BIOM-42. IMMUNOHISTOCHEMICAL ASSESSMENT OF MEMBRANOUS SOMATOSTATIN TYPE 2A RECEPTOR (SST2A) EXPRESSION ACROSS HIGH-RISK PEDIATRIC CENTRAL NERVOUS SYSTEM (CNS) TUMORS

INTRODUCTION 77Lu-DOTATATE, a radionuclide therapy which binds SST2A, has demonstrated efficacy in neuroendocrine tumors and evidence of CNS penetration, supporting potential expansion within pediatric neuro-oncology. Understanding the prevalence of SST2A expression across pediatric CNS tumors is essential to identify patients who may benefit from somatostatin receptor-targeted therapy and to further elucidate the oncogenic role of SST2A. METHODS SST2A immunohistochemistry (IHC) was performed on tumor specimens and interpreted by two experienced pathologists (blinded), utilizing semi-quantitative scoring of membranous expression within viable tumor. Immunoreactive cell percentage was visually scored as 0 (none), 1 (< 10%), 2 (10-50%), 3 (51-80%), or 4 (>80%). Staining intensity was scored as 0 (none), 1 (weak), 2 (moderate), or 3 (strong). Combined scores for each specimen were calculated by multiplying percent immunoreactivity and staining intensity values (range=0-12). RESULTS A total of 117 tumor samples from 113 patients were analyzed. Significant differences in SST2A IHC scores were observed across histopathologic diagnoses, with consistently high scores in medulloblastoma (mean±SD=7.6±3.6 [n=36]) and meningioma (5.7±3.4 [n=15]), compared to minimal or absent expression in ATRT (0.3±0.6 [n=3]), ETMR (1.0±0 [n=3]), ependymoma (grades I-III; 0.2±0.7 [n=26]), and high-grade glioma (grades III-IV; 0.4±0.7 [n=22]). Pineoblastoma (3.8±1.5 [n=4]) and other embryonal tumors (2.3±3.8 [n=8]) exhibited intermediate, variable expression. Among expressors, there was no association between SST2A IHC score and patient age, sex, presence of metastases, likelihood of relapse, or prior treatment. In a subset of paired primary and recurrent specimens from 3 patients, SST2A IHC scores remained largely unchanged. Among medulloblastomas, SST2A IHC scores were higher in non-SHH (8.6±3.2) than SHH (5.0±3.3) molecular subgroups (p=0.033). CONCLUSIONS High membranous SST2A expression was demonstrated in medulloblastoma, meningioma, and some rarer embryonal tumors with potential diagnostic, biologic, and therapeutic implications. Somatostatin receptor-targeted therapy such as 177Lu-DOTATATE deserves further investigation in these highly SST2A-expressing pediatric CNS tumors.

OMIC-09. MAPPING THE HISTONE MUTATIONAL LANDSCAPE ACROSS ADULT AND PEDIATRIC CANCER GENOMES UNCOVERS NOVEL SOMATIC MUTATIONS IN PEDIATRIC HIGH-GRADE GLIOMAS

There is a growing role for mutations affecting histone linker and histone core-encoding genes across several adult and pediatric cancers. However, the extent to which somatic histone mutations may bridge across different cancers as common tumorigenic events – particularly in the context of pediatric CNS tumors – remains unclear. To address this knowledge gap, we set out to define a comprehensive pan-cancer landscape of somatic histone mutations. We first queried the ICGC PCAWG and TCGA Pan-Cancer Atlas representing >12,500 adult and pediatric cancer patients. We found lymphomas to be most enriched for histone mutations (50–75%) and, in particular, for mutations in linker histones (HIST1H1B-E), yet also in specific core histone genes (eg, HIST2H2BE). Moreover, we observed a significant enrichment of histone mutations in adult high-grade vs low-grade gliomas (10% vs 6%, P<0.05, n=922 patients). Interrogation of whole genome data from 800 pediatric CNS tumor genomes (PBTA/OpenDIPG), identified novel (non-H3K27/non-H3G34) somatic histone mutations in 5–10% of subjects, including pediatric high-grade gliomas (pHGGs) and diffuse midline gliomas (DMGs). We found an overlapping set of histone genes to be recurrently mutated in non-CNS cancers and pediatric CNS tumors alike (eg, HIST1H1B/C/E). Notably, the only pediatric primary CNS lymphoma patient also harbored a histone linker alteration (HIST1H1B), similar to adult non-CNS lymphoma patients. We validated novel somatic histone mutations in DMGs by Sanger sequencing. Ongoing studies include in vitro assessment of the impact of these mutations on cell proliferation, chromatin accessibility, histone spacing, and gene expression. In addition, we will further assess associations with clinical outcome, age, and tumor subtypes. Collectively, oncohistone vulnerabilities were identified and defined as histone gene families recurrently mutated across all cancer types. Our analyses of adult and pediatric cancer genomes have uncovered previously unknown mutations affecting histone linker and core proteins, which may play a yet-undefined role in tumor etiology.

