Anaplastic Pleomorphic Xanthoastrocytoma Research Articles

5-ALA fluorescence-guided resection of a recurrent anaplastic pleomorphic xanthoastrocytoma: illustrative case.

BACKGROUND5-aminolevulinic acid (5-ALA)–induced fluorescence of neoplastic tissue is known to occur in a number of high-grade gliomas. This fluorescence helps surgeons maximize safe resection by distinguishing previously indiscernible neoplastic tissue from brain parenchyma. Still, the effectiveness of 5-ALA has not been fully explored for all central nervous system tumors. Consequently, the full spectrum of tumors that would benefit from fluorescence-guided surgery using 5-ALA is unknown.OBSERVATIONSThis report describes successfully utilizing 5-ALA to achieve complete resection of a recurrent anaplastic pleomorphic xanthoastrocytoma (APXA).LESSONSAPXA tumor cells accumulate sufficient amounts of 5-ALA and its fluorescent metabolite to produce visible intraoperative fluorescence. However, further investigation is needed to determine if 5-ALA fluorescent labeling routinely occurs in patients with APXAs.

A clinicopathologic study of malignancy in VCP-associated multisystem proteinopathy

BackgroundValosin containing protein (VCP) is an important protein with many vital functions mostly related to the ubiquitin–proteasome system that provides protein quality control. VCP-associated inclusion body myopathy with Paget disease of bone and frontotemporal dementia, also termed VCP disease and multisystem proteinopathy (MSP 1), is an autosomal dominant disorder caused by monoallelic variants in the VCP gene on human chromosome 9. VCP has also been strongly involved in cancer, with over-activity of VCP found in several cancers such as prostate, pancreatic, endometrial, esophageal cancers and osteosarcoma. Since MSP1 is caused by gain of function variants in the VCP gene, we hypothesized our patients would show increased risk for developing malignancies. We describe cases of 3 rare malignancies and 4 common cancers from a retrospective dataset.ResultsUpon surveying 106 families with confirmed VCP variants, we found a higher rate of rare tumors including malignant peripheral nerve sheath tumor, anaplastic pleomorphic xanthoastrocytoma and thymoma. Some of these subjects developed cancer before displaying other classic VCP disease manifestations. We also present cases of common cancers; however, we did not find an increased rate compared to the general population. This could be related to the early mortality associated with this disease, since most patients die in their 50–60 s due to respiratory failure or cardiomyopathy which is earlier than the age at which most cancers appear.ConclusionThis is the first study that expands the phenotype of VCP disease to potentially include rare cancers and highlights the importance of further investigation of the role of VCP in cancer development. The results of this study in VCP disease patients suggest that patients may be at an increased risk for rare tumors. A larger study will determine if patients with VCP disease develop cancer at a higher rate than the general population. If that is the case, they should be followed up more frequently and screened for recurrence and metastasis of their cancer.

Anaplastic Pleomorphic Xanthoastrocytoma versus Pleomorphic Xanthoastrocytoma

Pleomorphic xanthoastrocytoma (PXA), WHO grade II, is a rare entity accounting for <1% of all astrocytic tumors. It affects children and young adults and is commonly found in the temporal lobe. Anaplastic PXA (APXA) has a similar location and clinical manifestation as that of PXA but has a significantly worse prognosis than the latter. WHO 2016 defined PXA as having >5/10 HPF mitosis and with or without necrosis as APXA (grade III). Herein, we present two such cases with unusual locations and ages: (1) APXA inside lateral ventricle, in a 10-year-old female child and (2) PXA in a 39-year adult male. Histologically, both cases revealed a tumor comprised a highly pleomorphic heterogeneous population of cells, eosinophilic granular bodies, and psammoma bodies, however, necrosis and increased mitosis (>5/10 HPF) were appreciated only in the first case. Immunohistochemistry is supported by strongly positive glial fibrillary acidic protein, vimentin, and synaptophysin. This study analyzed all the characteristics of both these entities with their unusual presentations to prevent future misdiagnoses.

