
==== Front
J Neurosurg Case Lessons
J Neurosurg Case Lessons
J Neurosurg Case Lessons
Journal of Neurosurgery: Case Lessons
2694-1902
American Association of Neurological Surgeons

39250830
10.3171/CASE24387
CASE24387
OncologyOncologyStereotactic-RadiosurgeryStereotactic RadiosurgeryTechniqueTechniqueDiagnostic-TechniqueDiagnostic TechniqueCase Lesson
KEAP1-mutant atypical meningioma: illustrative case
Harary Paul M BS 1
Hori Yusuke S MD 1
Persad Amit R. L MD 1
Tayag Armine NP 1
Ustrzynski Louisa DNP, MBA 1
Emrich Sara C NP 1
Rahimy Elham MD 2
Park David J MD, PhD 1
Li Gordon MD 1
Chang Steven D MD, MBA 1
1 Departments of Neurosurgery, Stanford University School of Medicine, Stanford, California
2 Radiation Oncology, Stanford University School of Medicine, Stanford, California
Correspondence David J. Park: Stanford University School of Medicine, Stanford, CA. djpark@stanford.edu.
INCLUDE WHEN CITING Published September 9, 2024; DOI: 10.3171/CASE24387.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

09 9 2024
09 9 2024
8 11 CASE2438721 6 2024
19 7 2024
© 2024 the authors
2024
the authors
https://creativecommons.org/licenses/by-nc-nd/4.0/ CC BY-NC-ND 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

BACKGROUND

While genetic testing of tumors is commonly used to inform the selection of systemic therapies, there is limited evidence for the application of radiotherapy for brain cancer. Recent studies have shown that Kelch-like ECH-associated protein 1 (KEAP1), a key regulator of cellular responses to oxidative and electrophilic stress, is associated with radioresistance in multiple cancer types. Several studies have reported the clinical significance of KEAP1 mutation in brain metastasis; however, the effect of KEAP1 mutations on radioresponse in meningioma has never been reported.

OBSERVATIONS

The authors present the case of a 40-year-old female with a KEAP1 mutation–positive atypical meningioma that was initially treated with resection followed by intensity-modulated radiation therapy (IMRT). Recurrence was observed at 15 months, requiring reoperation and adjuvant stereotactic radiosurgery (SRS). An excellent treatment response was observed at 7 months post-SRS with an improvement in reported symptoms, although bevacizumab was required for the resolution of radiation necrosis observed 2 months post-SRS.

LESSONS

To the authors’ knowledge, this is the first report of KEAP1-mutant meningioma, including its clinical course after comprehensive management. Notably, treatment included multimodal radiotherapy with IMRT followed by SRS. SRS led to an excellent treatment response at the 7-month follow-up. However, radiation necrosis developed after both radiotherapy treatments, suggesting that radiological modification can be beneficial in patients with KEAP1 mutations.

https://thejns.org/doi/10.3171/CASE24387

meningioma
KEAP1
radioresistance
stereotactic radiosurgery
ABBREVIATIONS

CT = computed tomography
IMRT = intensity-modulated radiation therapy
KEAP1 = Kelch-like ECH-associated protein 1
MRI = magnetic resonance imaging
NRF2 = nuclear factor erythroid-derived 2-like 2
RIM = radiation-induced meningioma
ROS = reactive oxygen species
SRS = stereotactic radiosurgery
VP = ventriculoperitoneal
WHO = World Health Organization.
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pmcIndividual response to radiotherapy is known to vary significantly based on the genetic and molecular profile of a given tumor.1–4 Recently, several genes, including PIK3CA, KRAS, and MET, have been shown to be associated with local recurrence following radiotherapy across multiple types of cancers.5–8 In addition, a rank-based radiosensitivity index has been established based on the correlation of 10 radiosensitivity genes with a survival fraction across 48 cancer cell lines.9 Notably, this index has been successfully applied to available datasets for glioblastoma,10 pancreatic cancer,11 and breast cancer.12 However, while genomically guided radiotherapy remains an area of significant interest,13 further evidence may be required before it is integrated into standard clinical practice.