LGG-16. TO BE PRECISE - KNOW YOUR TARGETS: INSTITUTIONAL EXPERIENCE WITH TUMOR TARGETED THERAPY FOR RECURRENT/PROGRESSIVE PEDIATRIC LOW-GRADE GLIOMA AND PLEXIFORM NEUROFIBROMA

Introduction The oncogenic drivers of pediatric CNS tumors are rapidly being identified with the implementation of high throughput genetic screening. Precision medicine approaches to treatment have shown promising results, but data remains limited in the community oncology setting. We aim to describe our institutional experience using targeted therapies for plexiform neurofibroma and recurrent/progressive pediatric low-grade glioma (pLGG). Methods We performed a retrospective chart review of all patients treated with tumor targeted therapies for recurrent/progressive pLGG and plexiform neurofibroma over the past 5 years. Results Ten patients treated with tumor targeted therapies were identified. Regimens included combination Dabrafenib and Trametinib (n=3), Trametinib monotherapy (n=2), Selumetinib (n=3), Vemurafenib (n=1), and Larotrectinib (n=1). Median age at therapy initiation was 11.5 years (range 1.1 - 18 years). Tumor molecular status included BRAFV600E mutation (n=4), NF1 mutation (n=2), KIAA1549-BRAF fusion (n=1), NACC-NTRK fusion (n=1), and FGFR1 mutation (n=1). Patients trialed an average of 2 treatment regimens prior to targeted therapy initiation (range 0–5). Mean duration of therapy was 14.5 months (range .5–33 months) with 8 patients remaining on treatment. Based on modified RANO criteria, responses included partial (n=1), stable disease (n=8), and progressive disease (n=1). Progressive disease was noted after 4 months of treatment with Dabrafenib and Trametinib combination therapy, but rate of tumor growth was decreased. Subjective functional improvement was seen in 50% of patients. The most common toxicities included rash (n=5) and pyrexia (n=2). Trametinib was discontinued in one patient due to intra-tumoral hemorrhage of unclear etiology. Conclusion Treatment of pediatric CNS tumors with targeted agents appears to be feasible and efficacious in the community oncology setting. Multi-institutional clinical trials are currently ongoing for each of these therapies. There remains a need for community oncology institutional data regarding their use.

IMMU-01. IMMUNE CHECKPOINT INHIBITION FOR PEDIATRIC CNS TUMORS: A SINGLE INSTITUTION EXPERIENCE

INTRODUCTION Immune checkpoint inhibition through PD-1 and CTLA-4 blockade has shown efficacy in some adult malignancies and is being investigated in pediatrics. We describe our institutional experience with immune checkpoint inhibition in pediatric CNS tumors. METHODS We performed a retrospective chart review of patients with recurrent, progressive, or refractory pediatric CNS tumors treated with immunotherapy at Dana-Farber/Boston Children’s Hospital between 2018–2019. RESULTS Eleven patients were identified, with median age of 11 years (range:3–9). Diagnoses included DIPG (n=3), HGG (n=4), ependymoma (n=1), craniopharyngioma (n=1), HGNET (n=1) and NGGCT (n=1). Eight patients had recurrent disease (5 local; 3 disseminated); three had refractory disease (non-recurrent). Nine patients were treated with combination therapy (ipilimumab/nivolumab); two patients received monotherapy with either nivolumab or pembrolizumab. Median time from initial diagnosis-to-treatment was 8 months (range 0.8–156). Ten patients received radiation therapy (RT) prior to immunotherapy, with one receiving concurrent RT. Median duration of treatment was 6.1 months (range:1–19). Therapy was discontinued in nine patients: seven due to disease progression and two due to adverse events (colitis, transaminitis). Other pertinent toxicities included type 1 diabetes, hypothyroidism and skin toxicity. Based on iRANO criteria, best responses included partial (n=4), stable (n=6) and progressive disease (n=1). Durable response (>12months) was noted in two patients (HGG and progressive NGGCT). CONCLUSION Immune checkpoint inhibition appears to have clinical benefit and is relatively well tolerated in this cohort of patients. Results from recently completed prospective clinical trials will be critical to inform clinical decisions.

EPID-06. DIAGNOSTIC INTERVAL TIME OF PEDIATRIC CNS TUMORS: A REPORT OF THE CANCER IN YOUNG PEOPLE IN CANADA (CYP-C) DATABASE