Summary of virtual tumor board platforms and implementation in neuro-oncology.

e13604 Background: Virtual tumor board [VTB] platforms are an important aspect of cancer management. They enable easier access to a multidisciplinary team of experts. VTBs are an emerging resource across various cancer care networks in the United States. Methods: We performed a systematic search of all VTBs incorporating a platform designed for this specific role. We reviewed Xcures, Genomet, Oncolens, Navify Tumor Board, Medical University of South Carolina [MUSC] Virtual Tumor Board, Virtual Tumor Board Tahoe Forest Cancer Center, UC Davis Health Care Center VTB and MassiveBio. Summary data examined include year of launch, demographics, characteristics of cases, average response time, advantages, and how they handle protected health information. Results: 30% of all VTBs examined launched in 2017. All had a HIPAA compliant online environment. Xcures records were reviewed where the median age of female patients was 57yrs and the median age of male patients was 55 years. The data showed that 44% (4.4 out of every 10 patients) with a confirmed treatment chose VTB integrated option. 76% of patients in Xcures registry consist primary CNS tumors. With at least 556 patients in tumor registry which included 46% Glioblastoma cases [96% primary;, 4% secondary], 13% Diffuse midline glioma with H3K27M-mutant cases, 5% Diffuse intrinsic pontine glioma cases, 3% Astrocytoma and Diffuse Astrocytoma cases, 3% Anaplastic astrocytoma cases; Glioma and Diffuse Glioma, 1% Anaplastic Oligodendroglioma cases and < 1% Gliosarcoma, Oligodendroglioma, Pilocytic astrocytoma, Anaplastic pleomorphic Xanthoastrocytoma, Fibrillary astrocytoma, Oligoastrocytoma and Pleomorphic Xanthoastrocytoma cases. In the MUSC VTB, 9 neuro-oncology cases were reviewed. They meet weekly, and average response time was within 24hrs of case review.Patient demographics were not recorded. Genomet Virtual Board de-identifies all patient information; this is a virtual platform primarily focused on neuro-oncology cases. Cases involved a median of 5 specialist most commonly neuro-oncologists, neurosurgeons, radiation oncologists, molecular pathologists and neuroradiologists. Participants had an average of 23 cases reviewed. Case review revealed an age range from 6 months to 84 years [mean age 44.5 years] with 69.6% males and 30.4% females, 43.5% glioblastoma, 8.7% adenocarcinoma, 8.7% infra-tentorial tumor, < 5% each: pineoblastoma, melanoma, hemangioblastoma and pilocytic astrocytoma. Average response time observed in all cases was ≤24 hours. Detailed metrics for number/percentages of brain tumor cases were not available for most other platforms at time of submission. This will be updated at presentation. Conclusions: VTBs have allowed for quicker expert analysis of cases. This has resulted in an accelerated number of cases reviewed with a shortened communication time. More studies are needed to gain additional insight into user engagement

Anaplastic Pleomorphic Xanthoastrocytoma with Extracranial Bone Metastasis: A Case Report and Literature Review (P15-9.004)

Anaplastic Pleomorphic Xanthoastrocytoma with Extracranial Bone Metastasis: A Case Report and Literature Review (P15-9.004)

Anaplastic pleomorphic xanthoastrocytoma - single-center analysis of 42 patients

To study neuroimaging, morphological features of tumors, as well as factors affecting treatment and prognosis. A retrospective study enrolled 42 patients operated on at the Burdenko Neurosurgery Center between 2003 and 2020. MR characteristics of anaplastic pleomorphic xanthoastrocytoma were analyzed. All patients underwent resection of tumor (total resection in 83.3% of cases). Redo surgeries were performed in 1/3 of patients. Mutational status of BRAF V600E was assessed in all patients. Adjuvant radio- and chemotherapy was performed in more than 80% of cases. Tyrosine kinase inhibitors were administered in 19% of cases. The follow-up period was 152 months (median 34 months). We found no pathognomonic MR signs of this disease. Indeed, anaplastic pleomorphic xanthoastrocytoma have the same signal characteristics as other malignant gliomas. The BRAF V600E mutation status was positive in 54.8% of cases. None patient had IDH-1 mutation. Mean Ki-67 index was 12.5%. The overall survival was 79 months (range 4-152). Seven (17%) patients are alive for more than 90 months. Only Ki-67 index and BRAF mutation significantly influenced the treatment prognosis and overall survival regardless the use of tyrosine kinase inhibitors. Such well-known factors for malignant glioma as patient age, total resection and adjuvant therapy did not significantly affect overall survival. Perhaps, searching for new molecular genetic features will reveal additional significant factors of prognosis in patients with anaplastic pleomorphic xanthoastrocytoma.

