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PURPOSE Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically ( P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively ( P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance ( P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.

BackgroundDiffuse intrinsic pontine gliomas (DIPG) generally occur in young school-age children, although can occur in adolescents and young adults. The purpose of this study was to describe clinical, radiological, pathologic, and molecular characteristics in patients ≥10 years of age with DIPG enrolled in the International DIPG Registry (IDIPGR).MethodsPatients ≥10 years of age at diagnosis enrolled in the IDIPGR with imaging confirmed DIPG diagnosis were included. The primary outcome was overall survival (OS) categorized as long-term survivors (LTS) (≥24 months) or short-term survivors (STS) (ResultsAmong 1010 patients, 208 (21%) were ≥10 years of age at diagnosis; 152 were eligible with a median age of 12 years (range 10-26.8). Median OS was 13 (2-82) months. The 1-, 3-, and 5-year OS was 59.2%, 5.3%, and 3.3%, respectively. The 18/152 (11.8%) LTS were more likely to be older (P < .01) and present with longer symptom duration (P < .01). Biopsy and/or autopsy were performed in 50 (33%) patients; 77%, 61%, 33%, and 6% of patients tested had H3K27M (H3F3A or HIST1H3B), TP53, ATRX, and ACVR1 mutations/genome alterations, respectively. Two of 18 patients with IDH1 testing were IDH1-mutant and 1 was a LTS. The presence or absence of H3 alterations did not affect survival.ConclusionPatients ≥10 years old with DIPG have a median survival of 13 months. LTS present with longer symptom duration and are likely to be older at presentation compared to STS. ATRX mutation rates were higher in this population than the general DIPG population.

Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair–deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. Significance: Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction. This article is highlighted in the In This Issue feature, p. 995

Importance Prompt recognition of a child with a cancer predisposition syndrome (CPS) has implications for cancer management, surveillance, genetic counseling, and cascade testing of relatives. Diagnosis of CPS requires practitioner expertise, access to genetic testing, and test result interpretation. This diagnostic process is not accessible in all institutions worldwide, leading to missed CPS diagnoses. Advances in electronic health technology can facilitate CPS risk assessment. Objective To evaluate the diagnostic accuracy of a CPS prediction tool (McGill Interactive Pediatric OncoGenetic Guidelines [MIPOGG]) in identifying children with cancer who have a low or high likelihood of having a CPS. Design, Setting, and Participants In this international, multicenter diagnostic accuracy study, 1071 pediatric (

Background: The COVID-19 pandemic has had a major impact on access to health care resources. Our objective was to estimate the impact of the COVID-19 pandemic on the incidence of childhood cancer in Canada. We also aimed to compare the proportion of patients who enrolled in clinical trials at diagnosis, presented with metastatic disease or had an early death during the first 9 months of the COVID-19 pandemic compared with previous years. Methods: We conducted an observational study that included children younger than 15 years with a new diagnosis of cancer between March 2016 and November 2020 at 1 of 17 Canadian pediatric oncology centres. Our primary outcome was the monthly age-standardized incidence rates (ASIRs) of cancers. We evaluated level and trend changes using interventional autoregressive integrated moving average models. Secondary outcomes were the proportion of patients who were enrolled in a clinical trial, who had metastatic or advanced disease and who died within 30 days. We compared the baseline and pandemic periods using rate ratios (RRs) and 95% confidence intervals (CIs). Results: Age-standardized incidence rates during COVID-19 quarters were 157.7, 164.6, and 148.0 per million, respectively, whereas quarterly baseline ASIRs ranged between 150.3 and 175.1 per million (incidence RR 0.93 [95% CI 0.78 to 1.12] to incidence RR 1.04 [95% CI 0.87 to 1.24]). We found no statistically significant level or slope changes between the projected and observed ASIRs for all new cancers (parameter estimate [β], level 4.98, 95% CI −15.1 to 25.04, p = 0.25), or when stratified by cancer type or by geographic area. Clinical trial enrolment rate was stable or increased during the pandemic compared with baseline (RR 1.22 [95% CI 0.70 to 2.13] to RR 1.71 [95% CI 1.01 to 2.89]). There was no difference in the proportion of patients with metastatic disease (RR 0.84 [95% CI 0.55 to 1.29] to RR 1.22 [0.84 to 1.79]), or who died within 30 days (RR 0.16 [95% CI 0.01 to 3.04] to RR 1.73 [95% CI 0.38 to 15.2]). Interpretation: We did not observe a statistically significant change in the incidence of childhood cancer, or in the proportion of children enrolling in a clinical trial, presenting with metastatic disease or who died early during the first 9 months of the COVID-19 pandemic, which suggests that access to health care in pediatric oncology was not reduced substantially in Canada.

BACKGROUND RAF alterations are oncogenic drivers found in most pediatric low-grade gliomas (LGGs). Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II pan‑RAF inhibitor. METHODS FIREFLY-1 (NCT04775485) is a multicenter phase 2 study evaluating the safety and efficacy of tovorafenib monotherapy. Registrational arm 1 enrolled patients with recurrent/progressive LGG harboring an activating BRAF alteration. Patients aged 6 months–25 years who progressed following ≥ 1 prior line of systemic therapy were eligible. Tovorafenib 420 mg/m2 (≤ 600 mg) was administered weekly (tablet or liquid suspension formulation) until progression or for ≥ 26, 28-day cycles. The primary endpoint (arm 1) was overall response rate, as defined by RANO criteria, per independent review. RESULTS As of April 14, 2022, 25 patients were enrolled to arm 1 and had ≥ 6 months of follow-up. Median age at enrollment was 8 years (range 3–18). Most patients had astrocytomas (92%), 48% with optic pathway involvement. Patients were heavily pretreated (56% with ≥ 3 prior lines of therapy), and 72% previously received MAPK pathway-targeted agents. Tumors harbored BRAF fusions (84%) or BRAF V600E mutations (16%). Per independent assessment, partial responses (1 unconfirmed) were seen in 14 (64%) of 22 evaluable patients, with 6 additional patients having stable disease, and a clinical benefit rate of 91%. Responses were achieved in tumors with BRAF fusions and V600E mutations. Most treatment-emergent adverse events (AEs) were grade 1 or 2 (96%). The most common grade ≥ 3 AEs were anemia (12%), vomiting, increased blood creatinine phosphokinase and maculopapular rash (8% each). Seven patients (28%) required dose modification for treatment-related AEs; no patients discontinued tovorafenib due to AEs. Updated results, including efficacy per RAPNO assessments will be presented. CONCLUSIONS Tovorafenib was generally well tolerated and showed encouraging evidence of antitumor activity in children with pretreated BRAF-altered LGG.