Recent studies have revealed that Kelch-like ECH-associated protein 1 (KEAP1), along with its target, nuclear factor erythroid-derived 2-like 2 (NRF2), is commonly mutated in cancer.14–18 The KEAP1-NRF2 pathway is a primary mediator of cellular responses to oxidative and electrophilic stress, with KEAP1 acting as a negative regulator of the transcription factor NRF2. Therefore, loss-of-function mutations in KEAP1 lead to a pathogenic buildup of NRF2 and overactivation of antioxidant response genes.19 Mutations in KEAP1 have been shown to be associated with radioresistance in multiple cancer types.8, 20, 21 Of note, a recent investigation of KEAP1 variants in 232 patients with non–small cell lung cancer found that pathogenic mutations were significantly associated with radioresistance. Furthermore, the authors demonstrated glutaminase inhibition to be an effective strategy for radiosensitization of KEAP1-mutant cells. Overall, this suggests that KEAP1 status may be valuable in facilitating personalized radiotherapy treatment.

To our knowledge, the effect of KEAP1 status on stereotactic radiosurgery (SRS) outcomes has not yet been investigated in the management of meningioma. Herein, we describe the first case of a patient with KEAP1 mutation–positive atypical meningioma treated with comprehensive management, including resection followed by multimodal radiotherapy.

Illustrative Case

Presentation

A 40-year-old female presented with a complex medical history of childhood medulloblastoma and atypical meningioma, World Health Organization (WHO) grade II. When she was 2 years old, her posterior fossa medulloblastoma was treated with resection followed by craniospinal irradiation and chemotherapy. Her course was complicated by tumor recurrence as well as postsurgical hydrocephalus, which required the placement of a ventriculoperitoneal (VP) shunt. At age 35 years, multiple VP shunt revisions were performed. Notably, at this time, computed tomography (CT) imaging performed at an outside institution did not demonstrate any abnormalities besides hydrocephalus. She had cognitive disability at baseline (third grade reading level) due to prior treatments, although there was no evidence of residual medulloblastoma.

At 2 years prior to the current presentation, the patient developed confusion, headache, and gait instability. Head CT revealed a large left paramedian supratentorial mass measuring 8.7 × 5.1 × 6.4 cm (Fig. 1A). Subsequent T1-weighted contrast-enhanced magnetic resonance imaging (MRI) confirmed the presence of a heterogeneously enhancing and hemorrhagic tumor (Fig. 1B). She underwent surgical craniotomy with subtotal resection at an outside hospital. Postoperative scans showed a partially resected mass in the middle to inferior aspect (Fig. 1C– E). Pathology was consistent with atypical meningioma, WHO grade II. Adjuvant intensity-modulated radiation therapy (IMRT) was completed by 4 months after the resection (54 Gy in 30 fractions to the cavity and residual tumor with margin). Follow-up MRI performed at 12 months post-IMRT showed a residual mass measuring 6.9 × 3.9 × 4.5 cm (as compared to 7.5 × 4.3 × 5.3 cm prior to treatment), with findings suggestive of radiation necrosis. Notably, there were additional, smaller meningiomas along the neuroaxis, which were slow growing and demonstrated behavior consistent with WHO grade I tumors. FIG. 1. Images obtained 2 years prior to the current presentation. Axial CT (A) showing a large left paramedian supratentorial mass measuring 8.7 × 5.1 × 6.4 cm. Postcontrast T1-weighted MRI (B) demonstrating a heterogeneously enhancing and hemorrhagic tumor. Postoperative axial (C), coronal (D), and sagittal (E) MRI showing partial resection of a mass in the middle to inferior aspect.