Clinical-pathological study of 28 glial and mixed neuronal-glial tumors diagnosed within the first year of life.

Our purpose was to investigate the incidence of gliomas and neuronal-glial tumors, their outcome, and H3.3K27M, BRAFV600E, and IDH status in children within 1 year of age affected by CNS tumor. We collected 28 consecutive gliomas and mixed tumors. Immunohistochemistry and/or molecular analyses were performed on formalin-fixed/paraffin-embedded specimens. 24 (86%) tumors were supratentorial. 15 (54%) tumors were astrocytomas (5 glioblastomas, 1 anaplastic astrocytoma, 1 pilocytic astrocytoma, 3 pilomixoid astrocytomas, 2 subependymal giant cell astrocytomas, 3 astrocytomas not otherwise specified (NOS)), 4 (14%) were anaplastic ependymomas, and 9 (32%) were mixed tumors (5 gangliogliomas, 2 gangliocytomas, 2 desmoplastic infantile gangliogliomas (DIGs)). Alive patients were: 4 (67%) affected by high-grade astrocytoma (mean follow-up 64 months), 4 (67%) affected by low-grade astrocytoma (mean follow-up 83 months), 2 (67%) affected by astrocytoma NOS (mean follow-up 60 months), 1 (25%) affected by anaplastic ependymoma (follow-up 12 months), and 9 (100%) affected by mixed tumors (mean follow-up 74 months). H3.3K27M and IDH were not-mutated in any tumor (100%). BRAFV600E mutation was documented in 6 (21%) tumors (4 gangliogliomas, 1 gangliocytoma, and 1 astrocytoma NOS resulted as anaplastic pleomorphic xanthoastrocytoma 8 years later). Gliomas and mixed tumors diagnosed within 1 year of age are morphologically heterogeneous. Moreover, analogously to those affecting older children, they are IDH1-2 and H3.3K27M (when located outside midline) not-mutated while BRAFV600E mutation is typical of gangliogliomas/gangliocytomas and pleomorphic xanthoastrocytomas. High-grade astrocytomas have a more favorable prognosis compared with the same lesions occurring later in life while ependymomas have a poorer outcome.

Anaplastic pleomorphic xanthoastrocytoma with epithelioid morphology misdiagnosed and treated as melanoma.

Anaplastic pleomorphic xanthoastrocytoma with epithelioid morphology misdiagnosed and treated as melanoma.

Central Nervous System Tumors in Children.

Central Nervous System Tumors in Children.

CSIG-04. UNCOUPLING OF ETS1 FROM MAPK PATHWAY SIGNALS AS RESISTANCE MECHANISM TOWARDS BRAF INHIBITORS IN BRAF-MUTATED CHILDHOOD GLIOMA

Abstract BACKGROUND High-grade gliomas are among the most aggressive brain tumors across all age groups. BRAF is within the most frequently altered genes in pediatric glioma, sometimes connected with telomerase reverse transcriptase (TERT) promoter mutations, predicting a particularly aggressive course of disease. Precision medicine approaches targeting the MAPK pathway have shown promising results in patients with BRAF-mutated glioma. Although acquired insensitivity to BRAF inhibitors appears as major issue for therapy failure, underlying molecular mechanisms are still poorly understood. METHODS Cell models from an anaplastic pleomorphic xanthoastrocytoma with BRAF V600E and TERT promoter mutations and the recurrent tumor, operated following MAPK pathway-targeting therapy, were established. Furthermore, a dabrafenib-resistant subline of the recurrent tumor was generated. The patient-derived cell models were genetically characterized using array-based genomic hybridization (aCGH). Sensitivity of the cells towards different MAPK pathway inhibitors was tested. Basal expression and activation of MAPK pathway and downstream signals were analyzed by qRT-PCR and Western blots. RESULTS Screening a panel of both primary and immortalized glioma cell models with different BRAF and TERT promoter status revealed significantly induced MAPK pathway activation and enhanced TERT levels in BRAF V600E and TERT promoter double-mutant gliomas. Furthermore, cells with both mutations were hyper-sensitive towards BRAF-targeting agents and BRAF inhibition resulted in reduced TERT levels. ETS1 expression was strongly increased in the recurrent tumor and identified as important player in telomerase re-activation. aCGH revealed gains of chromosomal regions encoding for different ETS-factors in the dabrafenib-resistant subline. Western blot analyses suggested a BRAF/ERK-independent survival mechanism in the dabrafenib-resistant subline. Accordingly, dabrafenib insensitivity triggered cross-resistance towards the MEK inhibitor trametinib. Uncoupled from the MAPK pathway, ETS1 expression was further upregulated in the dabrafenib-resistant subline. CONSLUSION: Taken together, our data demonstrate that MAPK-independent ETS transcription factor upregulation is a central mechanism of BRAF inhibitor therapy failure in BRAF-mutated pediatric glioma patients.