BACKGROUND Plexiform neurofibromas (PN) are observed in up to 50% of patients with neurofibromatosis type 1 (NF1). Trametinib has been used widely to treat PN but limited data has been reported on its efficacy within a clinical trial. METHODS This ongoing multicenter phase II trial includes patients with pediatric low-grade glioma and PN. Patients received daily oral trametinib (MEK inhibitor) for eighteen 28-day cycles. The volumes of PN were centrally quantified using a new semi-automatic 3D segmentation method. RESULTS As of May 15, 2022, 46 patients with PN were enrolled in the study and the recruitment was completed for this study arm. Thirty-four completed treatment and were available for analysis. For these patients, the median age was 10.5 years (range 0.7-19.8). The median volume of PN at baseline was 51cm3 (range 2.6 to 487.6). Among the 34 patients, 28 (82.4%) completed 18 cycles as planned. Two patients discontinued due to adverse reaction, three patients refused to continue treatment and one patient discontinued treatment based on physician decision. Median duration of treatment was 16.8 months (range 2.8 to 16.8). Median duration of follow-up was 30.4 months (range 8.2 to 42). A total of 38 PN were available for volumetric analysis. Using RECIST evaluation, the overall response rate was 13.1%. Volumetric assessment demonstrated an overall response rate of 64.7% (22/34 patients), and 65.8% (25/38 PN) of PN showed a decrease of more than 20% in volume. Median volume change was -30% (range -93.5 to 14.3). Thirty-one patients (91.1%) had durable response without progression (lasting ≥ 1 year). After discontinuation of treatment, one patient underwent surgery and three patients resumed MEK inhibitor. CONCLUSION We report outcome and volumetric quantification of PN treated with trametinib within a large clinical trial. Based on the current results, trametinib is effective and offers durable response.

Purpose Constitutional mismatch repair deficiency (CMMRD) is a highly penetrant cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. As several cancer syndromes are clinically similar, accurate diagnosis is critical to cancer screening and treatment. As genetic diagnosis is confounded by 15 or more pseudogenes and variants of uncertain significance, a robust diagnostic assay is urgently needed. We sought to determine whether an assay that directly measures MMR activity could accurately diagnose CMMRD. Patients and Methods In vitro MMR activity was quantified using a 3′-nicked G-T mismatched DNA substrate, which requires MSH2-MSH6 and MLH1-PMS2 for repair. We quantified MMR activity from 20 Epstein-Barr virus–transformed lymphoblastoid cell lines from patients with confirmed CMMRD. We also tested 20 lymphoblastoid cell lines from patients who were suspected for CMMRD. We also characterized MMR activity from patients with neurofibromatosis type 1, Li-Fraumeni syndrome, polymerase proofreading-associated cancer syndrome, and Lynch syndrome. Results All CMMRD cell lines had low MMR activity (n = 20; mean, 4.14 ± 1.56%) relative to controls (n = 6; mean, 44.00 ± 8.65%; P < .001). Repair was restored by complementation with the missing protein, which confirmed MMR deficiency. All cases of patients with suspected CMMRD were accurately diagnosed. Individuals with Lynch syndrome (n = 28), neurofibromatosis type 1 (n = 5), Li-Fraumeni syndrome (n = 5), and polymerase proofreading-associated cancer syndrome (n = 3) had MMR activity that was comparable to controls. To accelerate testing, we measured MMR activity directly from fresh lymphocytes, which yielded results in 8 days. Conclusion On the basis of the current data set, the in vitro G-T repair assay was able to diagnose CMMRD with 100% specificity and sensitivity. Rapid diagnosis before surgery in non-neoplastic tissues could speed proper therapeutic management.

BACKGROUND/RATIONAL: Following initial irradiation sparing therapy, many young children with relapsed medulloblastoma can be salvaged with craniospinal irradiation (CSI). However, the interval to relapse is short and neurocognitive sequelae remain a major concern. The contribution of molecular subgrouping may help refine indications and modalities of salvage strategies in this population. METHOD: From a cohort of 151 young children with molecularly characterized relapsed medulloblastoma, subset analysis of the SHH medulloblastoma was conducted to describe the practice of salvage radiotherapy and associated post-relapse survival (PRS). RESULTS: Sixty-seven SHH medulloblastoma patients (46 M0; 54 GTR; 11 non-ND/MBEN) received salvage therapy with curative intent. Before relapse, 54 (80.6%) received conventional chemotherapy (CC), 13 (19.4%) high-dose chemotherapy (HDC), while seven had additional focal radiotherapy (fRT). Median time to relapse was 11.1 months (range 3.8-41.0) and 43.3% were localized. Thirty patients (16 localized relapse) underwent surgery. Forty-seven (71.2%) received salvage radiotherapy (20 with CC; 10 with HDC; 15 alone, two unknown). CSI and fRT accounted for 82% and 18% respectively. CSI median dose was 36Gy (range 18-39Gy). Ten patients (eight with localized relapse) received CSI doses ≤23.4Gy. Nineteen patients (28.8%) did not receive any radiotherapy (nine HDC; 10 CC only). Radiotherapy was associated with better 3-year PRS (73.0% versus 36.1%; p=0.001). All patients treated with CSI ≤ 23.4Gy were alive at median follow-up of 69 months(24-142). Six of nine patients treated with HDC without irradiation were alive at last follow-up. Sixty-three percent of patients received reduced dose CSI(≤23.4Gy), fRT, or no radiotherapy, and their PRS did not significantly differ from those who received CSI ≥ 30.6Gy (p = 0.54). CONCLUSION: While salvage CSI provided PRS benefit in this SHH medulloblastoma cohort, we report the use of reduced salvage radiotherapy and irradiation avoidance in 63% of the patients, with 60% alive at last follow-up.

