Pediatric Low Grade Research Articles

Novel therapies for pediatric low grade glioma.

Current biological findings provide new insights into the genetics driving growth of low-grade gliomas in pediatric patients. This has provided new targets for novel therapies. The purpose of this paper is to review novel therapies for pediatric low-grade gliomas that have been published in the past 24 months. Low-grade gliomas are often driven by mitogen activated protein kinase (MAPK) alterations either with BRAF V600E point mutations or BRAF fusions. Current advances have also highlighted novel fusions of fibroblast growth factor receptor (FGFR), myeloblastosis family of transcription factors (MYB), meningioma 1 tumor suppressor (MN1), neurotrophic receptor kinase family of receptors (NTRK), Kristen RAS (Rat Sarcoma Virus) oncogene homolog in mammals (KRAS), Receptor tyrosine kinase ROS proto oncogene 1 (ROS1), protein kinase C alpha (PRKCA), and platelet derive growth factor receptor (PDGFR) amplification. Novel therapies have been employed and are showing encouraging results in pediatric low-grade gliomas. Current trials are underway with newer generation pan RAF inhibitors and mitogen activated protein kinase - kinase (MEK) inhibitors. Other early phase clinical trials have provided safety data in pediatric patients targeting FGFR fusion, NTRK fusion, PDGFR amplification and ROS1 mutations. Historical treatment options in pediatric low-grade gliomas have utilized surgery, radiation therapy and conventional chemotherapy. Recently greater insight into their biology has found that alterations in MAPK driven pathways are often the hallmark of tumorigenesis. Targeting these novel pathways has led to tumor control and shrinkage without the use of conventional chemotherapy. Caution should be taken however, since these treatment options are still novel, and we do not fully appreciate the long-term effects. Nonetheless a new era of targeted medicine is here.

Advances in pediatric gliomas: from molecular characterization to personalized treatments.

Pediatric gliomas, consisting of both pediatric low-grade (pLGG) and high-grade gliomas (pHGG), are the most frequently occurring brain tumors in children. Over the last decade, several milestone advancements in treatments have been achieved as a result of stronger understanding of the molecular biology behind these tumors. This review provides an overview of pLGG and pHGG highlighting their clinical presentation, molecular characteristics, and latest advancements in therapeutic treatments. Conclusion: The increasing understanding of the molecular biology characterizing pediatric low and high grade gliomas has revolutionized treatment options for these patients, especially in pLGG. The implementation of next generation sequencing techniques for these tumors is crucial in obtaining less toxic and more efficacious treatments. What is Known: • Pediatric Gliomas are the most common brain tumour in children. They are responsible for significant morbidity and mortality in this population. What is New: • Over the last two decades, there has been a significant increase in our global understanding of the molecular background of pediatric low and high grade gliomas. • The implementation of next generation sequencing techniques for these tumors is crucial in obtaining less toxic and more efficacious treatments, with the ultimate goal of improving both the survival and the quality of life of these patients.

Abstract 5200: Multiparametric MRI along with machine learning informs on molecular underpinnings, prognosis, and treatment response in pediatric low grade glioma