INNV-06. BRAF AND MEK DUAL INHIBITORS THERAPY IN RECURRENT OR ANAPLASTIC PLEOMORPHIC XANTHOASTROCYTOMA (PXA)

Abstract BACKGROUND AND OBJECTIVE Recurrent and anaplastic pleomorphic xanthoastrocytoma (PXA) tumors are challenging to treat due to their rarity and lack of management consensus. About 80% of PXAs harbor BRAF gene mutation. Although the development of BRAF inhibitors has dramatically improved the outcomes for patients with BRAF V600E mutant tumors, resistance develops in the majority of cases. We hypothesize that dual BRAF/MEK inhibitors therapy can improve tumor control and patient survival without added toxicity. METHODS Medical records from 2010 to 2021 in Memorial Hermann Texas Medical Center were reviewed. Patients diagnosed with PXA who received BRAF and/or MEK inhibitors therapies were identified. The data evaluated included age, sex, treatment received, side effects, and outcomes, as well as results from blood tests, pathology, next generation sequencing and MRI. Side effects were evaluated according to the CTCAE Version 5.0. RESULTS Five patients with recurrent or anaplastic PXA were identified. The median age at diagnosis was 22 years old (range 14-66 years old), with 60% male, and 60% grade III. All patients received BRAF/MEK dual inhibitors therapy at various stages of PXA treatment. The median follow-up was 72 months (range 17-108 months). One patient (66 years old) experienced short-term disease stability for 5 months and who died from tumor related brain hemorrhage while off therapy for 9 months. Four patients experienced long-term disease control (17, 22, 94, 108 months, respectively) while three of them remain on dual therapy and one patient died from systemic PXA progression. Dual BRAF/MEK inhibitors were well tolerated with only grade 1-2 adverse effects (AE) including skin rash, fatigue, mild abdominal discomfort, diarrhea. No grade III-V AE were detected. CONCLUSION BRAF/MEK dual inhibitor can provide potential clinical benefit to PXA patients with BRAF mutations. Our study supports the concurrent use of BRAF/MEK inhibitors for best tumor control without unexpected AE.

Identification of BRAF p. V600E-Mutant and Wild-Type by MR Imaging in Pleomorphic Xanthoastrocytoma and Anaplastic Pleomorphic Xanthoastrocytoma.

Compared with BRAF p. V600E wild-type pleomorphic xanthoastrocytoma, BRAF p. V600E-mutant pleomorphic xanthoastrocytoma showed a higher survival rate. In this study, we focused on finding preoperative MR imaging differences between BRAF p. V600E mutant and wild-type in pleomorphic xanthoastrocytoma and anaplastic pleomorphic xanthoastrocytoma. Twenty-three patients with pathologically confirmed pleomorphic xanthoastrocytoma or anaplastic pleomorphic xanthoastrocytoma in our hospital were retrospectively analyzed from January 2015 to December 2020. They were divided into a BRAF p. V600E-mutant group (including 6 pleomorphic xanthoastrocytomas and 5 anaplastic pleomorphic xanthoastrocytomas) and a wild-type group (including 8 pleomorphic xanthoastrocytomas and 4 anaplastic pleomorphic xanthoastrocytomas). The preoperative MR imaging characteristics of these groups were statistically compared. The wild-type pleomorphic xanthoastrocytoma group presented with more aggressive conventional and advanced MR imaging features than the mutant pleomorphic xanthoastrocytoma group, including greater mean maximum tumor diameter (3.1 [SD, 0.9] cm versus 1.7 [SD, 0.4 ] cm, P < .05), more frequent heterogeneous contrast enhancement of solid portions (100% versus 0%, P < .001), more obvious peritumoral edema (mean, [2.1 SD, 0.7] cm versus 0.6 [SD, 0.2] cm, P < .01), and lower mean minimum relative ADC (896 [SD, 86] versus 988 [SD, 73], P < .05) and mean relative ADC (1060 [SD, 159] versus 1248 [SD, 116], P < .05) on DWI. However, there was no significant difference in either conventional or advanced MR imaging features between the wild-type anaplastic pleomorphic xanthoastrocytoma group and the mutant anaplastic pleomorphic xanthoastrocytoma group. Neurosurgeons should carefully interpret MR images before an operation and select appropriate surgical strategies according to genotype prediction.