BACKGROUND: High-grade gliomas (HGG) with replication-repair deficiency (RRD) harbour high mutation burden (TMB) and are rapidly fatal following chemo-radiation approaches. Although hypermutation results in objective responses and prolonged survival in >30% of patients undergoing PD1-blockade, salvage following failure of PD1-inhibition remains a challenge. METHODS: We performed a real-world study of Ipilimumab (anti-CTLA4) in combination with Nivolumab/Pembrolizumab for patients failing single-agent PD1-inhibition. RESULTS: Among 68 consortium patients with relapsed HGG treated with single-agent PD1-inhibitors, progression was observed in 43 (63%). Ipilimumab was added to 20/43 (46.5%), 14 (32.5%) received best supportive care (BSC), and 9 (21%) received miscellaneous therapies. For patients receiving CTLA4/PD1-inhibition, median age at progression was 12.3-years (IQR: 9; 15.6). Time from anti-PD1 initiation to progression was 8-months (IQR: 3.8; 18.5). Germline predisposition was observed in all patients (CMMRD: 70%, Lynch: 25%, polymerase-proofreading deficiency: 5%). All HGG were hypermutant (median TMB: 182 mutations/Mb; IQR: 15.6; 369.4). Centralized radiology review revealed objective responses in 3/20 (15%, all ultra-hypermutant: 320, 496, 834 mutations/Mb), stable disease in 5 (25%), and 12 (60%) eventually progressed (iRANO). Following failure of PD1-blockade, estimated progression-free and overall survival at 18-months for patients receiving CTLA4/PD1-inhibition were 11% and 25%, respectively. Importantly, survival was superior to patients receiving BSC (median OS 1-year on the anti-CTLA4/PD1combination (range:1-48 months). The combinational immunotherapy resulted in significant autoimmune toxicity in 11/20 (55%), warranting immunosuppressive therapy in all, and treatment abandonment in 6 patients. CONCLUSION: Combined CTLA4/PD1-blockade after failure of single-agent PD1-inhibition revealed objective responses and prolonged survival in an otherwise rapidly-fatal disease. This needs to be assessed in the context of significant autoimmunity, supporting the need for the current prospective trial (NCT04500548), and novel strategies to limit treatment-related toxicity.

Cancers arising from germline DNA mismatch-repair or polymerase-proofreading deficiencies (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion/deletion (MS-indel) burden in humans and are lethal due to inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICI) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI in these patients. ICI treatment of 45 progressive/recurrent tumours from 38 patients revealed durable objective responses in the majority, culminating in 3-year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations/Mb) enriched for combined MMRD+PPD, while MS-indels predicted response in MMRD tumours with lower mutation burden (10-100 mutations/Mb). Further, both mechanisms were associated with increased immune infiltration even in “immunologically-cold” tumours such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and associated with immune activation in both the tumour microenvironment and systemically. Further, patients with flare continuing ICI treatment achieved durable responses. Our study demonstrates improved survival for patients with tumours not previously known to respond to ICI, including CNS and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained responses to immunotherapy.

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion–deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10–100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in ‘immunologically cold’ tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy., Hypermutation and microsatellite burden determine responses and long-term survival following PD-1 blockade in children and young adults with refractory cancers resulting from germline DNA replication repair deficiency.

Primary CNS tumors are the leading cause of cancer-related death in pediatrics. It is essential to understand treatment trends to interpret national survival data. In Canada, children with CNS tumors are treated at one of 16 tertiary care centers. We surveyed pediatric neuro-oncologists to create a national standard of practice to be used in the absence of a clinical trial for seven of the most prevalent brain tumors in children. This allowed description of practice across the country, along with a consensus. This had a multitude of benefits, including understanding practice patterns, allowing for a basis to compare in future research and informing Health Canada of the current management of patients. This also allows all children in Canada to receive equivalent care, regardless of location.

BACKGROUND Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. It is known that the majority of PLGG have activation of the MAPK/ERK pathway. METHODS This multicenter phase II included three progressing/refractory PLGG groups: NF1 patients, KIAA1549-BRAF fusion patients and patients with other activation of the MAPK/ERK pathway (excluding V600E). Primary objective is to evaluate overall response rate after daily oral trametinib administration for 18 cycles each 28 days duration. Secondary objectives include the assessment of progression-free survival, tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment. RESULTS As of June 1 2020, 37 patients have been enrolled (NF1: 7 patients, KIAA1549-BRAF fusion: 22, other: 8 (including 5 patients with FGFR1 alterations). Median age is 9.3 years (range 2.3–25.4). Median follow-up is 8.8 months (range 0–19.3). Twenty-eight patients are evaluable. Best response includes: 4 partial response (PR) (14%), 5 minor response (MR) (18%), 18 stable disease (64%), 1 progressive disease (3.5%). Median time to response is 2.8 months (range 2.4–11.3). Median duration of response is 8.0 months (range 0.6–16.8. Progression free survival at 12 months is 83.1% (95% CI 70.5–98.0%) and median progression free survival has not reached. Nine patients (24%) discontinued treatment: 3 for progressive disease, 4 adverse events (3 alanine aminotransferase increase, 1 paronychia), 2 for other reasons. CONCLUSION Trametinib is a potentially effective targeted therapy for patients with recurrent/refractory PLGG. Overall treatment is well tolerated. This ongoing trial will continue to gather data on response rate, duration of response and safety of trametinib for PLGG.

Objectives Chronic metabolic disturbances related to cancer treatment are well reported among survivors of pediatric acute lymphoblastic leukemia (ALL). However, few studies have investigated the incidence of these complications during the phase of chemotherapy. We evaluated the incidence of acute metabolic complications occurring during therapy in our cohort of patients diagnosed with ALL. Methods A prospective study involving 50 ALL pediatric patients diagnosed and treated between 2012 and 2016 in our oncology unit. We collected weight, blood pressure, fasting plasma glucose and hemoglobin A1C (HBA1c) levels during the two years of therapy. Results Obesity and overweight occurred in 43 and 25%, respectively among patients and have been reached at 12 months of chemotherapy. About 26% of the patients developed high blood pressure and 14% experienced hyperglycemias without meeting diabetes criteria. There was a significant decrease of HBA1c levels between the beginning and the end of therapy (p Conclusions Increase of body mass index in our ALL pediatric patients occurred during the first months of therapy and plateaued after a year of treatment. We should target this population for early obesity prevention. HbA1c levels measured during therapy did not reveal diabetes criteria. Hence, fasting blood glucose levels are sufficient to monitor ALL pediatric patients’ glycemia.