The patient presented to our hospital 1 year 3 months after the completion of IMRT at an outside hospital. She had developed headaches, increased urinary frequency, and lethargy and could not follow commands to conduct a full neurological examination during the emergency department visit. A 2-minute seizure was observed, followed by 2 additional seizures. The head CT workup revealed peritumoral and intraventricular hemorrhage (Fig. 2A). Brain MRI showed heterogeneous enhancing nodularity both posteriorly and anteriorly within the prior IMRT field. The posterior growth appeared to be solid tumor with elevated perfusion, whereas the anterior mass was consistent with radiation necrosis and extended into the motor cortex. In addition, a T1-intense region, representing hemorrhage, was found. Furthermore, an 11-mm rightward midline shift was observed (Fig. 2B). A left parietal reoperation craniotomy for resection of the posteriorly located tumor mass was then performed, with the resulting pathology consistent with atypical meningioma, WHO grade II. Therefore, this indicated local recurrence within the prior IMRT field. Given the proximity to the motor cortex and findings of radiation necrosis, the anterior lesion was not resected. Importantly, Stanford Actionable Mutation Panel (STAMP) testing of the resected meningioma revealed a premature stop codon mutation in KEAP1 (Q359*), indicating likely loss of function. This loss of KEAP1 function may predicate nuclear accumulation of NRF2 and increased transcription of genes mediating xenobiotic metabolism, drug efflux, and oxidative damage response.20, 22, 23 In addition, a variance of unknown significance in neurofibromatosis type 2 was found. Postoperative MRI showed gross-total resection of the posterior mass, with an expected residual area of enhancement along the left corpus callosum/cingulate of previously identified radiation necrosis (Fig. 3A–C). Following surgery, she had physical therapy and speech therapy and was discharged to a rehabilitation facility. In addition, her dose of levetiracetam was increased from 1000 mg twice daily to 1750 mg twice daily. FIG. 2. Axial CT at 1 year 3 months post-IMRT showing peritumoral and intraventricular hemorrhage (A). Axial postcontrast T1-weighted MRI (B) showing heterogeneously enhancing nodularity both anteriorly (dashed arrow) and posteriorly (solid arrow). The posterior T1-intense region represents hemorrhage.

FIG. 3. Postoperative axial (A), coronal (B), and sagittal (C) MRI showing that the majority of the tumor was resected except for a residual lesion along the left corpus callosum/cingulate (dashed arrows). Axial (D), coronal (E), and sagittal (F) MRI at the 3-month follow-up showing regrowth of the enhancement in the previously resected posterior region (solid arrows), suggesting recurrence, while the anterior lesion remained stable (dashed arrow).

Three-month follow-up MRI revealed a rapid regrowth of enhancement in the previously resected posterior region (Fig. 3D– F), suggesting rapid local recurrence, while the anterior lesion remained consistent with radiation necrosis. While right homonymous hemianopia was suspected at this time, visual field testing was difficult because of her baseline impaired comprehension. She was noted to have right-sided weakness (manual muscle testing 3/5). The patient then underwent CyberKnife SRS (Accuray Inc.) to the posterior locally recurrent lesion 4 months after her most recent resection (Fig. 4). A total of 30 Gy was prescribed to the 69% isodose line in 5 fractions. At 2 months post-SRS, MRI showed a slight increase in the size of the posterior nodular enhancing component (Fig. 5A– C) and worsening T2/fluid-attenuated inversion recovery vasogenic edema with decreased overall perfusion in both the anterior and posterior regions, suggesting increased posttreatment radiation necrosis. In addition, the patient developed worsening cognition and gait instability. The treatment team then decided that bevacizumab might provide the most benefit with regard to neurological functional stability. She completed 5 cycles of bevacizumab by 5 months post-SRS. The 7-month post-SRS MRI showed a significant decrease in the size of both the anterior and the posterior residual enhancements following bevacizumab treatment (Fig. 5D– F) as well as decreased edema. The patient’s overall clinical condition and symptoms were notably improved, including significant increases in balance, supported by physical therapy, and cognition. FIG. 4. CyberKnife radiosurgery plan: axial (A), coronal (B), and sagittal (C) MRI. The contoured target volume (red line) received a dose of 30 Gy prescribed to the 69% isodose line (green line) in 5 fractions.

FIG. 5. Axial (A), coronal (B), and sagittal (C) MRI at 2 months post-SRS, indicating a slight increase in the size of the posterior nodular enhancing component (solid arrows). Internal necrotic areas suggest radiation necrosis. The anterior necrotic region remained stable in size (dashed arrow). Axial (D), coronal (E), and sagittal (F) MRI at 7 months post-SRS showing a significant decrease in the size of both anterior and posterior enhancements.

Patient Informed Consent

The necessary patient informed consent was obtained in this study.