Prevalence of BRAFV600 in glioma and use of BRAF Inhibitors in patients with BRAFV600 mutation-positive glioma: systematic review.

BackgroundDetailed prevalence estimates of BRAFV600 mutations and BRAF inhibitor (BRAFi) treatment responses in V600-mutant glioma will inform trial development.MethodsOur systematic review analyzed overall prevalence of BRAFV600 mutations in glioma and BRAFi treatment response.ResultsBased on 13 682 patients in 182 publications, the prevalence of BRAFV600 in epithelioid glioblastoma (eGBM) was 69% [95% CI: 45–89%]; pleomorphic xanthoastrocytoma (PXA): 56% [48–64%] anaplastic pleomorphic xanthoastrocytoma (aPXA): 38% [23–54%], ganglioglioma (GG): 40% [33–46%], and anaplastic ganglioglioma (aGG): 46% [18–76%]. Prevalence in astroblastoma was 24% [8–43%], desmoplastic infantile astrocytoma (DIA): 16% [0–57%], subependymal giant cell astrocytoma (SEGA): 8% [0–37%], dysembryoplastic neuroepithelial tumor (DNET): 3% [0–11%], diffuse astrocytoma (DA): 3% [0–9%], and pilocytic astrocytoma (PA): 3% [2–5%]. We reviewed 394 V600-mutant gliomas treated with BRAFi from 130 publications. One hundred and twenty-nine pediatric low-grade gliomas showed 4 (3.1%) complete response (CR); 53 (41.1%) partial response (PR); 64 (49.6%) stable disease (SD) and 8 (6.2%) progressive disease (PD). 25 pediatric high-grade gliomas showed CR; PR; SD; PD in 4 (16.0%); 10 (40.0%), 4 (16.0%); and 7 (28.0%) respectively. Thirty-nine adult low-grade gliomas showed CR; PR; SD; PD of 4 (10.3%); 17 (43.6%); 16 (41.0%) and 2 (5.1%) respectively. Ninety-seven adult high-grade gliomas showed CR; PR; SD; PD of 6 (6.2%); 31 (32.0%); 27 (27.8%); and 33 (34.0%) respectively.Conclusions BRAFV600 prevalence is highest in eGBM, PXA, aPXA, GG, aGG, and lower in astroblastoma, DIA, SEGA, DNET, DA, and PA. Our data provide the rationale for adjuvant clinical trials of BRAFi in V600-mutant glioma.