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPG) are midline gliomas that arise from the pons and the majority are lethal within a few months after diagnosis. Due to the lack of histological diagnosis the epidemiology of DIPG is not completely understood. The aim of this report is to provide population-based data to characterize the descriptive epidemiology of this condition in Canadian children. PATIENTS AND METHODS: A national retrospective study of children and adolescents diagnosed with DIPG between 2000 and 2010 was undertaken. All cases underwent central review to determine clinical and radiological diagnostic characteristics. Crude incidence figures were calculated using age-adjusted (0-17 year) population data from Statistics Canada. Survival analyses were performed using the Kaplan-Meier method. RESULTS: A total of 163 patients with pontine lesions were identified. Central review determined one-hundred and forty-three patients who met clinical, radiological and/or histological criteria for diagnosis. We estimate an incidence rate of 1.9 DIPG/1,000,000 children/year in the Canadian population over a 10 years period. Median age at diagnosis was 6.8 years and 50.3% of patients were female. Most patients presented with cranial nerve palsies (76%) and ataxia (66%). Despite typical clinical and radiological characteristics, histological confirmation reported three lesions to be low-grade gliomas and three were diagnosed as CNS embryonal tumor not otherwise specified (NOS). CONCLUSIONS: Our study highlights the challenges associated with epidemiology studies on DIPG and the importance of central review for incidence rate estimations. It emphasizes that tissue biopsies are required for accurate histological and molecular diagnosis in patients presenting with pontine lesions and reinforces the limitations of radiological and clinical diagnosis in DIPG. Likewise, it underscores the urgent need to increase the availability and accessibility to clinical trials.

Replication repair deficiency (RRD) leading to hypermutation is an important driving mechanism of high-grade glioma (HGG) occurring predominantly in the context of germline mutations in RRD-associated genes. Although HGG presents specific patterns of DNA methylation corresponding to oncogenic mutations, this has not been well studied in replication repair-deficient tumors. We analyzed 51 HGG arising in the background of gene mutations in RRD utilizing either 450 k or 850 k methylation arrays. These were compared with HGG not known to be from patients with RRD. RRD HGG harboring secondary mutations in glioma genes such as IDH1 and H3F3A displayed a methylation pattern corresponding to these methylation subgroups. Strikingly, RRD HGG lacking these known secondary mutations clustered together with an incompletely described group of HGG previously labeled “Wild type-C” or “Paediatric RTK 1”. Independent analysis of two comparator HGG cohorts showed that other RRD/hypermutant tumors clustered within these subgroups, suggesting that undiagnosed RRD may be driving some HGG clustering in this location. RRD HGG displayed a unique CpG Island Demethylator Phenotype in contrast to the CpG Island Methylator Phenotype described in other cancers. Hypomethylation was enriched at gene promoters with prominent demethylation in genes and pathways critical to cellular survival including cell cycle, gene expression, cellular metabolism, and organization. These data suggest that methylation arrays may provide diagnostic information for the detection of RRD HGG. Furthermore, our findings highlight the unique natural selection pressures in these highly dysregulated, hypermutant cancers and provide the novel impact of hypermutation and RRD on the cancer epigenome.

PURPOSE Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors. PATIENTS AND METHODS We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E–mutated glioma treated with BRAF inhibition across 29 centers from multiple countries. RESULTS Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy ( P < .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of CDKN2A, were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively ( P = .02). CONCLUSION Use of BRAF inhibition results in robust and durable responses in BRAF V600E–mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas.

Objective The objective of this study was to describe the outcome of healthy children presenting with newly-diagnosed neutropenia in an infectious context. Results A total of 184 episodes of neutropenia were included in children aged 3 months to 5 years. There were 118 (64%) episodes of moderate neutropenia and 66 (36%) of severe neutropenia (SN). SN episodes were more likely related to intensification of antibiotic regimen used and further investigations. The median duration of neutropenia was 8.5 days. Chronic benign neutropenia occurred in 7 (4%) patients. Conclusion SN led to intensification of antibiotic therapy, but no children encountered an unfavorable outcome and the neutropenia episodes were short-lived.

BackgroundThe aim of this study is to present a national surveillance report on pediatric central nervous system (CNS) tumors in Canada during the period between 2001 and 2015.MethodsAll pediatric patients with a diagnosis of primary CNS tumors were collected by the Cancer in Young People in Canada (CYP-C) surveillance system that includes every patient less than 15 years of age with a tumor seen in one of the 17 pediatric oncology centres in Canada. This registry included malignant and benign CNS tumors. We calculated the age-adjusted incidence rates (AAIRs) per 100 000 person-years for CNS tumors overall and by age group, major histology subgroups, and geographical distribution over the country.ResultsOverall, 3306 patients less than 15 years old had been diagnosed with a CNS tumor in Canada in 2001–2015 with a 1.23:1 male to female ratio. The overall AAIR is 3.80. The three most frequent groups of tumors were low-grade gliomas (36.4%), high-grade gliomas (22.3%), and embryonal tumors (18.7%) with incidence rates of 1.41, 0.86, and 0.72 per 100 000 person-years, respectively. The incidence rate of pediatric CNS tumors is stable during the period 2001–2015 in Canada and no significant differences were seen between malignant and benign tumors over the country.ConclusionsThese data represent all the pediatric patients 0–14 years old with a CNS tumor in the Canadian population. Incidence rates by age group, sex, and subgroups of tumors are similar to those seen in the literature.

Background Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. Up to 50% will be refractory to conventional chemotherapy. It is now known that the majority of PLGG have activation of the MAPK/ERK pathway. The same pathway is also activated in plexiform neurofibromas (PNs) which are low-grade tumors involving peripheral nerves in patients with neurofibromatosis type 1 (NF1). These lesions are known to be refractory to chemotherapy. Specific MEK inhibitors such as trametinib are now available and have been approved for other cancers harboring mutations in the MAPK/ERK pathway such as melanoma. We have observed significant responses to trametinib in patients with refractory PLGG in our institutions and results from the phase I study are promising. The treatment appears not only efficacious but is also usually well tolerated. We hypothesize that we will observe responses in the majority of refractory PLGG and PN treated with trametinib in this phase 2 study. Methods The primary objective is to determine the objective response rate of trametinib as a single agent for treatment of progressing/refractory tumors with MAPK/ERK pathway activation. The TRAM-01 study is a phase II multicentric open-label basket trial including four groups. Group 1 includes NF1 patients with progressing/refractory glioma. Group 2 includes NF1 patients with plexiform neurofibroma. Group 3 includes patients with progressing/refractory glioma with KIAA1549-BRAF fusion. Group 4 includes other patients with progressing/refractory glioma with activation of the MAPK/ERK pathway. Eligible patients for a given study group will receive daily oral trametinib at full dose for a total of 18 cycles of 28 days. A total of 150 patients will be enrolled in seven Canadian centers. Secondary objectives include the assessment of progression-free survival, overall survival, safety and tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment. Discussion Trametinib will allow us to target directly and specifically the MAPK/ERK pathway. We expect to observe a significant response in most patients. Following our study, trametinib could be integrated into standard treatment of PLGG and PN. Trial registration ClinicalTrials.gov Identifier: NCT03363217 December 6, 2017.