Abstract We report a comprehensive radiogenomic analysis, including multiparametric MRI and RNA sequencing of 502 tumors across 13 histological types of pediatric low-grade glioma (PLGG). Through an unsupervised analysis of treatment-naïve imaging, we were able to identify 3 distinct imaging clusters that were associated with different molecular pathways according to transcriptomic pathway analysis. Using xCell enrichment scores as input for clustering, we discovered three distinct immunological groups based on immune cell infiltration. The results suggested the presence of an ‘immune-hot” cluster within the tumors with a poorer prognosis, which may potentially benefit from emerging immunotherapies. We subsequently generated a radiomic signature that was able to predict immunological profiles. We also developed a clinicoradiomic predictive model that can assess patients’ risk of progression and predict treatment response. Finally, we evaluated the transcriptomic pathways that were most predictive of clinicoradiomic risk scores and identified the biological pathways most predictive of risk of progression in PLGG, when adjusting for molecular subtype, race, reported gender, age at diagnosis, and the anatomic location of the tumor. This is the first large-scale radiogenomic analysis in PLGG that can aid in prognostication, assessing patients’ risk of progression, predicting treatment response in conventional therapies, and early stratification of patients to identify potential candidates for targeted therapies. Citation Format: Ali Nabavizadeh, Adam Kraya, Komal Rathi, Meen Chul Kim, Nastaran Khalili, Ariana Familiar, Varun Kesherwani, Hannah Anderson, Deep Gandhi, Aria Mahtabfar, Sina Bagheri, Xiaoyan Huang, Yuankun Zhu, Alexander Sickler, Saksham Phul, Sabine Mueller, Mateusz P Koptyra, Philip B Storm, Jeff Ware, Yuanquan Song, Michael J Fisher, Arastoo Vossough, Christos Davatzikos, Adam C Resnick, Anahita Fathi Kazerooni. Multiparametric MRI along with machine learning informs on molecular underpinnings, prognosis, and treatment response in pediatric low grade glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5200.

Abstract 5221: The first-in-class ERK inhibitor ulixertinib (BVD-523) shows activity in MAPK-driven pediatric low-grade glioma models as single agent and in combination with MEK inhibitors or senolytics

Abstract Ulixertinib (BVD-523) is a well-tolerated, orally delivered, catalytic ERK1/2 inhibitor, which has shown promising responses in adult patients with mitogen-activated protein kinase (MAPK)-driven solid tumors. Pediatric low grade gliomas (pLGGs) are the most common pediatric brain tumors, with the most frequent driving alterations (KIAA:BRAF fusion, BRAF V600E mutation) occurring in the MAPK pathway. To investigate the anti-tumoral activity of ulixertinib in pLGG, cell lines recapitulating both main MAPK alterations were used: DKFZ-BT66 (pilocytic astrocytoma; KIAA:BRAF fusion) and BT40 (pleomorphic xanthoastrocytoma; BRAF V600E mutation and CDKN2A/B deletion). The potential synergism of combinations with MEK inhibitors, senolytics, and chemotherapy was investigated in vitro using metabolic activity and MAPK activity assays. The most promising combinations were validated in vitro by analysis of viable, dead, and apoptotic cells through high-content microscopy. The most clinically relevant combinations were further validated in vivo: 1) in two zebrafish embryo models (respectively, BT40 and DKFZ-BT66 yolk sac injection) and 2) in NSG mice (BT40 orthotopic PDX) including in vivo pharmacokinetic and -dynamic analyses. Our data demonstrate ulixertinib’s ability to inhibit MAPK pathway activity in all used models. Ulixertinib treatment reduced cell viability in the BRAF V600E mutated cell line at a remarkably low concentration of 62.7 nM (compared to other cell lines’ IC50 from the Genomics of Drug Sensitivity in Cancer database). In vivo pharmacokinetic and -dynamic analyses showed good penetrance of the drug into mouse brain tissue, with concentrations above the in vitro IC50 and reduction of MAPK activity as assessed by Western blot. Furthermore, ulixertinib treatment slowed tumor growth and significantly increased survival in NSG mice with orthotopic BT40 xenografts. Ulixertinib showed indications for anti-proliferative synergy in vitro, according to the Loewe and Bliss independence models, in combination with MEK inhibitors (trametinib, binimetinib) or senolytics (navitoclax, A1331852). Combinations with chemotherapy (carboplatin, vinblastine) were at most additive. Indications for synergy with binimetinib and navitoclax were confirmed in the zebrafish embryo xenograft models for both MAPK-altered backgrounds. The combination of ulixertinib with navitoclax was further investigated in the BT40 PDX mouse model, where tumor growth and survival were comparable to ulixertinib monotherapy. In conclusion, our data indicate a strong potential for ulixertinib as a clinically relevant therapeutic option for the treatment of pLGG to be further investigated in upcoming clinical trials. Potential synergism with MEK inhibitors and senolytics was noted and warrants further investigation. Citation Format: Romain Sigaud, Lisa Rösch, Charlotte Gatzweiler, Julia Benzel, Laura von Soosten, Heike Peterziel, Sara Najafi, Simay Ayhan, Nina Hofmann, Kathrin I. Förster, Jürgen Burhenne, Rémi Longuespée, Cornelis M. van Tilburg, David T. Jones, Stefan M. Pfister, Deborah Knoerzer, Brent Kreider, Max Sauter, Kristian W. Pajtler, Marc Zuckermann, Ina Oehme, Olaf Witt, Till Milde. The first-in-class ERK inhibitor ulixertinib (BVD-523) shows activity in MAPK-driven pediatric low-grade glioma models as single agent and in combination with MEK inhibitors or senolytics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5221.