Prevalence of BRAF V600 in primary gliomas: a systematic review

Abstract Aims Glioma is a fatal disease that causes significant years of life lost to an individual. Mutations in the driver gene BRAF, such as the V600 alteration, may contribute to gliomagenesis in adults and children through abnormal signaling causing uncontrolled cell proliferation. The use of BRAF-inhibitor drugs including Vemurafenib and Dabrafenib have shown a favorable response in 48% and 50% of melanoma patients with BRAF V600 mutations respectively. BRAF inhibitors and MEK inhibitors have shown efficacy in certain paediatric gliomas in the recurrent setting. Despite the potential benefit of BRAF inhibitors, the prevalence of BRAF V600 within primary gliomas is not fully discovered. Some studies identify the prevalence to be over 50%, while others find the prevalence to be around 1%. We performed a comprehensive systematic review to determine the prevalence of BRAF V600 within the adult and paediatric glioma population in different diagnostic groups. Method A systematic literature search was performed using Ovid MEDLINE and Embase from genesis to the 22nd October 2020. Studies were not restricted by language. Studies were eligible if patients were histologically diagnosed according to WHO guidelines as a primary glioma evaluating the prevalence of BRAF V600 and included ≥ 10 primary glioma patients. The review protocol was registered in PROSPERO (CRD42019127704). Search results were managed using Endnote. Two independent reviewers assessed the eligibility of the publications using Rayyan, conflicts were evaluated by a third reviewer. Included articles were extracted by one reviewer and confirmed by a second reviewer. Risk of bias assessments were conducted using Hoy et al’s risk of bias tool. Results were synthesized using “metaprop” in R. The meta-analysis was carried out in R which produced forest plots. Results Our cohort included 182 studies with a total of 13669 adult and paediatric glioma patients classified diagnostically according to WHO guidelines. Among 48 glioma entities, BRAF V600 was identified most commonly in epithelioid glioblastoma with a prevalence of 69% (95% confidence interval (CI): 45-89%), followed by pleomorphic xanthoastrocytoma with a prevalence of 56% (95% CI: 48-64%), anaplastic pleomorphic xanthoastrocytoma with a prevalence of 38% (95% CI: 23-54%), ganglioglioma with a prevalence of 40% (95% CI: 33-46%), and anaplastic ganglioglioma with a prevalence of 46% (95% CI: 18-76%). Other glioma entities were found to have a prevalence of BRAF V600, these include astroblastoma (24%), desmoplastic infantile astrocytoma (16%), subependymal giant cell astrocytoma (8%), dysembryoplastic neuroepithelial tumour (3%), diffuse astrocytoma (3%), and pilocytic astrocytoma (3%). Conclusion To our knowledge, this is the largest systematic review examining the prevalence of BRAF V600 in adult and paediatric glioma classified according to diagnostic WHO criteria. However, there were some limitations in this review. The sample sizes of some studies were very small, and the method of mutational analysis for BRAF V600 varied between papers. We found BRAF V600 in a significant prevalence of epithelioid glioblastoma, pleomorphic xanthoastrocytoma, anaplastic pleomorphic xanthoastrocytoma, ganglioglioma, and anaplastic ganglioglioma. Of interest, BRAF V600 mutation was found in a lower prevalence of astroblastoma, desmoplastic infantile astrocytoma, subependymal giant cell astrocytoma, dysembryoplastic neuroepithelial tumour, diffuse astrocytoma, and pilocytic astrocytoma. Consideration of assessment of BRAF V600 mutation may enable further treatment options with BRAF and/or MEK inhibitors in these particular diagnostic entities.

Anaplastic pleomorphic xanthoastrocytoma misdiagnosed as cerebral sparganosis-identification of the "mirror image".

Anaplastic pleomorphic xanthoastrocytoma misdiagnosed as cerebral sparganosis-identification of the "mirror image".

Malignant transformation of pleomorphic xanthoastrocytoma in pregnant patient: Clinical case and ethical dilemma

Background: Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytic tumor, accounting for <1% of astrocytic tumors. Due to its rarity, etiology, natural history, and biologic behavior is not completely explained. We present a case of malignant transformation of a PXA to glioblastoma in pregnant patient 6 month after tumor biopsy.Case Description: A 28-year-old female patient was presented with a newly onset of headache, nausea, and right-sided hemiparesis at 21st week of pregnancy. Magnetic resonance imaging (MRI) revealed cystic mass in the left frontal region. Patient underwent biopsy to confirm pathohistological analysis; the tumor tissue corresponded to an anaplastic PXA. Two weeks after initial biopsy, open surgery along with gross total tumor removal was performed confirming pathohistological analysis. Six months later, after childbirth, and control MRI revealed a recurrent tumor mass: the patient underwent surgical resection and the tumor tissue corresponded to a glioblastoma. The patients were further treated with radiation and chemotherapy according to oncologist.Conclusion: Distinguishing between PXA patients who have a good prognosis and those at risk for early progression is very important for the PXA clinical management. Despite cellular pleomorphism, mitotic index and the extent of resection are shown to be the main predictors for recurrence-free survival and overall survival rates. The standard therapy management is not yet established. Our patient treatment was associated with a significant ethical dilemma. Respecting patient’s wishes to deliver a baby, nor radio or chemo treatments were done. Further studies are necessary to provide factors responsible for malignant transformation of PXA. In addition, in ethically sensitive situation, such as tumor in pregnant patient, good communication, respecting patient’s wishes, and a multidisciplinary teamwork is the key for better outcome.

