitors after tumor progression while on BRAF inhibitor monotherapy.23 Further molecular studies may help in understanding the synergistic action and if the combination may delay the development of tumor resistance.

Given the low prevalence of PXA, performing clinical trials for r&aPXA to answer management questions is difficult. Because there is no uniform chemotherapy SoC based on clinical trial results, providers often select medications based on retrospective data. Application of BRAF and/or MEK inhibitors against activating BRAF mutations, such as V600E, in patients with r&aPXA has generated provocative and promising results (supplemental eTable 1). It is reasonable to try dual inhibitors after XRT, either before or after subsequent tumor progression and prior to use of traditional chemotherapy. The benefits of early dual-inhibitor application may be multiple. The high likelihood of shrinking and/or curtailing tumor growth can improve patient function and quality of life while avoiding myelosuppression associated with traditional chemotherapy. BRAF and MEK inhibitors are also in the convenient per os formulation and the adverse effects in most patients are mild and reversible. Three generations of BRAF/MEK inhibitors are available and may be selected based on tolerance and treatment effect.

Although complete results are yet to be published, targeted drug therapy trials examining the utility of BRAF and MEK inhibitors are ongoing (ClinicalTrials.gov identifiers: NCT02684058, NCT03975829, NCT03919071, NCT01430351, NCT03973918). One study (NCT02034110) using dabrafenib and trametinib on rare tumors with BRAF mutation is showing a durable clinical benefit in BRAF  V600E–mutant low- and high-grade gliomas.32 The patient in Case 3, who was initially misdiagnosed and treated as having GBM, entered this clinical trial and was stable for 48 months while on the protocol. Trametinib is also being studied in combination with cyclin-dependent kinase inhibitors (NCT03434262). A recent NCI-MATCH (EAY131-H) trial (NCT02465060) evaluated dabrafenib and trametinib in tumors containing the BRAF  V600E mutation, including one PXA, after progression on SoC, and showed durable disease control.33 Further efforts to understand drug efficacy and mechanisms of drug resistance are also being conducted through surgical specimen analysis (NCT03593993).

Conclusions

Patients with BRAF  V600E–mutated r&aPXA that is refractory to standard or salvage treatments can be treated with dual BRAF and MEK inhibitors with a high likelihood of durable response and tolerable AEs. There is growing support for the concurrent and adjuvant use of these inhibitors to improve PFS and OS. Further investigations are warranted, including clinical trials of dual-inhibitor therapy to treat BRAF  V600E–mutated PXA.

References

  • 1.

    Truitt G, Gittleman H, Leece R, et al. Partnership for defining the impact of 12 selected rare CNS tumors: a report from the CBTRUS and the NCI-CONNECT. J Neurooncol 2019;144:5363.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Hussain F, Horbinski CM, Chmura SJ, et al. Response to BRAF/MEK inhibition after progression with BRAF inhibition in a patient with anaplastic pleomorphic xanthoastrocytoma. Neurologist 2018;23:163166.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Rodrigues A, Bhambhvani H, Medress ZA, et al. Differences in treatment patterns and overall survival between grade II and anaplastic pleomorphic xanthoastrocytomas. J Neurooncol 2021;153:321330.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Ida CM, Rodriguez FJ, Burger PC, et al. Pleomorphic xanthoastrocytoma: natural history and long-term follow-up. Brain Pathol 2015;25:575586.

  • 5.

    Hsiao SJ, Karajannis MA, Diolaiti D, et al. A novel, potentially targetable TMEM106B-BRAF fusion in pleomorphic xanthoastrocytoma. Cold Spring Harb Mol Case Stud 2017;3:a001396.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Phadnis SS, Chen L, Wang WL, et al. Disseminated anaplastic pleomorphic xanthoastrocytoma with posttreatment fat necrosis during combined BRAF and MEK inhibitors therapy. Pediatr Blood Cancer 2019;66:e27974.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Schreck KC, Guajardo A, Lin DDM, et al. Concurrent BRAF/MEK inhibitors in BRAF V600-mutant high-grade primary brain tumors. J Natl Compr Canc Netw 2018;16:343347.

  • 8.