LGG-32. Integrated biologic, radiologic and clinical analysis of pediatric low-grade gliomas during and after targeted therapy treatment

BACKGROUND: Pediatric low grade gliomas (pLGGs) are the most common central nervous system tumor in children, characterized by driver alterations in the RAS and MAPK pathways. Genomic advances have facilitated use of molecular targeted therapies, however their long-term impact on tumor behavior remains critically unanswered. METHODS: We performed an IRB-approved, retrospective chart and imaging review of pLGGs treated with off-label targeted therapy at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center from 2010 to 2020. Volumetric analysis was performed for BRAFV600E and BRAF fusion/duplication driven pLGG subsets. RESULTS: Fifty-five patients were identified (dabrafenib n = 15, everolimus n = 26, trametinib n = 11, and vemurafenib n = 3). Targeted agent was used as first or second-line therapy for 58% (32/55). Median duration of targeted therapy was 0.79 years (0.01 – 4.87), and overall median follow-up was 2.50 years (0.01 – 7.39). The 1-year, 3-year, and 5-year EFS from targeted therapy initiation were 62.1%, 38.2%, and 31.8%, respectively. Mean volumetric change for BRAFV600E mutated pLGG on BRAF inhibitors was -54.11%, and median time to best volumetric response was 8.28 months (n = 12). Median time to largest volume post-treatment was 2.86 months. Mean volumetric change for BRAF fusion/duplication pLGG on MEK inhibitors was +7.34% with median time to best volumetric response of 6.71 months (n = 7). Median time to largest volume post-treatment was 2.38 months. CONCLUSIONS: Our integrated clinical and volumetric data suggest the majority of patients receiving BRAF inhibitors or trametinib achieve reduction in tumor volume while on therapy and that tumor stability can be achieved following targeted therapy cessation. Moreover, volumetric analysis shows promise as a tool to assess targeted therapeutic response in pLGGs.

Clinical and molecular characteristics of pediatric low-grade glioma complicated with ventriculo-peritoneal shunt related ascites.

Ventriculo-peritoneal shunt (VPS) related ascites is a rare complication of pediatric low grade gliomas (pLGG). Physiopathology of this complication is not fully understood and there is paucity of data regarding the molecular profile of pLGG gliomas complicating with ascites and the optimal management of this unusual event. International multi-institutional retrospective analysis of patients diagnosed with BRAF altered pLGG and ascites arising as a complication of VPS. Demographics, tumor characteristics, therapeutic approaches and outcomes were recorded. Nineteen patients were identified. Median age at diagnosis was 14months (R: 2-144). Most patients (17; 89.4%) presented with lesions involving the optic pathway. Mean tumor standard volume was 34.8 cm2 (R: 12.5-85.4). Pilocytic Astrocytoma was the most frequent histological diagnosis (14;7 3.7%). Eight (42.1%) tumors harbored BRAF V600-E mutation and seven (36.8%) KIAA1549 fusion. The onset of ascites was documented at a median time of 5months following VPS insertion. Four (21%) patients were managed with paracentesis only, 7(36.8%) required both paracentesis and shunt diversion, 7(36.8%) required only a shunt diversion and 1 (5.2%) patient was managed conservatively. Chemotherapy regimen was changed in 10 patients following ascites. Eight patients received targeted therapy (4 dabrafenib/4 trametinib) and 5 were radiated. There were eleven survivors with a median OS of 69months (R: 3-144). Ascites is an early feature in the clinical course of young patients with midline BRAF altered pLGG, with high mortality rate observed in our cohort. The hypothesis of ascites as an adverse prognostic factor in pLGG warrants further prospective research.