International audience; Childhood brain tumors have suspected prenatal origins. To identify vulnerable developmental states, we generated a single-cell transcriptome atlas of >65,000 cells from embryonal pons and forebrain, two major tumor locations. We derived signatures for 191 distinct cell populations and defined the regional cellular diversity and differentiation dynamics. Projection of bulk tumor transcriptomes onto this dataset shows that WNT medulloblastomas match the rhombic lip-derived mossy fiber neuronal lineage and embryonal tumors with multilayered rosettes fully recapitulate a neuronal lineage, while group 2a/b atypical teratoid/rhabdoid tumors may originate outside the neuroectoderm. Importantly, single-cell tumor profiles reveal highly defined cell hierarchies that mirror transcriptional programs of the corresponding normal lineages. Our findings identify impaired differentiation of specific neural progenitors as a common mechanism underlying these pediatric cancers and provide a rational framework for future modeling and therapeutic interventions.

Pediatric pilocytic astrocytomas (PAs) are low grade gliomas and the most common brain tumors in children. They often represent a therapeutic challenge when incompletely resected as they can recur and progress despite the use of several lines of chemotherapeutic agents or even radiation therapy. Genetic alterations leading to activation of the mitogen-activated-protein-kinase pathway are a hallmark of this disease and offer an interesting therapeutic alternative through the use of targeted inhibitors. Here, we describe six children with sporadic PA who were treated with trametinib, a MEK inhibitor, following progression under conventional therapies. Retrospective chart review was performed. The median age at diagnosis was 2.3 years (y) old [range 11 months (m)–8.5 y old]. KIAA1549-BRAF fusion was identified in five cases, and hotspot FGFR1/NF1/PTPN11 mutations in one. All patients received at least one previous line of chemotherapy (range 1–4). The median time on treatment was 11 m (range 4–20). Overall, we observed two partial responses and three minor responses as best response; three of these patients are still on therapy. Treatment was discontinued in the patient with progressive disease. The most frequent toxicities were minor to moderately severe skin rash and gastro-intestinal symptoms. Two patients had dose reduction due to skin toxicity. Quality of life was excellent with decreased hospital visits and a close to normal life. Trametinib appears to be a suitable option for refractory pediatric low-grade glioma and warrants further investigations in case of progression.

Introduction Dickkopf-1 (DKK1) is a soluble protein and antagonist of the Wnt/β-catenin signaling pathway. DKK1 is found elevated in serum from patients affected with various types of cancers and in some instances, it is considered a diagnostic and prognostic biomarker. Elevated serum levels of DKK1 have also been detected in animal models of chronic inflammatory diseases. Previous work from our laboratory has demonstrated upregulation of DKK1 in cells and mouse models of the bone marrow failure (BMF) and cancer-prone disease Fanconi anemia (FA). The present study aimed to investigate whether DKK1 blood levels in patients are associated with FA or inflammatory responses to acute infections. Methods Plasma samples were collected from 58 children admitted to the Centre Mere-Enfant Soleil du Centre Hospitalier de Quebec-Universite Laval with signs of acute infections. Blood plasma specimens were also collected from healthy blood donors at the Hema-Quebec blood donor clinic. Plasmas from patients diagnosed with FA were also included in the study. DKK1 levels in blood plasmas were assessed by standard ELISA. Results Patients with acute infections showed dramatically high levels of DKK1 (6072 ± 518 pg/ml) in their blood compared to healthy blood donors (1726 ± 95 pg/ml). No correlations were found between DKK1 levels and C reactive protein (CRP) concentration, platelet numbers, or white blood cell counts. Patients with FA showed higher DKK1 plasma levels (3419 ± 147.5 pg/ml) than healthy blood donors (1726 ± 95 pg/ml) but significantly lower than patients with acute infections. Conclusion These findings suggest that blood DKK1 is elevated in response to infections and perhaps to inflammatory responses.

BACKGROUND Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. It is known that the majority of PLGG have activation of the MAPK/ERK pathway. METHODS This ongoing multicenter phase II trial includes three progressing/refractory PLGG groups: NF1 patients, KIAA1549-BRAF fusion patients and patients with other activation of the MAPK/ERK pathway (excluding V600E). The primary objective was to evaluate the overall response rate based on RANO criteria after daily oral trametinib administration for 18 cycles, lasting 28 days each. Secondary objectives include the assessment of progression-free survival, tolerability of trametinib, serum levels of trametinib and quality of life evaluation during treatment. RESULTS As of February 12 2021, 50 patients have been enrolled (NF1: n=10; KIAA1549-BRAF fusion: n=31; other: n=9 including 5 patients with FGFR1 alterations). Median age is 8.8 years (range 2.4-25.5). Median follow-up is 17.5 months (range 4.7-28.5). Forty-three patients are evaluable. The overall response includes: 4 partial response (PR) (9%), 18 minor response (MR) (42%), 17 stable disease (40%), 4 progressive disease (9%). Median time to response is 5.5 months (range 2.4-13.8). Median duration of response is 6.1 months (range 0.6-26.5). Progression free survival at 12 months is 79.9% (95% CI 68.5-93.6%) and median progression free survival has not yet been reached. Treatment was discontinued for 30 patients: 16 after completing 18 cycles as planned, 5 for progressive disease, 5 for adverse events, 4 for other reasons. A total of 8 patients progressed after discontinuation of treatment including 6 patients (37.5%) that completed 18 cycles. Five of these patients had achieved minor response prior to discontinuation. CONCLUSION Trametinib is a potentially effective targeted therapy for patients with recurrent/refractory PLGG. Treatment was overall well tolerated. This ongoing trial will continue to gather data on response rate, duration of response and safety of trametinib for PLGG.

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 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 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.