    Schindler G, Capper D, Meyer J, et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 2011;121:397405.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Burger MC, Ronellenfitsch MW, Lorenz NI, et al. Dabrafenib in patients with recurrent, BRAF V600E mutated malignant glioma and leptomeningeal disease. Oncol Rep 2017;38:32913296.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med 2015;373:726736.

  • 11.

    Kaley T, Touat M, Subbiah V, et al. BRAF inhibition in BRAFV600-mutant gliomas: results from the VE-BASKET study. J Clin Oncol 2018;36:34773484.

  • 12.

    Johanns TM, Ferguson CJ, Grierson PM, et al. Rapid clinical and radiographic response with combined dabrafenib and trametinib in adults with BRAF-mutated high-grade glioma. J Natl Compr Canc Netw 2018;16:410.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Schreck KC, Grossman SA, Pratilas CA. BRAF mutations and the utility of RAF and MEK inhibitors in primary brain tumors. Cancers (Basel) 2019;11:1262.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Lee EQ, Ruland S, LeBoeuf NR, et al. Successful treatment of a progressive BRAF V600E-mutated anaplastic pleomorphic xanthoastrocytoma with vemurafenib monotherapy. J Clin Oncol 2016;34:e8789.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Leaver KE, Zhang N, Ziskin JL, et al. Response of metastatic glioma to vemurafenib. Neurooncol Pract 2016;3:268271.

  • 16.

    Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987996.

  • 17.

    Dono A, Vu J, Anapolsky M, et al. Additional genetic alterations in BRAF-mutant gliomas correlate with histologic diagnoses. J Neurooncol 2020;149:463472.

  • 18.

    Brown NF, Carter T, Kitchen N, et al. Dabrafenib and trametinib in BRAFV600E mutated glioma. CNS Oncol 2017;6:291296.

  • 19.

    Chamberlain MC. Salvage therapy with BRAF inhibitors for recurrent pleomorphic xanthoastrocytoma: a retrospective case series. J Neurooncol 2013;114:237240.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Usubalieva A, Pierson CR, Kavran CA, et al. Primary meningeal pleomorphic xanthoastrocytoma with anaplastic features: a report of 2 cases, one with BRAF(V600E) mutation and clinical response to the BRAF inhibitor dabrafenib. J Neuropathol Exp Neurol 2015;74:960969.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Hofer S, Berthod G, Riklin C, et al. BRAF V600E mutation: a treatable driver mutation in pleomorphic xanthoastrocytoma (PXA). Acta Oncol 2016;55:122123.

  • 22.

    Amayiri N, Swaidan M, Al-Hussaini M, et al. Sustained response to targeted therapy in a patient with disseminated anaplastic pleomorphic xanthoastrocytoma. J Pediatr Hematol Oncol 2018;40:478482.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Migliorini D, Aguiar D, Vargas MI, et al. BRAF/MEK double blockade in refractory anaplastic pleomorphic xanthoastrocytoma. Neurology 2017;88:12911293.

  • 24.

    Lukas RV, Merrell RT. BRAF inhibition with concomitant tumor treating fields for a multiply progressive pleomorphic xanthoastrocytoma. CNS Oncol 2018;7:CNS10.

  • 25.

    Finch EA, Elton SW, Huang BY, et al. Long-term efficacy of single-agent vemurafenib for pleomorphic xanthoastrocytoma. J Pediatr Hematol Oncol 2020;42:152155.

  • 26.

    Thomas AA, Tucker SM, Nelson CJ, et al. Anaplastic pleomorphic xanthoastrocytoma with leptomeningeal dissemination responsive to BRAF inhibition and bevacizumab. Pediatr Blood Cancer 2019;66:e27465.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Bernstein A, Mrowczynski OD, Greene A, et al. Dual BRAF/MEK therapy in BRAF V600E-mutated primary brain tumors: a case series showing dramatic clinical and radiographic responses and a reduction in cutaneous toxicity. J Neurosurg 2019;1:16.

    • Search Google Scholar
    • Export Citation
  • 28.

    Petruzzellis G, Valentini D, Del Bufalo F, et al. Vemurafenib treatment of pleomorphic xanthoastrocytoma in a child with Down syndrome. Front Oncol 2019;9:277.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29.