Survival and functional outcomes in paediatric thalamic and thalamopeduncular low grade gliomas.

Childhood thalamopeduncular gliomas arise at the interface of the thalamus and cerebral peduncle. The optimal treatment is total resection but not at the cost of neurological function. We present long-term clinical and oncological outcomes of maximal safe resection. Retrospective review of prospectively collected data: demography, symptomatology, imaging, extent of resection, surgical complications, histology, functional and oncological outcome. During 16-year period (2005-2020), 21 patients were treated at our institution. These were 13 girls and 8 boys (mean age 7.6years). Presentation included progressive hemiparesis in 9 patients, raised intracranial pressure in 9 patients and cerebellar symptomatology in 3 patients. The tumour was confined to the thalamus in 6 cases. Extent of resection was judged on postoperative imaging as total (6), near-total (6) and less extensive (9). Surgical complications included progression of baseline neurological status in 6 patients, and 5 of these gradually improved to preoperative status. All tumours were classified as low-grade gliomas. Disease progression was observed in 9 patients (median progression-free survival 7.3years). At last follow-up (median 6.1years), all patients were alive, median Lansky score of 90. Seven patients were without evidence of disease, 6 had stable disease, 7 stable following progression and 1 had progressive disease managed expectantly. Paediatric patients with low-grade thalamopeduncular gliomas have excellent long-term functional and oncological outcomes when gross total resection is not achievable. Surgery should aim at total resection; however, neurological function should not be endangered due to excellent chance for long-term survival.

LGG-11. INSTITUTIONAL EXPERIENCE OF BRAF TARGETING THERAPY

BACKGROUNDThe use of BRAF inhibitors is widely accepted in adult oncology as treatment for BRAF mutated cancers. BRAF alterations are frequently found in both pediatric low grade and high-grade gliomas, which has opened a new door to targeted therapies for pediatric gliomas. Targeted therapy drugs are associated with predictable patterns of adverse events. However treating in children may potentiate unique challenges. We present our institutional experience of targeted therapy with a focus on adverse events.METHODSWe conducted a retrospective chart review of patients treated with BRAF and/or MEK inhibitors between 2015–2019.RESULTSThere are nine patients treated with either MEK inhibitor(n=) or the combination therapy(n=). The most common diagnosis was Pilocytic astrocytoma. Targeted therapy was chosen as salvage therapy in all patients. The most common side effect was a pruritic erythematous rash, observed in 8 out of 9 patients. Cardiac toxicity (Grade 2, n=1) and GI toxicity (Grade 3, n=1) were found in patients treated with MEK inhibitor. Both cases resulted in cessation of therapy or significant decreased dose respectively. While two patients died due to progression of disease and two other continued to progress, 5 patients have demonstrated stable disease while on therapy.CONCLUSIONSOur study revealed the incidence of severe adverse events in two patients with BRAF targeted therapy. Due to the potential life-long use of targeted therapy, it is important to follow guidelines of adverse event monitoring and to develop a prevention and management strategy for severe adverse events.