Discussion

Observations

Herein, we present the first reported case of KEAP1 loss of function in atypical meningioma. KEAP1-NRF2 pathway mutations have been a growing focus of research in oncology, particularly in lung,8, 24 pancreatic,25 esophageal,16 and head and neck26 cancers. For example, a study of 232 patients with non–small cell lung cancer found that mutations in KEAP1 and NRF2 were predictive of local recurrence following radiotherapy.24 Furthermore, authors of that study demonstrated radiosensitization of KEAP1-mutant cells via glutaminase inhibition in a cell line knockout model, thereby enhancing radiation-induced DNA damage. By comparison, research on this pathway in central nervous system malignancies is much more limited. While there have been clinical reports of KEAP1-NRF2 mutational profiling in glioma,27, 28 many studies were conducted exclusively using in vitro glioma models.29, 30 Overall, however, there is increasingly strong evidence of the role of KEAP1-NRF2 in clinical radioresistance, suggesting that it may have predictive value across multiple cancer types. In addition, this pathway may represent a therapeutic target for increasing the effectiveness of radiotherapy.

The KEAP1 mutation found in our patient’s meningioma has a very high likelihood of pathogenicity given that it results in a premature stop codon, leading to a truncated protein. KEAP1 loss leads to overexpression of NRF2 target genes, resulting in increased scavenging of free radicals. This decreases radiation-induced DNA damage, potentially conferring tumor cells with radioresistance. For example, patients with stage II or III lung cancer positive for KEAP1-NRF2 mutations have been shown to be likely to relapse following radiotherapy.8 Notably, KEAP1-NRF2 regulation of reactive oxygen species (ROS) has also been implicated in chemoresistance, given that some chemotherapy drugs act through the reduction of ROS.31 Therefore, mutations in this pathway have also been associated with chemoresistance. Collectively, this suggests that optimal treatment for patients with pathogenic KEAP1-NRF2 pathway mutations may include surgical debulking prior to chemoradiation to maximize the probability of eliminating resistant clones.

Given the mechanistic evidence associating KEAP1-NRF2 pathway mutations with treatment resistance, it stands to reason that the loss of function of KEAP1 may increase the risk of recurrence beyond atypical histological features alone. However, mutations in the KEAP1-NRF2 pathway have been shown to correlate with atypical meningioma. A study of NRF2 expression in gliomas and meningiomas reported that NRF2 scores were significantly higher in grade II versus grade I meningiomas.28 Interestingly, the authors also found an increased NRF2 score in grade I meningioma relative to nonneoplastic brain. However, a limitation of this study is its small sample size of 12 atypical meningiomas for comparison with grade I. In addition, a recent study explored mutations in another component of the KEAP1-NRF2 pathway, AURKA, specifically in the context of meningioma.32 Preclinical models, including cell lines and a murine model of meningioma, were used to elucidate the importance of this pathway in malignant meningioma phenotypes. Moreover, the application of an AURKA inhibitor resulted in enhanced tumor cell death through ferroptosis. Further study is warranted to better understand the individual contribution of KEAP1 loss of function to radiation response in brain malignancies across different histological classifications.

Intracranial hemorrhage in meningioma is a rare event, making the post-IMRT tumoral bleeding in our patient especially notable. For example, the reported incidence of hemorrhage in meningioma is approximately 0.5%–2.4%.33, 34 Importantly, a study of 173 patients with meningioma treated with Gamma Knife radiosurgery found that SRS treatment did not result in an elevated rate of posttreatment hemorrhage, suggesting that radiosurgery may not be a risk factor.35 This finding may be consistent with the course of our patient, wherein IMRT but not SRS was associated with hemorrhage. However, there are likely other factors associated with hemorrhage, which can occur spontaneously or postprocedurally, limiting the conclusions that can be drawn in this case.

Our patient’s past medical history of craniospinal radiation for pediatric medulloblastoma, with the development of numerous meningiomas throughout the craniospinal neuroaxis in her adulthood, suggests that her meningioma is radiation induced. Meningioma has been observed to be one of the most common radiation-induced tumors, particularly in children.36 In addition, radiation-induced meningioma (RIM) can be detected several decades following radiotherapy,37 as was seen in our patient, and have a more aggressive presentation.38 Notably, genomic profiling of RIM revealed chromosome 19 to be a common site of genetic mutation.39 Given that KEAP1 is located on the short arm of chromosome 19,40 this is consistent with our patient’s meningioma as radiation induced. In addition, RIM has been reported to have a higher rate of recurrence than spontaneous meningioma.41 Further study may reveal the molecular mechanism underlying this increased recurrence rate.