    Piña Y, Fusco MJ, Macaulay RJ, et al. Using personalized medicine in gliomas: a genomic approach to diagnosis and overcoming treatment resistance in a case with pleomorphic xanthoastrocytoma. J Neurol 2020;267:783790.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Kam KL, Snuderl M, Khan O, et al. Using methylation profiling to diagnose systemic metastases of pleomorphic xanthoastrocytoma. Neurooncol Adv 2020;2:vdz057.

  • 31.

    Forst DA, Nahed BV, Loeffler JS, et al. Low-grade gliomas. Oncologist 2014;19:403413.

  • 32.

    Subbiah V, Stein A, Van den Bent M, et al. ROR: dabrafenib plus trametinib in BRAF V600E–mutant high-grade and low-grade glioblastoma [abstract]. Presented at the AACR Annual Meeting 2021;April 10–15, 2021. Abstract CT025.

    • Search Google Scholar
    • Export Citation
  • 33.

    Salama AKS, Li S, Macrae ER, et al. Dabrafenib and trametinib in patients with tumors with BRAFV600E mutations: results of the NCI-MATCH Trial Subprotocol H. J Clin Oncol 2020;38:38953904.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

Submitted October 5, 2021; final revision received June 19, 2022; accepted for publication June 20, 2022.

Disclosures: C. Ware has disclosed having stock/ownership interest in Pfizer Inc. N. Tandon has disclosed holding an executive position with/serving on a governing board for/being employed by Braingrade and Nervonik Inc. The remaining authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: Research reported in this publication was partially funded by the Dr. Marni Rose Foundation.

Correspondence: Jay-Jiguang Zhu, MD, PhD, The Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, 6400 Fannin Street, Suite 2800, Houston, TX 77030. Email: jay.jiguang.zhu@uth.tmc.edu

Supplementary Materials

  • View in gallery

    Case 1: Left temporo-occipital PXA, WHO grade II. Top and bottom rows show a series of coronal post-contrast T1 and T2 images, respectively and chronologically. (A, B) At diagnosis, a well-defined avidly enhancing cortically based mass was identified at the mesial aspect of the left occipital lobe (arrows). (C, D) Postoperative MRI in July 2013 showed GTR (arrows). (E, F) MRI in April 2018 showed the first tumor progression at the left temporo-occipital junction (arrows) with a second GTR performed in the same month. (G, H) In August 2018, tumor progression occurred again and was treated with LITT (arrows). (I, J) Increased enhancement was identified at the surgical bed of the left temporo-occipital junction in March 2019 (arrows). (K, L) MRI in May 2020 showed no residual enhancing tumor in the same location (circles). (M, N) MRI in September 2021 showed no new lesion (circles).

    Abbreviations: GTR, gross total resection of enhancing mass; LITT, laser interstitial thermal therapy; PXA, pleomorphic xanthoastrocytoma; XRT, radiotherapy.

  • View in gallery

    Case 2: Metastatic anaplastic PXA, WHO grade III. MRI images of original tumor and surgical cavity are not shown. Axial post-contrast T1W MRI at different time points since February 2017 at (A, D, G, J) the level of the lateral ventricles, (B, E, H, K) the posterior fossa, and (C, F, I, L) the parotid glands. The arrow in (A) indicates areas of enhancement corresponding to posttreatment changes with subsequent resolution over the following scans, corroborated by volume loss and compensatory enlargement of the adjacent ventricle (arrows in D, G, J). MRI in February 2017 showed multiple enhancing foci, including one at the right CPA (arrow in B). GK radiotherapy was performed targeting the CPA mass in January 2019. The CPA mass showed continued contrast enlargement and central necrosis (arrows in E and H), and the patient developed LMD (arrowhead in H) in October 2019. The LMD and parenchymal infiltrative PXA tumor showed a partial response to treatment, as shown in (K). Findings from MRI October 2019 showed extracranial metastases in the spine (see supplemental eFigure 6A, B), cervical lymph nodes (not shown), and right parotid gland (arrows in I). MRI in May 2020 showed rapid growth of the metastatic lesion to the right parotid gland (arrows in I and L) despite partial initial response to treatment (arrows in F). The arrowhead in (L) indicates the tumor encasement of the cervical segment of the right internal carotid artery. MRI from October 2019 to May 2020 showed rapidly growing scalp metastases (arrowheads in G and J) (see supplemental eFigure 6C–G), with progressive neoplastic ulceration and superinfection (asterisk in G and J). The relentless extracranial tumor progression can be appreciated by comparing the images from April 2018 with the scans from October 2019 and May 2020 (F–L).