INTRODUCTION CNS tumors are the second most common neoplasm in children and have historically been associated with longer time to diagnosis. Data on the time-to-diagnosis for Canadian children with CNS tumors are limited and outdated. We aimed at evaluating the diagnostic interval time(DIT) for Canadian children, and identifying factors possibly associated with prolonged DIT. METHODS Using the CYP-C database, we analyzed data from children <15 years, diagnosed with CNS tumors between 2001–2015. DIT was defined as time in weeks, elapsed from the first contact with a healthcare provider to confirming diagnosis. We described DIT according to patient’s demographics, socioeconomic, geographic factors as well as tumor-related criteria. RESULTS Patients from all Canadian provinces, except Ontario, had available timepoints to calculate DIT. The cohort included 842 patients. Mean DIT for all patients was 11.7 weeks(median 1.4). Gliomas had the longest mean DIT and embryonal tumors had the shortest(14.6 and 3.6 weeks p<0.01). ATRT and medulloblastoma had a mean DIT of 1.3 and 4.3 weeks respectively. DIT for HGG was shorter than for LGG (6.4 versus 16.1 weeks, p<0.01). Metastatic disease, infratentorial tumors, or age £36 months had significantly shorter DIT (5.6 vs 12.4 vs 18.4, 7.4 vs 13.1 and 8.6). Sex, annual income(QAIPPE), and distance from tertiary center did not influence DIT. CONCLUSION The current diagnostic interval time for pediatric CNS tumors in Canada is 11.7 weeks(median 1.4weeks). These results only reflect the healthcare system’s contribution toward diagnosis confirmation, but not the patient interval before seeking medical attention.

SWK-08. DELAYED DIAGNOSIS OF CENTRAL NERVOUS SYSTEM (CNS) TUMORS IN CHILDREN: PERSPECTIVE FROM THE FRONTLINE

Delayed diagnosis of CNS tumors in children is well documented, partially due to challenges in recognizing rare diagnoses. Our objective was to describe Canadian family physicians’ attitudes and confidence in diagnosing and managing pediatric CNS tumors. A standardized questionnaire was administered at a Canadian national family physicians’ conference. Items were based on observations from our institutional study of prediagnostic symptomatic interval in pediatric CNS tumors. 449 surveys were completed. 302/443 (68%) physicians practice in cities. 153/447 (34%) report encountering parents that inquire about their children having brain tumors. 261/449 (58%) have not managed a pediatric brain tumor. 153/447 (34%) report they are not confident, 255/447 (57%) somewhat confident and 39/447 (9%) confident in managing a suspected brain tumor in a stable child. 259/447 (58%) would refer directly to a hospital/specialist. The reported median time for suspicion of a brain tumor was 8–14 days for children with vomiting and/or headache and 1 day for children with seizure and/or ataxia. 410/447 (97%) report not knowing any guidelines to help with management. 235/447 (53%) suggested barriers they experience to include 52/235 (22%) wait times for imaging/specialists, 37/235 (16%) geographical location of the child, 27/235 (12%) knowledge, 25/235 (11%) access to imaging/specialist, and 15/235 (6%) patient-related factors or system barriers, and 8/235 (3%) specialist attitudes. 68/235 (29%) identified no barriers in their practice. This study provides insight into family physicians’ perceived challenges and barriers in diagnosing and managing new suspected pediatric CNS tumors. Educational effort and overcoming systemic perceived barriers may increase physicians’ confidence.

PATH-31. THE IMPACT OF MOLECULAR PROFILING OF PEDIATRIC CNS TUMORS ON TUMOR DIAGNOSIS AND MANAGEMENT - A SINGLE CENTER EXPERIENCE

BACKGROUND Next generation sequencing (NGS) plays a role in neuro-oncology research and in clinical diagnosis and management. Here, we describe how NGS for pediatric CNS tumors impacted clinical diagnosis and therapy at a single institution. METHODS NGS was performed using the UCSF 500 Gene Panel (targeted sequencing platform covering about 500 cancer associated genes). Patients were selected for NGS based on tumor pathology /need to identify therapeutic targets. We collected data on patient demographics, tumor histology/pathway alterations/therapeutic targets/therapy and used descriptive statistics for data analysis. RESULTS Between January 2016 and July 2019, about one-third of patients with CNS tumors seen at our institution (N=29) were interrogated. NGS revealed pathway alterations in 20/29 patients. Treatment recommendations/modifications based on pathway alterations/therapeutic targets impacted the therapy of 18 patients. Patient groups: Medulloblastoma (N=6), alterations in WNT, SHH, and TP53 pathways (Vismodegib recommended for SHH pathway alteration but not used). High-grade glioma (N=4), alterations (with treatment changes) included, NF1(Trametinib, Everolimus); MSH2/MLH1(Nivolumab); CDKN2A/CDKN2B/CDKN2C(Abemaciclib); EGFR (Osimertinib, Afatinib); H3K27M (Panobinostat/ONC201); BRAFV600 (Dabrafenib, Trametinib); ATRT (N=1) SMARCB1; Low Grade Glioma (N=10), BRAFV600(Vemurafenib) /BRAFKIAA1549 fusion (Trametinib)/ PIK3CA; DIPG (N=5), H3K27M/BCOR/ P53/ACVR/PIK3CA (LY3023414, Everolimus)/PDGFR(Dasatinib); Ependymoma (N=3), PFA/PFB/RELA Fusion. Seven patients were treated with targeted therapy + conventional therapy. In 8 patients targeted therapy remains an option but not yet needed. CONCLUSIONS NGS of pediatric brain tumors is widely available and contributes to the diagnosis/therapy of pediatric CNS tumors. Optimal chemotherapy/targeted therapy combinations are areas of study.