Clinical management and genomic profiling of pediatric low-grade gliomas in Saudi Arabia

Pediatric Low Grade Gliomas (PLGGs) display heterogeneity regarding morphology, genomic drivers and clinical outcomes. The treatment modality dictates the outcome and optimizing patient management can be challenging. In this study, we profiled a targeted panel of cancer-related genes in 37 Saudi Arabian patients with pLGGs to identify genetic abnormalities that can inform prognostic and therapeutic decision-making. We detected genetic alterations (GAs) in 97% (36/37) of cases, averaging 2.51 single nucleotide variations (SNVs) and 0.91 gene fusions per patient. The KIAA1549-BRAF fusion was the most common alteration (21/37 patients) followed by AFAP1-NTRK2 (2/37) and TBLXR-PI3KCA (2/37) fusions that were observed at much lower frequencies. The most frequently mutated) genes were NOTCH1-3 (7/37), ATM (4/37), RAD51C (3/37), RNF43 (3/37), SLX4 (3/37) and NF1 (3/37). Interestingly, we identified a GOPC-ROS1 fusion in an 8-year-old patient whose tumor lacked BRAF alterations and histologically classified as low grade glioma. The patient underwent gross total resection (GTR). The patient is currently disease free. To our knowledge this is the first report of GOPC-ROS1 fusion in PLGG. Taken together, we reveal the genetic characteristics of pLGG patients can enhance diagnostics and therapeutic decisions. In addition, we identified a GOPC-ROS1 fusion that may be a biomarker for pLGG.

LG-77BRAIN PLASTICITY IN PEDIATRIC LOW-GRADE GLIOMAS

LG-77. BRAIN PLASTICITY IN PEDIATRIC LOW-GRADE GLIOMAS Yahya Ghazwani, Zoltan Patay, Zsila S. Sadighi, Santhosh Upadhyaya, Frederick Boop, Amar Gajjar, and Ibrahim Qaddoumi; St. Jude Children’s Research Hospital, Memphis,TN, USA BACKGROUND: Neural plasticity (NP) is a well-known phenomenon in the brain, especially in the context of long-existing lesions. Young age and immaturity are associated with high NP. Low-grade gliomas (LGGs) are slowgrowing tumors with good prognosis and are therefore an ideal tumor type to study NP. METHODS: We conducted a retrospective review of 5 patients with LGGs and studied clinical, radiologic, and pathological data for switching handedness. RESULTS: The median age of patients at diagnosis was 51 months (range, 23-93 months). Their median time from switching handedness to diagnosis was 1 month (range, 0.75-60 months). All 5 patients had pilocytic astrocytoma, and none of them had a genetic disorder. Tumors were located in theposterior fossa (n 1⁄4 2), left basal ganglia (n 1⁄4 2), and left thalamus (n 1⁄4 1). Twopatientshad paralysis, and three had paresis in the dominant hand. All the patients continued to prefer using the non-dominant hand, even though function of the dominant hand had recovered fully in only 1 patient after rehabilitation. CONCLUSION: Switching handedness is a major form of NP identified in 5 of our patients with same tumor type but interestingly diverse locations. Further studies of NP in LGGs are required to better understand these findings. Functional MRI studies at diagnosis and follow-up can provide further insight on the phenomenon of NP in patients with LGGs. Neuro-Oncology 18:iii78–iii96, 2016. doi:10.1093/neuonc/now075.77 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Low Grade Gliomas in Children.

Gliomas represent the most common solid tumor of the nervous system, and can occur as both low and high-grade tumors. Current risk stratification and treatment approaches rely heavily on the morphological classification of gliomas whereby low-grade gliomas have an excellent prognosis, particularly pilocytic astrocytomas, while high-grade gliomas have a poor prognosis. The past decade has witnessed a dramatic increase in scholars' knowledge of the biology of pediatric low-grade gliomas particularly through the advent of integrated genomics and next generation sequencing. Indeed, many of these biological advances are changing treatment paradigms, particularly in low-grade gliomas, where rationale targeted therapies are currently being explored in clinical trials. In this review the authors summarize the current approach to pediatric low grade gliomas and outline the biological advances over the past 10 years, which will be driving the next generation of clinical trials.

Health related quality of life (HRQOL) in long-term survivors of pediatric low grade gliomas (LGGs).