    Abbreviations: CPA, cerebellar pontine angle; GK, Gamma Knife; LMD, leptomeningeal carcinomatosis or disease; PXA, pleomorphic xanthoastrocytoma; T1W, T1 weighted.

  • View in gallery

    Case 3: Right parietal anaplastic PXA, WHO grade III. Images of the initial tumor are not included. Series of axial post-contrast T1 at different time points are presented. The patient had stable MRIs for 48 months until September 2019 (arrow in A). MRI on November 4, 2019, showed enlarging areas of enhancement along the medial wall of the surgical cavity, extending into the posteromedial aspect of the right frontal lobe (arrows in B). GTR was achieved on November 5, 2019, with diagnosis of aPXA (arrows in C). MRI in January 2020 showed small area of enhancing tumor at the left splenium (arrow in D). Twelve days after discontinuation of BRAF/MEK inhibitors, MRI on April 28, 2020, showed a burst of growth in the bilateral splenium, the ventricles, the septum pellucidum, and the periventricular white matter (arrows in E). Follow-up MRI on May 22, 2020, showed near-complete resolution of the areas of enhancement (arrows in F). In June 2020, MRI showed an increase of previous enhancement at the body of the corpus callosum and a new nodular enhancement in the precentral cortex (arrows in G). LITT was performed in July 2020, showing stable postablation changes (arrow in H). Follow-up MRI in October 2020 showed increase enhancement in the periventricular white matter, corpus callosum and septum pellucidum (arrows in I). MRI in December 2020 showed an increase enhancement at the corpus callosum and the ependymal linings of the bilateral lateral ventricles (arrows in J). Decrease in size and intensity of enhancement at the corpus callosum and bilateral lateral ventricles was noticed on follow-up scan in March 2021 (arrows in K), with stable radiologic changes seen on her last scan in July 2021 (arrows in L).

    Abbreviations: aPXA, anaplastic pleomorphic xanthoastrocytoma; GTR, gross total resection of enhancing mass; LITT, laser interstitial thermal therapy; T1W, T1 weighted; XRT, radiotherapy.

    aEncorafenib, binimetinib, nivolumab, ipilimumab.

  • View in gallery

    Case 4: Right temporal PXA, WHO grade II. Magnified coronal view T1 with contrast MRI except DWI MRI (J) and noncontrast CT head (H) are displayed. At the time of diagnosis in August 2019, a well-defined, centrally necrotic, avidly enhancing mass was seen centered at the medial aspect of the right temporal lobe (arrows in A). Residual versus recurrent disease within the right middle cranial fossa was observed on follow-up MRI in October 2019; areas of solid (arrows in B) and necrotic (arrowheads in B) residual tumor. In November 2019, MRI showed the first progression with enlargement of previous nodular enhancement at the right mesial temporal lobe (arrows in C). Vemurafenib + cobimetinib were started in December 2019 and then stopped in May 2020 by patient due to limited tolerance. MRI in February 2020 showed decreased size of the masses (arrow and arrowheads in D). MRI in May 2020 showed enlargement in the medial aspect of the right temporal lobe and ipsilateral supraclinoid region (arrow and arrowhead in E). MRI in October 2020 demonstrated significant enlargement of the lesion (arrow in F). Further increase in tumor size (arrows in G) and residual necrotic tumor (arrowhead in G), with extension to the cavernous sinus, was found on MRI in February 2021. CT without contrast on March 3, 2021, showed hyperdense signal consistent with hemorrhage in the right paraclinoid region (arrows in H). MRI on March 4, 2021, showed a new well-defined, centrally hemorrhagic lesion in the tumor area (arrowhead in I), enlargement of previous lesions (arrows in I), and ischemic changes at the right lateral and anterior aspect of the third ventricle (DWI MRI arrows in J).

    Abbreviations: DWI, diffusion-weighted imaging; PXA, pleomorphic xanthoastrocytoma; T1W, T1 weighted; XRT, radiotherapy.