Replication repair deficiency (RRD) is an important driving mechanism of pediatric high grade glioma (pHGG) occurring predominantly in the context of germline mutations in RRD-associated genes. Although pHGG present specific patterns of DNA methylation corresponding to driving oncogenic processes, methylation patterns have not been well studied in RRD tumors. We analyzed 52 RRD pHGG using either 450k or 850k methylation arrays. These arrays were compared with 234 PHGG driven by other genetic or epigenetic mechanisms and 10 additional pHGG samples known to be hypermutant. RRD pHGG displayed a methylation pattern corresponding to specific secondary mutations such as IDH1 and H3K27M. Strikingly, RRD pHGG lacking these known secondary mutations largely clustered together with a poorly described group previously labelled Wild type-C. Most of the hypermutant tumors clustered in a similar location suggesting undiagnosed RRD may be a driving force for tumors clustering in this location. Analysis of methylation patterns revealed that RRD pHGG displayed a unique CpG Island Demethylator Phenotype in contrast to the Methylator Phenotype described in other cancers. This effect was most concentrated at gene promotors. Prominent demethylation was observed in genes and pathways critical to cellular survival including cell cycle, gene expression, cellular metabolism and cellular organization. These data suggest that methylation profiles may provide diagnostic information for the detection of RRD pHGG. Furthermore, our findings highlight the unique natural selection pressures in these highly dysregulated, hypermutant cancers and provide novel impact of hypermutation and RRD on the cancer epigenome.

BACKGROUND Constitutional mismatch repair deficiency syndrome (CMMRD) is a severe cancer predisposition syndrome resulting in early onset central nervous system (CNS) and other cancers. International guidelines for surveillance exist but no study has systematically evaluated the efficacy of this protocol. METHODS We surveyed all confirmed CMMRD patients in the International Replication Repair Deficiency Consortium. A surveillance protocol consisting of frequent biochemical, endoscopic and imaging (CNS and total body MRI) studies were employed. Survival analyses and efficacy of each method were assessed. RESULTS Surveillance data were collected from 105 CMMRD individuals from 41 countries. Of the 193 malignant tumors, CNS malignancies were the most common (44%). The surveillance protocol uncovered 49 asymptomatic tumors including 16 glioblastomas and medulloblastomas. Five-year overall survival was 89% for tumors discovered by surveillance, and 61% for symptomatic tumors (p6 months as per protocol. Finally, of the low grade tumors identified asymptomatically, 5 were low grade gliomas. All of the low grade gliomas, which were not resected transformed to high grade tumors at a median of 1.6 ± 0.9 years. CONCLUSION These data support a survival benefit in CMMRD patients undergoing a surveillance protocol. Adherence to protocol and resection of lower grade lesions may improve survival for patients with CNS tumors.

INTRODUCTION Irradiation-sparing approaches are used in young children with medulloblastoma (MB) given the vulnerability of the developing brain to neurocognitive impairment. Limited data are available following relapse for these patients. We aimed to describe the management and outcomes of young children with MB who relapsed after initial treatment without craniospinal irradiation (CSI). METHODS International retrospective study including patients with MB diagnosed between 1995-2017, ≤ 72 months old, initially treated without CSI, who subsequently relapsed. RESULTS Data are available for 66 patients. The median age at initial diagnosis was 27 months (range, 6-72). At diagnosis, 27 patients had metastatic disease. Initial therapy included conventional chemotherapy or with high-dose chemotherapy (HDC) in 30 and 36 patients, respectively. Eight (12.1%) received upfront focal irradiation. Molecular subgrouping was available for 27 (41%) patients. Ten were SHH, five group 3, six group 4 and six others were non-WNT/non-SHH. The median time from initial diagnosis to relapse was 13 months (range, 3-63). Relapse was local, disseminated, or combined in 39%, 32%, and 29%, respectively. The median time to death from relapse was 18 months. Curative intent therapy was given in 53 patients with irradiation (81%), conventional chemotherapy without HDC (40%), and HDC (25%). For patients who received irradiation, 85% received CSI (median dose 33 Gy, 18-41.4) and 15% focal irradiation. Ten patients received chemotherapy without salvage irradiation. The median follow-up time was 44 months (range, 4-255), 33 (62%) patients who underwent curative-intent therapy were alive, including 8/10 SHH, 2/3 group 3, 2/6 group 4, and 4/5 non-WNT/non-SHH. Three of four patients with SHH and treated without salvage radiotherapy are survivors. The 5-year OS for curative intent was 70%. CONCLUSION A substantial proportion of young children who relapse following irradiation-sparing strategies can be salvaged. A proportion of children with SHH MB can be salvaged without salvage radiotherapy.

Embryonal tumors are a heterogeneous group of central nervous system (CNS) tumors whose subgroups have varying incidence and outcome. Despite these differences, they are often grouped as a single entity for study purposes. To date, there are no Canadian multi-institutional studies examining the incidence and outcome of all embryonal subtypes. The current study is an observational study reviewing embryonal tumors in all patients less than 36 months of age diagnosed with a CNS tumor in Canada from 1990 to 2005. Embryonal tumors accounted for 26.9% of all CNS tumors. Medulloblastomas were the highest proportion of the embryonal tumors at 61.5%. Atypical teratoid/rhabdoid tumors (AT/RT) had the second highest proportion of embryonal tumors at 18%. The proportion of primitive neuroectodermal tumors (PNET) was 16%, with 2.6 and 1.9% for congenital medulloepithelioma and ependymoblastoma tumors, respectively. AT/RT and PNET were more common in younger age groups. Medulloblastoma became more prevalent with increasing age, with its highest prevalence in the 25 to 36 month age group. Survival rates for our Canadian population at 18 and 24 months were 0.74 and 0.68 for medulloblastoma, 0.64 and 0.60 for PNET, and 0.36 and 0.29 for AT/RT, respectively. Overall, our data are comparable with published international rates for embryonal tumors. These incidence and outcome figures can guide future research into these rare tumors.

While 2/3 of patients with ATRT are less than 3 years at diagnosis, the literature suggests younger children present with more aggressive disease and poorer outcome. However, little data exist on characteristics and outcome of patients diagnosed with ATRT in the first year of life. In particular, it is unclear whether they access similar treatments as do older children. We compared the cohort of patients ≤12 months from the Canadian ATRT registry to all cases extracted from the literature reported between 1996 and 2014 to describe their clinical and treatment characteristics, and potential prognostic factors. Twenty-six (33.7%) patients from the Canadian registry were ≤12 months at diagnosis as were 120 cases identified in the literature. Post-operatively, 46% of the registry's patients underwent palliation as opposed to 10.8% in the literature cohort. Palliative patients were significantly younger than those who received active therapy (3.3 vs. 6.6 months). While the use of high-dose chemotherapy (HDC) was relatively similar in both cohorts (42.9 and 35.5% respectively), radiotherapy (RT) use was significantly lower in the Canadian cohort (14.3 vs 44.9%). Children ≤6 months, who received active therapy, had a worst outcome than older ones. Gross total resection, HDC and adjuvant RT were associated with better outcomes. Eighty percent of the tested patients had evidence of germline mutation of INI1. While 1/3 of ATRT occurs within the first year of life, a large proportion only received palliative therapy. Even when actively treated, children ≤6 months fare worse. Some selected patients benefit from HDC.