The purpose of this study was to assess the health-related quality of life (HRQOL) and the impact of treatment on HRQOL in long-term survivors of pediatric low-grade gliomas (LGGs) using an adult instrument. QOL of 121 patients with a diagnosis of LGG from the Mayo Clinic were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30 for cancer in general) and (EORTC QLQ-BN20 specific for brain tumors). Median follow-up was 21.9 years for the participants. Median age at diagnosis was 11.8 years and at assessment was 33 years. Mean (standard deviation) global QOL score for the study was 78 (18) and 76.4 (22.8) in a reference population of healthy adults. Using QLQ-C30, radiation treated patients compared to non-radiation patients reported lower physical functioning (p = 0.002), role functioning (p = 0.004), and more constipation problems (p < 0.001). Patients with tumor recurrence reported lower role functioning (p = 0.016), social functioning (p = 0.040), and more financial problems (p = 0.029) compared to their counterparts. Using QLQ-BN20, patients with deep tumors compared to cortical tumors reported more bladder control problems (p = 0.016). Radiation treated patients also reported more bladder control problems (p < 0.001) compared to their counterparts. In the multivariable analysis, radiation therapy remained an independent predictor of physical and role functioning as well as symptoms related to brain tumors like visual disorders and motor dysfunction. Global QOL of long-term survivors of pediatric LGGs is similar to that of a reference population of healthy adults. The following tumor and treatment related factors were most consistently associated with poorer QOL: CNS tumor location, post-operative radiation, and tumor recurrence. Future studies are necessary to identify strategies to improve QOL in this subgroup of patients.

Abstract B4: Growth-factor-driven rescue to receptor tyrosine kinase inhibitors in pediatric low-grade astrocytoma and ependymoma

Abstract Introduction: Brain tumors are still the leading cause of cancer morbidity and mortality among children, despite different therapeutic options including neurosurgery, chemotherapy and radiation. Up to now, several clinical studies have been started investigating the importance of receptor tyrosine kinase (RTK) inhibitors upon progression free survival in various pediatric brain tumors. However, it has been shown that single targeted kinase inhibition failed due to tumor resistance mechanisms. The present study will extend our previous observations that vascular endothelial growth receptor (VEGFR) 2, platelet derived growth factor receptor (PDGFR) β, Src, the epidermal growth factor receptor (ErbB) family, and hepatocyte growth factor receptor (HGFR/cMet) are potential drugable targets in pediatric low grade astrocytoma and ependymoma with investigations concerning growth-factor-driven rescue. Material and methods: Expression of various RTKs in pediatric low grade astrocytoma (Res-186, Res-259, UW-467) and ependymoma (Res-196) cell lines were determined using flow cytometry analyses. Growth-factor-driven rescue during RTK inhibition with agents including sorafenib, dasatinib, canertinib and crizotinib were analyzed on cell viability level measured with WST-1 cell viability assays and on phosphorylation level of the crucial downstream PI3K/Akt and MAPK/Erk survival signaling pathways using western blot analyses. Results: VEGFR-1, fibroblast growth factor receptor (FGFR) 1, ErbB-1, HGFR and recepteur d'origine nantais (RON) were highly expressed (respectively 52-77%, 34-51%, 63-90%, 83-98%, 65-95%) and their respective inhibitors showed induced decrease of tumor cell viability. EGF, HGF and FGF, which are normally environmentally expressed in brain (tumor) tissue, showed to be effective rescue inducing growth factors resulting in increased cell survival especially during treatment with dasatinib (complete rescue) or sorafenib (partial rescue) in both low grade astrocytoma and ependymoma. Growth-factor-driven rescue was less prominent when canertinib or crizotinib were used. Rescue was underscored by activating downstream Akt and/or Erk phosphorylation. Combination treatment showed to be able to overcome the growth-factor-driven resistance. Conclusions: In conclusion, our study highlights the extensive importance of environmentally present growth factors in developing resistance towards RTK inhibitors. It is of great interest to anticipate upon these results for the design of new therapeutic trials with RTK inhibitors in pediatric low grade astrocytoma and ependymoma. Citation Format: Mariska Sie, Wilfred F.A. den Dunnen, Harm Jan Lourens, Tiny G.J. Meeuwsen-de Boer, Frank J.G. Scherpen, Kim R. Kampen, Eelco W. Hoving, Eveline S.J.M. de Bont. Growth-factor-driven rescue to receptor tyrosine kinase inhibitors in pediatric low-grade astrocytoma and ependymoma. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B4.

