Response to BRAF/MEK Inhibition After Progression With BRAF Inhibition in a Patient With Anaplastic Pleomorphic Xanthoastrocytoma

Hussain, Faiz; Horbinski, Craig; Chmura, Steven J.; Yamini, Bakhtiar; Lukas, Rimas V.

doi:10.1097/nrl.0000000000000194

Cited by 12 publications

(11 citation statements)

References 16 publications

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“…BRAF V600E mutations can be found in 95% of all PCPs and case series report the successful exploitation of BRAF inhibitors in this entity [ 21 , 57 , 58 ]. In order to prevent early resistance to BRAF inhibition, the BRAF inhibitor dabrafenib can be combined with the MEK inhibitor trametinib according to protocols established for BRAF mutated melanoma [ 24 , 25 , 41 , 68 ]. In line with this our index patient was by far the best treatment outcome in the entire cohort.…”

Section: Discussionmentioning

confidence: 99%

“…To date, precision oncology predominantly focuses on molecular matching approaches using monotherapies to target one mutation with one drug, although many cancer entities are molecular heterogeneous diseases and the possibility of evasive resistance is a known phenomenon. Exceptions are the combination of BRAF and MEK inhibitors for BRAF mutated melanoma, PCPs and PXAs as also applied in our cohort [ 24 , 25 , 41 , 68 ]. In line with that, targeting a larger fraction of molecular alterations yields a higher 'matching score' and can correlate with significantly improved disease control rates, PFS and OS rates [ 71 ] .…”

Section: Discussionmentioning

confidence: 99%

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Molecular matched targeted therapies for primary brain tumors—a single center retrospective analysis

et al. 2022

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Purpose Molecular diagnostics including next generation gene sequencing are increasingly used to determine options for individualized therapies in brain tumor patients. We aimed to evaluate the decision-making process of molecular targeted therapies and analyze data on tolerability as well as signals for efficacy. Methods Via retrospective analysis, we identified primary brain tumor patients who were treated off-label with a targeted therapy at the University Hospital Frankfurt, Goethe University. We analyzed which types of molecular alterations were utilized to guide molecular off-label therapies and the diagnostic procedures for their assessment during the period from 2008 to 2021. Data on tolerability and outcomes were collected. Results 413 off-label therapies were identified with an increasing annual number for the interval after 2016. 37 interventions (9%) were targeted therapies based on molecular markers. Glioma and meningioma were the most frequent entities treated with molecular matched targeted therapies. Rare entities comprised e.g. medulloblastoma and papillary craniopharyngeoma. Molecular targeted approaches included checkpoint inhibitors, inhibitors of mTOR, FGFR, ALK, MET, ROS1, PIK3CA, CDK4/6, BRAF/MEK and PARP. Responses in the first follow-up MRI were partial response (13.5%), stable disease (29.7%) and progressive disease (46.0%). There were no new safety signals. Adverse events with fatal outcome (CTCAE grade 5) were not observed. Only, two patients discontinued treatment due to side effects. Median progression-free and overall survival were 9.1/18 months in patients with at least stable disease, and 1.8/3.6 months in those with progressive disease at the first follow-up MRI. Conclusion A broad range of actionable alterations was targeted with available molecular therapeutics. However, efficacy was largely observed in entities with paradigmatic oncogenic drivers, in particular with BRAF mutations. Further research on biomarker-informed molecular matched therapies is urgently necessary.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Molecular matched targeted therapies for primary brain tumors—a single center retrospective analysis

et al. 2022

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“…And, more recently, there are reports of BRAF MEKi. Similarly, few case reports have shown promising results after combination therapy with BRAF MEKi in PXA patients with BRAF mutations [12][13][14].…”

Section: Discussionmentioning

confidence: 99%

“…The median progression-free survival was 5.5 months in all the gliomas treated, and more than 39.1 months in a PXA case [11]. There are several case reports of combined BRAF MEKi in PXA patients [12][13][14]. As well as an enhanced response to BRAF inhibition when combined with autophagy inhibition in glioma cell lines [15].…”

Section: Introductionmentioning

confidence: 99%

Using personalized medicine in gliomas: a genomic approach to diagnosis and overcoming treatment resistance in a case with pleomorphic xanthoastrocytoma

et al. 2019

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Introduction A patient who was initially considered to have a glioblastoma (GBM) had molecular analysis, showing that it was a pleomorphic xanthoastrocytoma (PXA). Up to 78% of PXA tumors have BRAF V600E mutations. Primary brain tumors with BRAF mutations can have a good response to BRAF MEK inhibitors (BRAF MEKi), and there may be a synergistic response when combined with autophagy inhibitors. Presentation of the case A 20-year-old man found to have a large brain mass with midline shift underwent resection. He was diagnosed with "GBM" and treated with radiation and temozolomide with subsequent disease recurrence. Review of histology showed malignant PXA with BRAF V600E mutation. Treatment with Dabrafenib and Trametinib was started, and tumor size increased in size after 14 months of treatment. Given studies showing that resistance to BRAF inhibition can be overcome by autophagy inhibition, chloroquine was added. Patient has been on "triple" therapy for 15 months and has radiographically Stable Disease. At MCC, 3% of patients with gliomas have BRAF mutations who could potentially benefit from this combination therapy. Conclusion This is the first report of a PXA patient receiving therapy with BRAF MEKi and an autophagy inhibitor with prolonged stable disease. This patient highlights the importance of a molecular interrogation in gliomas to provide an integrated diagnosis and effective treatment. This may be useful in up to 3% of glioma patients with BRAF mutations. Molecular testing in neuro-oncology is providing new avenues of diagnosis and treatment, and detailed molecular interrogation should be considered routine.

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“…There have been a number of reports utilizing BRAF inhibitor monotherapy or BRAF+MEK inhibitors. Favorable responses have ranged from stable disease to complete responses [58][59][60][61][62][63][64]. In the largest published nonrandomized trial over 40% of patients with PXA treated with BRAF-inhibiting monotherapy exhibited radiographic response.…”

Section: Systemic Therapymentioning

confidence: 99%

Pleomorphic xanthoastrocytoma: a brief review

et al. 2019

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Pleomorphic xanthoastrocytoma (PXA) is a rare primary CNS tumor. Recent advances in the molecular characterization are helping to define subtypes of tumor. The discovery of BRAF mutations within a substantial percentage of PXA fosters a clearer understanding of the pathophysiology of these tumors with clear prognostic and therapeutic implications. These findings are expected to provide insight into the spectrum of clinical behavior observed in PXA, ranging from cure with surgery to diffuse dissemination throughout the neuraxis. This review details the clinical presentation including radiographic appearance of PXA. Pathology, including molecular pathology is discussed. Therapeutic management including surgical resection, radiotherapy and systemic therapies are reviewed.

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Response to BRAF/MEK Inhibition After Progression With BRAF Inhibition in a Patient With Anaplastic Pleomorphic Xanthoastrocytoma

Cited by 12 publications

References 16 publications

Molecular matched targeted therapies for primary brain tumors—a single center retrospective analysis

Molecular matched targeted therapies for primary brain tumors—a single center retrospective analysis

Using personalized medicine in gliomas: a genomic approach to diagnosis and overcoming treatment resistance in a case with pleomorphic xanthoastrocytoma

Pleomorphic xanthoastrocytoma: a brief review

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