Notably, our follow-up for evaluation of the response to SRS has been limited to only 7 months thus far, though with a strong response. The median time to progression following SRS treatment of grade II and III meningioma has recently been reported as 30 months, suggesting that longer follow-up is needed in our case.42 In addition, a median marginal dose of 25 Gy was used for patients who received 5 fractions at the time of the first recurrence of WHO grade II/III meningioma compared to 30 Gy in our patient.42 While most evidence to date on the use of SRS for meningioma has focused on its application as an upfront treatment, a phase I/II clinical trial is currently underway investigating the recurrent setting.43 Specifically, this trial will evaluate reirradiation with SRS, with or without ipilimumab, for the management of recurrent grade II/III meningioma. Importantly, the use of SRS in a recurrent setting may be particularly relevant to approaches to radioresistant malignancies, given the increased likelihood of requiring retreatment. A 7-month follow-up scan for our patient demonstrated an excellent SRS treatment response, although worsening radiation necrosis required the use of bevacizumab. Compared to the poor local response following IMRT, this may suggest that SRS is better suited for treating KEAP1 mutation–positive meningioma in certain clinical scenarios. In addition, growing evidence suggests that IMRT requires dose escalation to as high as 60 Gy or greater for adequate local control of grade II meningioma.44 This finding may be particularly relevant to subtotally resected lesions, as in our case. However, our patient’s prior history of craniospinal radiation and associated neurocognitive effects may have contributed to the decision to avoid dose escalation with IMRT at an outside hospital, instead continuing with 54 Gy in 30 fractions. SRS for recurrent tumors may allow for safer dose escalation in such clinical contexts.

A 5-fraction plan was chosen based on our institution’s experience in treating recurrent brain tumors after prior radiation. In addition, such an approach in this setting has been reported in the scientific literature, with results supporting the use of a 30-Gy dose and 5-fraction plan for the treatment of resistant disease.45 Furthermore, our patient required a large treatment volume for coverage of the resection cavity, which is well-suited to multifraction treatment. This may also mitigate the risk of radiation necrosis, which was elevated due to prior radiation treatment.

An important limitation of our report is the inclusion of only 1 patient. We believe the observations in this case add to the literature and may be hypothesis generating, particularly given the clinical evidence associating the KEAP1 mutation with radioresistance in other tumor types. However, larger studies are warranted to obtain a more complete understanding of the contribution of mutations in this pathway to treatment outcomes.

Lessons

Given the growing evidence of the KEAP1-NRF2 pathway in chemoradiation resistance, genomic profiling of tumors for relevant mutations may reveal predictive biomarkers of radioresponse and enhance patient stratification. This may be a particularly important consideration in cases of RIM or atypical central nervous system malignancies. The KEAP1 loss of function status of our patient’s meningioma is consistent with the poor response to IMRT, whereas SRS still demonstrated efficacy in the management of the KEAP1-mutated tumor. This suggests that KEAP1 profiling can be used to inform treatment decisions. In addition, pathway-directed therapy for KEAP1-NRF2 mutations may represent a means to augment radioresponse. This includes small molecule inhibitors of components of this pathway as well as glutaminase inhibitors. Further study of the biological mechanisms of meningioma radioresponse may support precision radiotherapy.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Park, Harary, Hori. Acquisition of data: Harary, Hori, Tayag, Emrich, Rahimy, Li. Analysis and interpretation of data: Harary, Hori, Persad, Chang. Drafting the article: Harary, Hori, Persad, Tayag, Chang. Critically revising the article: Park, Harary, Hori, Persad, Tayag, Rahimy, Li, Chang. Reviewed submitted version of manuscript: Park, Harary, Hori, Persad, Tayag, Ustrzynski, Li, Chang. Approved the final version of the manuscript on behalf of all authors: Park. Administrative/technical/material support: Park. Study supervision: Park, Hori, Li, Chang.

Correspondence

David J. Park: Stanford University School of Medicine, Stanford, CA. djpark@stanford.edu.
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