  • View in gallery

    Case 5: Right occipital aPXA, WHO grade III with axial view post-contrast T1 images at different time points. At diagnosis in December 2019, a well-defined, heterogeneous centrally necrotic, avidly enhancing, and vascular mass is seen at the medial aspect of the right temporal lobe (arrows in A). Only STR was achieved due to its immediate proximity to eloquent area (arrows in B). Follow-up MRI in March 2020 showed reduction of right parietal occipital enhancement with resolved midline shift (arrows in C). MRI in June 2020 showed first progression with a solid enhancing mass at the right parieto-occipital lobe (arrows in D). MRI in July 2020 showed a decrease in size of the enhancing mass (arrows E). MRI in September 2020 showed a reduction of enhancing tumor (arrows F). A new tiny enhancing nodule located posteriorly to the surgical cavity was identified (arrowhead in F). MRI in November 2020 after GK XRT showed stable disease except mildly increased nodular enhancement along the lingual gyrus (arrowhead in G). Stable disease was observed in all subsequent MRIs, as shown in March 2021 and September 2021 (arrows and arrowhead in H, I).

    Abbreviations: aPXA, anaplastic pleomorphic xanthoastrocytoma; GK, Gamma Knife; STR, subtotal resection; T1W, T1 weighted; XRT, radiotherapy

  • 1.

    Truitt G, Gittleman H, Leece R, et al. Partnership for defining the impact of 12 selected rare CNS tumors: a report from the CBTRUS and the NCI-CONNECT. J Neurooncol 2019;144:5363.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Hussain F, Horbinski CM, Chmura SJ, et al. Response to BRAF/MEK inhibition after progression with BRAF inhibition in a patient with anaplastic pleomorphic xanthoastrocytoma. Neurologist 2018;23:163166.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Rodrigues A, Bhambhvani H, Medress ZA, et al. Differences in treatment patterns and overall survival between grade II and anaplastic pleomorphic xanthoastrocytomas. J Neurooncol 2021;153:321330.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Ida CM, Rodriguez FJ, Burger PC, et al. Pleomorphic xanthoastrocytoma: natural history and long-term follow-up. Brain Pathol 2015;25:575586.

  • 5.

    Hsiao SJ, Karajannis MA, Diolaiti D, et al. A novel, potentially targetable TMEM106B-BRAF fusion in pleomorphic xanthoastrocytoma. Cold Spring Harb Mol Case Stud 2017;3:a001396.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Phadnis SS, Chen L, Wang WL, et al. Disseminated anaplastic pleomorphic xanthoastrocytoma with posttreatment fat necrosis during combined BRAF and MEK inhibitors therapy. Pediatr Blood Cancer 2019;66:e27974.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Schreck KC, Guajardo A, Lin DDM, et al. Concurrent BRAF/MEK inhibitors in BRAF V600-mutant high-grade primary brain tumors. J Natl Compr Canc Netw 2018;16:343347.

  • 8.

    Schindler G, Capper D, Meyer J, et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 2011;121:397405.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Burger MC, Ronellenfitsch MW, Lorenz NI, et al. Dabrafenib in patients with recurrent, BRAF V600E mutated malignant glioma and leptomeningeal disease. Oncol Rep 2017;38:32913296.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med 2015;373:726736.

  • 11.

    Kaley T, Touat M, Subbiah V, et al. BRAF inhibition in BRAFV600-mutant gliomas: results from the VE-BASKET study. J Clin Oncol 2018;36:34773484.

  • 12.

    Johanns TM, Ferguson CJ, Grierson PM, et al. Rapid clinical and radiographic response with combined dabrafenib and trametinib in adults with BRAF-mutated high-grade glioma. J Natl Compr Canc Netw 2018;16:410.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Schreck KC, Grossman SA, Pratilas CA. BRAF mutations and the utility of RAF and MEK inhibitors in primary brain tumors. Cancers (Basel) 2019;11:1262.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Lee EQ, Ruland S, LeBoeuf NR, et al. Successful treatment of a progressive BRAF V600E-mutated anaplastic pleomorphic xanthoastrocytoma with vemurafenib monotherapy. J Clin Oncol 2016;34:e8789.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Leaver KE, Zhang N, Ziskin JL, et al. Response of metastatic glioma to vemurafenib. Neurooncol Pract 2016;3:268271.