P14.74 Grade II and III pleomorfic xanthoastrocitoma: a monocentric, retrospective analysis

Abstract BACKGROUND Pleomorphic xanthoastrocytoma (PXA) represent an astrocytic neoplasm that is typically well circumscribed and can have a relatively favorable prognosis. Tumor progression to anaplastic PXA (WHO grade III), however, is associated with a more aggressive biologic behavior and worse prognosis. The factors that drive anaplastic progression are largely unknown. The activating BRAF mutation is a genetic alteration that could be present in both PXA and anaplastic PXA; Identification of the mutation can be important as BRAF V600E mutant protein could be targeted therapeutically by small molecule inhibitors of both RAF and MEK. The low frequency of these tumors has fostered heterogeneity of therapeutic approaches, particularly in adult patients. We performed a monocentric, retrospective study on adult patients with a PXA diagnosis treated by our Institution, in order to search for markers of diagnosis and prognosis. MATERIAL AND METHODS All consecutive patients older than 18 years with a histological diagnosis of a primary grade II and III pleomorphic xanthoastrocytoma operated and treated by our Institution from 2011 to 2021 were consecutively and retrospectively included in the study. All pathological diagnoses and PXA cases were reviewed according to the WHO classification. Histological and molecular characteristics, including BRAF mutation status, as well as clinical data, treatment modalities, and patient outcome were analyzed and described. RESULTS 21 patients were included, 10 males and 11 females, with a median age of 40 years old (range 18–66). In 10 patients the histology showed an anaplastic PXA and in 11 patients a grade II tumor. Genetic features, including IDH status were available to all patients and BRAF mutation study was available in 8/10 anaplastic PXA. All patients underwent main surgery. Anaplastic features were associated with minimal PFS, whereas BRAF mutation tended to be associated with a better PFS. CONCLUSION Anaplastic features and BRAF mutation can lead to identify subgroups with distinct prognosis. These results should be validated in a larger and prospective study.

Sequencing of a central nervous system tumor demonstrates cancer transmission in an organ transplant.

Four organ transplant recipients from an organ donor diagnosed with anaplastic pleomorphic xanthoastrocytoma developed fatal malignancies for which the origin could not be confirmed by standard methods. We identified the somatic mutational profiles of the neoplasms using next-generation sequencing technologies and tracked the relationship between the different samples. The data were consistent with the presence of an aggressive clonal entity in the donor and the subsequent proliferation of descendent tumors in each recipient. Deleterious mutations in BRAF, PIK3CA, SDHC, DDR2, and FANCD2, and a chromosomal deletion spanning the CDKN2A/B genes, were shared between the recipients' lesions. In addition to demonstrating that DNA sequencing tracked a donor/recipient cancer transmission, this study established that the genetic profile of a donor tumor and its potential aggressive phenotype could have been determined before transplantation was considered. As the genetic correlates of tumor invasion and metastases become better known, adding genetic profiling by DNA sequencing to the data considered for transplant safety should be considered.

Abstract CT025: Dabrafenib plus trametinib in BRAF V600E-mutant high-grade (HGG) and low-grade glioma (LGG)