Abstract 5558: Interplay between BRAF, p16, p53, and MIB1 in pediatric low grade gliomas

Abstract BRAF rearrangements and BRAF V600E point mutations are recurring events in pediatric low-grade gliomas. However, their clinical significance, including possible interactions between these markers and other glioma biomarkers, is unclear. In this study a retrospective cohort of 198 pediatric low-grade gliomas (including 40 treated with adjuvant therapy) was analyzed for BRAF rearrangements, BRAF V600E, p16/CDKN2A deletion, p53 expression, and MIB1 proliferation index. In tumors with BRAF rearrangement, homozygous p16 deletion correlated with shorter PFS (P = 0.04). High MIB1 proliferation index strongly trended toward correlating with worse response to adjuvant therapy (P = 0.06). On multivariate analyses, the two most consistently powerful independent adverse prognostic markers were midline location (P = 0.0001) and p16 deletion (P = 0.03). Tumors with BRAF V600E had a strong trend toward an increased risk for progression (hazard ratio = 2.48, P = 0.07), whereas those with BRAF rearrangement had a milder trend toward reduced risk (hazard ratio = 0.54, P = 0.15). These data suggest that p16 deletion adversely impacts the outcomes of BRAF-driven gliomas; that high proliferation index may be a better marker of progression risk than BRAF; that BRAF rearrangement and BRAF V600E might not necessarily produce comparable outcomes; and that none of these markers is stronger than tumor location in determining prognosis in pediatric low-grade gliomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5558. doi:1538-7445.AM2012-5558

Abstract 2129: Pediatric diffuse intrinsic pontine gliomas are genetically distinct from high and low grade astrocytomas

Abstract Tumors of the central nervous system constitute the most common type of solid pediatric tumors and account for the majority of mortality and morbidity in pediatric oncology. Brainstem glioma (BSG) is a type of brain tumor that arises in the medulla, pons or midbrain and accounts for approximately 10-20% of pediatric brain tumors. Diffuse gliomas of the pontine region, diffuse intrinsic pontine glioma (DIPG) are the most common type of brainstem tumor, accounting for about 58-78% of BSG and the number one cause of brain tumor related death in children with a 1-2 year survival. Despite this very little is understood about the biology of these tumors. To try to address this lack of knowledge we have undertaken genomic analysis of a series of DIPGs and compared their copy number changes to those seen in pediatric supratentorial high grade astrocytomas as well as low grade astrocytomas. Post mortem tumor and matched normal brain samples (n= 9) and surgical samples (n= 4) were collected for a series of DIPG patients. We performed high-resolution genetic analysis using whole-genome single-nucleotide polymorphism (SNP) arrays (Affymetrix 500K and 6.0). Data analysis was conducted using Partek Genome Suite and Copy Number Analysis Tool (Affymetrix). Analysis of copy number alterations returned hits in several cancer related pathways including MAPK, Wnt, prostate cancer and gliomagenesis. DIPG copy number was also compared to that of pediatric high grade (n= 20) and low grade (n= 30) astrocytomas. Unsupervised Pearson's Dissimilarity clustering resulted in 3 distinct groups. One contained 6 DIPGs; the second contained mostly LGA with a few HGA, while the third group contained mostly HGA with the remaining DIPGs clustering with this group. Although there were some similarities, DIPG are genetically distinct from supratentorial high grade and low grade astrocytomas. A better understanding of DIPG biology is needed in order to develop agents targeted more specifically towards this disease particularly given the dismal prognosis and unresponsive nature of these tumors to conventional treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2129.