  • 16.

    Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987996.

  • 17.

    Dono A, Vu J, Anapolsky M, et al. Additional genetic alterations in BRAF-mutant gliomas correlate with histologic diagnoses. J Neurooncol 2020;149:463472.

  • 18.

    Brown NF, Carter T, Kitchen N, et al. Dabrafenib and trametinib in BRAFV600E mutated glioma. CNS Oncol 2017;6:291296.

  • 19.

    Chamberlain MC. Salvage therapy with BRAF inhibitors for recurrent pleomorphic xanthoastrocytoma: a retrospective case series. J Neurooncol 2013;114:237240.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Usubalieva A, Pierson CR, Kavran CA, et al. Primary meningeal pleomorphic xanthoastrocytoma with anaplastic features: a report of 2 cases, one with BRAF(V600E) mutation and clinical response to the BRAF inhibitor dabrafenib. J Neuropathol Exp Neurol 2015;74:960969.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Hofer S, Berthod G, Riklin C, et al. BRAF V600E mutation: a treatable driver mutation in pleomorphic xanthoastrocytoma (PXA). Acta Oncol 2016;55:122123.

  • 22.

    Amayiri N, Swaidan M, Al-Hussaini M, et al. Sustained response to targeted therapy in a patient with disseminated anaplastic pleomorphic xanthoastrocytoma. J Pediatr Hematol Oncol 2018;40:478482.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Migliorini D, Aguiar D, Vargas MI, et al. BRAF/MEK double blockade in refractory anaplastic pleomorphic xanthoastrocytoma. Neurology 2017;88:12911293.

  • 24.

    Lukas RV, Merrell RT. BRAF inhibition with concomitant tumor treating fields for a multiply progressive pleomorphic xanthoastrocytoma. CNS Oncol 2018;7:CNS10.

  • 25.

    Finch EA, Elton SW, Huang BY, et al. Long-term efficacy of single-agent vemurafenib for pleomorphic xanthoastrocytoma. J Pediatr Hematol Oncol 2020;42:152155.

  • 26.

    Thomas AA, Tucker SM, Nelson CJ, et al. Anaplastic pleomorphic xanthoastrocytoma with leptomeningeal dissemination responsive to BRAF inhibition and bevacizumab. Pediatr Blood Cancer 2019;66:e27465.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Bernstein A, Mrowczynski OD, Greene A, et al. Dual BRAF/MEK therapy in BRAF V600E-mutated primary brain tumors: a case series showing dramatic clinical and radiographic responses and a reduction in cutaneous toxicity. J Neurosurg 2019;1:16.

    • Search Google Scholar
    • Export Citation
  • 28.

    Petruzzellis G, Valentini D, Del Bufalo F, et al. Vemurafenib treatment of pleomorphic xanthoastrocytoma in a child with Down syndrome. Front Oncol 2019;9:277.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29.

    Piña Y, Fusco MJ, Macaulay RJ, et al. Using personalized medicine in gliomas: a genomic approach to diagnosis and overcoming treatment resistance in a case with pleomorphic xanthoastrocytoma. J Neurol 2020;267:783790.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Kam KL, Snuderl M, Khan O, et al. Using methylation profiling to diagnose systemic metastases of pleomorphic xanthoastrocytoma. Neurooncol Adv 2020;2:vdz057.

  • 31.

    Forst DA, Nahed BV, Loeffler JS, et al. Low-grade gliomas. Oncologist 2014;19:403413.

  • 32.

    Subbiah V, Stein A, Van den Bent M, et al. ROR: dabrafenib plus trametinib in BRAF V600E–mutant high-grade and low-grade glioblastoma [abstract]. Presented at the AACR Annual Meeting 2021;April 10–15, 2021. Abstract CT025.

    • Search Google Scholar
    • Export Citation
  • 33.

    Salama AKS, Li S, Macrae ER, et al. Dabrafenib and trametinib in patients with tumors with BRAFV600E mutations: results of the NCI-MATCH Trial Subprotocol H. J Clin Oncol 2020;38:38953904.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
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