Abstract Background: More effective treatments are needed to improve outcomes in HGG and LGG. Activating BRAF mutations occur in ~3% of glioblastomas and 15% of LGGs. BRAF inhibitor dabrafenib + MEK inhibitor trametinib combination is FDA-approved in BRAF V600-positive melanoma, NSCLC, and anaplastic thyroid cancer. Methods: We conducted a nonrandomized, open-label, phase 2 basket study (NCT02034110) of dabrafenib + trametinib in pts with BRAF V600E mutation-positive rare cancers; here we report results for the HGG and LGG cohorts. Adult pts with histologically confirmed recurrent/progressive HGG (Grade III, IV) or LGG (Grade I, II) per WHO 2007 classification received oral dabrafenib, 150 mg twice daily, and oral trametinib, 2 mg once daily, until unacceptable toxicity, disease progression, or death. The primary endpoint was investigator-assessed objective response rate (ORR) using RANO criteria. Secondary endpoints included progression-free survival (PFS), duration of response (DOR), overall survival (OS), and safety; molecular characterization of baseline tumor samples was an exploratory endpoint. Results: As of Sept 14, 2020, 45 pts (23 male) were enrolled in the HGG cohort; 35 discontinued, 6 remained on treatment, 4 were in follow up. The majority had glioblastoma (69%), followed by anaplastic pleomorphic xanthoastrocytoma and anaplastic astrocytoma (each 11%); of pts with known IDH/MGMT status, 3/29 pts had IDH1 mutations and 8/17 had MGMT promoter methylation. Prior therapies included radiotherapy (98%), surgery, and chemotherapy (93% each). Median (range) follow-up was 12.7 (1.1-56.1) months (mo); ORR was 33% (3 CR, 12 PR); median DOR was 36.9 mo (95% CI, 7.4-44.2). Median PFS and OS were 3.8 mo (95% CI, 1.8-9.2) and 17.6 mo (95% CI, 9.5-45.2), respectively. The LGG cohort enrolled 13 pts (4 male); 7 discontinued, 5 remained on treatment, 1 was in follow up. Most common histologies were ganglioglioma (31%), diffuse astrocytoma, and pleomorphic xanthoastrocytoma (each 15%); of pts with known IDH/MGMT status, 1/8 pts had IDH1 mutation and 0/2 had MGMT promoter methylation. Prior therapies included surgery (92%), radiotherapy (62%), and chemotherapy (38%). Median (range) follow-up was 32.2 (0.8-71.8) mo; ORR was 69% (1 CR, 6 PR, 2 MR); median DOR, PFS, and OS were not reached. Overall, 54/58 pts (93%) experienced adverse events (AEs) across cohorts, most commonly (≥30%) fatigue (50%), headache (43%), nausea (34%), and pyrexia (33%); 31 pts (53%) had grade ≥3 AEs, most commonly (≥5%) fatigue, decreased neutrophil count (9% each), headache, and neutropenia (5% each). Next-generation sequencing showed a heterogenous landscape and low tumor mutation burden. Conclusions: Dabrafenib + trametinib demonstrated promising efficacy in pts with BRAF V600E mutation-positive recurrent/refractory HGG and LGG. The safety profile was consistent with the known safety profile for other indications. Citation Format: Vivek Subbiah, Alexander Stein, Martin van den Bent, Antje Wick, Filip Y. de Vos, Nikolas von Bubnoff, Myra E. van Linde, Albert Lai, Gerald W. Prager, Mario Campone, Angelica Fasolo, Jose A. Lopez-Martin, Tae Min Kim, Ralf-Dieter Hofheinz, Jean-Yves Blay, Daniel C. Cho, Anas Gazzah, Damien Pouessel, Jeffrey Yachnin, Aislyn Boran, Paul Burgess, Palanichamy Ilankumaran, Eduard Gasal, Patrick Y. Wen. Dabrafenib plus trametinib in BRAF V600E-mutant high-grade (HGG) and low-grade glioma (LGG) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT025.

Differences in treatment patterns and overall survival between grade II and anaplastic pleomorphic xanthoastrocytomas.

Pleomorphic xanthoastrocytomas (PXAs) are classified as a grade II neoplasm, typically occur in children, and have favorable prognoses. However, their anaplastic counterparts remain poorly understood and vaguely characterized. In the present study, a large cohort of grade II PXA patients were compared with primary anaplastic PXA (APXA) patients to characterize patterns in treatment and survival. Data were collected from the National Cancer Institute's SEER database. Univariate and multivariate Cox regressions were used to evaluate the prognostic impact of demographic, tumor, and treatment-related covariates. Propensity score matching was used to balance baseline characteristics. Kaplan-Meier curves were used to estimate survival. A total of 346 grade II PXA and 62 APXA patients were identified in the SEER database between 2000 and 2016. Kaplan-Meier analysis revealed substantially inferior survival for APXA patients compared to grade II PXA patients (median survival: 51months vs. not reached) (p < 0.0001). After controlling across available covariates, increased age at diagnosis was identified as a negative predictor of survival for both grade II and APXA patients. In multivariate and propensity-matched analyses, extent of resection was not associated with improved outcomes in either cohort. Using a large national database, we identified the largest published cohort of APXA patients to date and compared them with their grade II counterparts to identify patterns in treatment and survival. Upon multivariate analysis, we found increased age at diagnosis was inversely associated with survival in both grade II and APXA patients. Receipt of chemoradiotherapy or complete surgical resection was not associated with improved outcomes in the APXA cohort.