BACKGROUND Children with pediatric low grade glioma’s (PLGG) harboring BRAF V600E mutation have poor outcome due to relative resistance to chemo-radiation and higher risk of malignant transformation. However, the role of targeted BRAF inhibition in these tumors is poorly defined. METHODS We assembled an international cohort of children with BRAF V600E mutant gliomas treated with BRAF inhibition, from 29 centers participating in the PLGG taskforce, and collected response, survival and molecular parameters. RESULTS Sixty-seven patients were treated with BRAFi (56 PLGG and 11 high grade gliomas) for a median time of 17.4 months (6 – 61 months), with 13 PLGG treated upfront. Objective responses was observed in 80% of PLGG patients compared to 28% with conventional chemotherapy (p< 0.001). Rapid responses were observed in most PLGG patients (median of 4 months), sustained in 86% of tumors up to 5 years while on therapy. In contrast, only 36% of PHGG responded to BRAFi with all but one tumor progressing within 18 months. Seventeen patients with PLGG discontinued BRAFi and 76.5% (13/17) progressed rapidly after discontinuation (median time 2.3 months). However, upon re-challenge with BRAFi therapy, 90% achieved an objective response. Poor prognostic factors to conventional therapies such as concomitant homozygous deletion of CDKN2A or H3K27M mutation were not associated with lack of response to BRAFi. Overall these responses translated to 2-year progression-free survival of 0.636 (95%CI 0.505–0.802) and 0.43 (95% CI 0.32–0.57) for BRAFi and chemotherapy treated BRAF V600E PLGG respectively (p=0.003). CONCLUSION The use of BRAFi results in objective, robust and durable responses in BRAF V600E PLGG and is associated with favorable survival. Larger prospective studies will be required to determine appropriate regiments, and long-term functional outcomes with BRAFi therapy in childhood gliomas.

Pediatric brain tumors with replication repair deficiency (RRD) are hypermutant and may respond favorably to immune checkpoint inhibition (ICI). We are collecting ongoing clinical and molecular data from patients with RRD hypermutant cancers treated with ICI as a part of our consortium registry study. Companion biomarkers include tumor mutational burden (TMB), neoantigens and genetic signatures obtained from whole genome and exome sequencing. Immune inference is obtained from RNAseq. Additionally, T-cell receptor rearrangement data are collected from the tumor and blood throughout treatment. From 2015–2018, 53 patients were treated with ICI and combination therapies. Of these 39 had brain tumors, with 93% having high grade gliomas. Two-year overall survival for the entire cohort is 47+/-8%, which compares favorably with historical controls. Tumor location had major impact on outcome. Non-CNS solid tumor patients have 2-year OS of 78+/-11%, all failures occurring within the first 2 months, and sustained responses are observed for 3 years. In contrast, OS for brain tumors is 39+/-10% with late recurrences observed even after 2 years of therapy (p=0.02). Large tumor size and total tumor burden are associated with higher rates of “flare” and poor outcome throughout all cancers. While all tumors are hypermutant, TMB and predicted neoantigens do not correlate with response. However, specific signatures extracted from SNVs and indels are significantly associated with response to ICI and favorable outcome (p=0.005). Notably, RRD IDH1 mutant glioblastomas have particularly poor response to ICI. Interestingly, glioblastomas (n=8) which failed single agent ICI had favorable responses to combination immunotherapies with prolonged survival of 65%+/-8% one year after failure vs 0 for untreated patients (p=0.01). The favorable outcome and responses to ICI are encouraging. Since brain tumors respond less favorably to ICI than other solid tumors, combination therapies based on tumor and immune signatures of these cancers may be beneficial.

BACKGROUND Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. It is now known that the majority of PLGG have activation of the MAPK/ERK pathway. We hypothesize that we will observe responses in recurrent/refractory PLGG treated with trametinib. METHODS This is a multicenter phase II including three progressing/refractory PLGG groups: NF1 patients, KIAA1549-BRAF fusion patients and patients with other activation of the MAPK/ERK pathway (excluding V600E). Patients will receive daily oral trametinib for a total of 18 cycles of 28 days. A total of 104 patients will be enrolled in seven Canadian centers. Secondary objectives include the assessment of progression-free survival, tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment. RESULTS As of January 7 2020, 28 patients have been enrolled (NF1: 6 patients, KIAA1549-BRAF fusion: 17, other: 5 including 3 patients FGFR1 alteration). Median age is 8.5 years (range 2.5–25.4 years). Median follow-up is currently 4.6 months (range 0.16–14.7 months). Twenty patients are currently evaluable. Best response includes: 1 complete response (5%), 3 partial response (15%), 4 minor response (20%), 8 stable disease (40%), 4 progressive disease (20%). 8 patients (28,5%) discontinued treatment: 4 for progressive disease, 3 adverse event (alanine aminotransferase increase), 1 withdrew. CONCLUSION Trametinib is potential effective targeted therapy for patients with recurrent/refractory PLGG. Overall treatment is well tolerated. This ongoing trial will continue to gather data on response rate, duration of response and safety of trametinib for PLGG.

Children with pediatric gliomas harboring BRAF V600E mutation have a poor outcome with current chemoradiation strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors. We collected clinical, imaging, molecular and outcome information from BRAF V600E glioma patients treated with BRAFi across 29 centers from multiple countries. Sixty-seven patients were treated with BRAFi (56 pediatric low grade gliomas, PLGG and 11 pediatric high grade gliomas, PHGG) for up to 5.6 years. Objective responses were observed in 80% of PLGGs compared to 28% with conventional chemotherapy (p

Pediatric brain tumors with replication repair deficiency (RRD) are hypermutant and may respond to immune checkpoint inhibition (ICI). We performed a consortium registry study of ICI in recurrent RRD cancers. Clinical and companion biomarkers were collected longitudinally on all patients. Biomarkers included tumor mutational burden (TMB), neoantigens and genetic signatures obtained from whole genome and exome sequencing. Immune inference was obtained by RNAseq and T cell rearrangement was collected in the tumor and in blood throughout treatment. Of the 46 tumors on the study, 32 were brain tumors with glioblastoma in 96%. Rapid, objective responses (>50%) were observed in 50% of glioblastomas. Three year overall survival for the whole cohort was 48+/-8% which compares favorably with historical controls. Brain tumors fared worse with OS of 39+/-10% and late recurrences observed even after 2 years of therapy (p=0.02). Tumor size and acute “flare” constitute poor outcome throughout all cancers. While all tumors are hypermutant, TMB and predicted neoantigens correlated with response to ICI (p=0.02). Specific signatures extracted from SNVs and total mutations predicted response to ICI and favorable outcome (p=0.005). RNA inference and TCR reveal that the FLARE phenotype is mostly acute nonspecific immune response and not true progression. Finally, glioblastomas (n=8) which failed single agent ICI had favorable responses to combinational immunotherapies with prolonged survival of 65%+/-8% at one year after failure vs 0 for other patients (p=0.01). RRD glioblastomas exhibit favorable outcome and responses to ICI. Combinational therapies based on tumor and immune signatures of these cancers are necessary.

In the original article, the author names were published incorrectly. The names are correct in this publication.

BACKGROUND: Hypermutation constitute an important subgroup of cancers and confers sensitivity to immune checkpoint inhibition (ICI). Glioblastoma arising in children with Constitutional Mismatch Repair Deficiency Syndrome (CMMRD) are ultrahypermutant. Our objective was to quantify the frequency of hypermutant tumors in children, determine whether mutational signatures can predict germline mutations, and treat hypermutant tumors with ICIs. METHODS: Deep panel sequencing of 2984 pediatric tumors (585 brain tumors). Tumor mutation burden was correlated to mutation burden from exome and genome sequencing (R(2) = 0.94). Mutational signatures were analyzed to predict source of hypermutation. Data on 36 patients with hypermutant tumors identified by sequencing were enrolled on an ICI registry trial. RESULTS: Hypermutant tumors (>10 mut/MB) comprised 5% of all pediatric tumors (n=143). These were highly enriched for replication repair mutations (p

Medulloblastoma is the most common malignant brain tumor in children. Published survival rates for this tumor are ∼70%; however, there is limited published information on outcome after disease recurrence. This was an observational study which included all persons under the age of 18 years diagnosed with medulloblastoma from 1990 to 2009 inclusive in Canada. Data collected included date of diagnosis, age at diagnosis, sex, stage, pathology, treatment, recurrence, and current status. Survival rates were determined. In total, 550 cases were ascertained meeting the study criteria. The overall survival rate at 1 year was 83.6%±1.7%, at 3 years 77.2%±1.9%, and at 5 years 72.5%±20%. The progression-free survival rates were 78%±1.9%, 70%±2.1%, and 69±2.1% at 1, 3, and 5 years from initial diagnosis. In total, 173 (31.2%) were reported to have had tumor recurrence and 23 (11.4%) of them were alive at the time of survey with an overall survival rate at 1 year of 38.3%±4%, at 2 years of 16.9%±3.3%, and at 5 years of 12.4%±2.8%. Our data confirm that children with recurrent medulloblastoma have a poor prognosis, supporting the need for novel treatment approaches for this group.

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively ( P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy.

BACKGROUND: A significant amount of childhood brain tumors emerge from cancer predisposition syndromes. Although tumor sequencing is common practice, it is currently impossible to infer germline mutations from tumor data. Glioblastoma Multiforme arising in children with Biallelic Mismatch Repair Deficiency Syndrome (bMMRD) are ultrahypermutant which is highly specific to this syndrome and confers eligibility for immune checkpoint inhibition therapy (ICI). Our objective was to quantify the frequency of hypermutant tumors in children, determine whether mutational signatures can predict germline mutations, and treat hypermutant tumors with ICIs. METHODS: Deep panel sequencing (1000x) of 315 genes in 2984 pediatric tumors (585 brain tumors) and 79 842 adult tumors (3910 brain tumors) was performed. An algorithm was devised to determine mutation burden from 2 MB of panel sequencing data and results correlated strongly with mutation burden from exome sequencing (R2 = 0.94). Mutational signatures were analyzed to predict source of hypermutation. Patients with hypermutant brain tumors identified by panel sequencing were treated with ICI. RESULTS: Hypermutant tumors (>10 mut/MB) comprised 5% of all pediatric tumors (n=143). These were highly enriched for replication repair mutations (p=100 Mut/MB harbored MMR/polymerase mutations suggesting germline bMMRD (p =10–7). Clinical data collected on 15 ultrahypermutant tumors revealed germline mutations in replication repair genes in all patients. Of the 22 patients with hypermutant cancers treated with ICI, 16 had brain tumors, and favorable sustained responses are observed. CONCLUSION: High mutation burden is a sensitive predictor of germline bMMRD. Hypermutant tumors are more common in the pediatric setting than previously appreciated, opening novel therapeutic avenues. ICI shows promise for hypermutant pediatric cancers.

Medulloblastoma is the most common malignant brain tumor in children. There was a perception of pediatric neuro-oncologists that the incidence had declined in Canada. An epidemiological survey was undertaken to determine the incidence of this tumor in Canada and if a change had indeed occurred. All patients 14 years and under diagnosed with medulloblastoma from 1990 to 2009 inclusive in Canada were included. Data collected included date of diagnosis, age at diagnosis, gender, stage, pathology, treatment, recurrence and current status. Data were analysed for change in incidence over time. Data were obtained on 574 eligible patients. The mean overall incidence per 1,000,000 persons was 4.82 (95 % CI 4.28-5.35) for the study time period. The mean age at diagnosis was 5.8 years, and there was a male predominance. Although there was an increase in incidence over the first three time periods (24 % for 1990-1994, 27.5 % for 1995-1999, 27.7 % for 2000-2004), the most recent time period (2005-2009) showed a decrease (21 %). This was true for male children while the incidence was stable for females. The mean incidence rate was double for children under the age of 5 years (7.92 per million) compared to those over 5 years (3.64 per million).This study showed that from 1990 to 2009 the incidence of medulloblastoma was relatively stable, with a slight decrease in the last five-year time period.

The determination of optimal therapy for ependymoma (EP) in infants is ongoing. We describe the incidence, management and outcomes of Canadian infants with EP to discern potential future research questions. Of 579 cases registered in a national database of children