Final results of the Choroid Plexus Tumor study CPT-SIOP-2000

INTRODUCTION: Standards for chemotherapy against choroid plexus tumors (CPT) have not yet been established. METHODS: CPT-SIOP-2000 (NCT00500890) was an international registry for all CPT nesting a chemotherapy randomization for high-risk CPT with Carboplatin/Etoposide/Vincristine (CarbEV) versus Cyclophosphamide/Etoposide/Vincristine (CycEV). Patients older than three years were recommended to receive irradiation: focal fields for non-metastatic CPC, incompletely resected atypical choroid plexus papilloma (APP) or metastatic choroid plexus papilloma (CPP); craniospinal fields for metastatic CPC/APP and non-responsive CPC. High risk was defined as choroid plexus carcinoma (CPC), incompletely resected APP, and all metastatic CPT. From 2000 until 2010, 158 CPT patients from 23 countries were enrolled. RESULTS: For randomized CPC, the 5/10 year progression free survival (PFS) of patients on CarbEV (n = 20) were 62%/47%, respectively, compared to 27%/18%, on CycEV (n = 15), (intention-to-treat, HR 2.6, p = 0.032). Within the registry, histological grading was the most influential prognostic factor: for CPP (n = 55) the 5/10 year overall survival (OS) and the event free survival (EFS) probabilities were 100%/97% and 92%/92%, respectively; for APP (n = 49) 96%/96% and 76%/76%, respectively; and for CPC (n = 54) 65%/51% and 41%/39%, respectively. Without irradiation, 12 out of 33 patients with CPC younger than three years were alive for a median of 8.52 years. Extent of surgery and metastases were not independent prognosticators. CONCLUSIONS: Chemotherapy for Choroid Plexus Carcinoma is feasible and effective. CarbEV is superior to CycEV. A subset of CPC can be cured without irradiation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11060-021-03942-0

Phase II Trial of Dabrafenib Plus Trametinib in Relapsed/Refractory BRAF V600-Mutant Pediatric High-Grade Glioma

PURPOSE: BRAF V600 mutation is detected in 5%-10% of pediatric high-grade gliomas (pHGGs), and effective treatments are limited. In previous trials, dabrafenib as monotherapy or in combination with trametinib demonstrated activity in children and adults with relapsed/refractory BRAF V600-mutant HGG. METHODS: This phase II study evaluated dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600-mutant pHGG. The primary objective was overall response rate (ORR) by independent review by Response Assessment in Neuro-Oncology criteria. Secondary objectives included ORR by investigator determination, duration of response (DOR), progression-free survival, overall survival (OS), and safety. RESULTS: A total of 41 pediatric patients with previously treated BRAF V600-mutant HGG were enrolled. At primary analysis, median follow-up was 25.1 months, and 51% of patients remained on treatment. Sixteen of 20 discontinuations were due to progressive disease in this relapsed/refractory pHGG population. Independently assessed ORR was 56% (95% CI, 40 to 72). Median DOR was 22.2 months (95% CI, 7.6 months to not reached [NR]). Fourteen deaths were reported. Median OS was 32.8 months (95% CI, 19.2 months to NR). The most common all-cause adverse events (AEs) were pyrexia (51%), headache (34%), and dry skin (32%). Two patients (5%) had AEs (both rash) leading to discontinuation. CONCLUSION: In relapsed/refractory BRAF V600-mutant pHGG, dabrafenib plus trametinib improved ORR versus previous trials of chemotherapy in molecularly unselected patients with pHGG and was associated with durable responses and encouraging survival. These findings suggest that dabrafenib plus trametinib is a promising targeted therapy option for children and adolescents with relapsed/refractory BRAF V600-mutant HGG

Atypical teratoid/rhabdoid tumors (ATRTs) with SMARCA4 mutation are molecularly distinct from SMARCB1-deficient cases

Atypical teratoid/rhabdoid tumors (ATRTs) are very aggressive childhood malignancies of the central nervous system. The underlying genetic cause are inactivating bi-allelic mutations in SMARCB1 or (rarely) in SMARCA4. ATRT-SMARCA4 have been associated with a higher frequency of germline mutations, younger age, and an inferior prognosis in comparison to SMARCB1 mutated cases. Based on their DNA methylation profiles and transcriptomics, SMARCB1 mutated ATRTs have been divided into three distinct molecular subgroups: ATRT-TYR, ATRT-SHH, and ATRT-MYC. These subgroups differ in terms of age at diagnosis, tumor location, type of SMARCB1 alterations, and overall survival. ATRT-SMARCA4 are, however, less well understood, and it remains unknown, whether they belong to one of the described ATRT subgroups. Here, we examined 14 ATRT-SMARCA4 by global DNA methylation analyses. We show that they form a separate group segregating from SMARCB1 mutated ATRTs and from other SMARCA4-deficient tumors like small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) or SMARCA4 mutated extra-cranial malignant rhabdoid tumors. In contrast, medulloblastoma (MB) samples with heterozygous SMARCA4 mutations do not group separately, but with established MB subgroups. RNA sequencing of ATRT-SMARCA4 confirmed the clustering results based on DNA methylation profiling and displayed an absence of typical signature genes upregulated in SMARCB1 deleted ATRT. In summary, our results suggest that, in line with previous clinical observations, ATRT-SMARCA4 should be regarded as a distinct molecular subgroup

Phase I/II intra-patient dose escalation study of vorinostat in children with relapsed solid tumor, lymphoma, or leukemia

Background: Until today, adult and pediatric clinical trials investigating single-agent or combinatorial HDAC inhibitors including vorinostat in solid tumors have largely failed to demonstrate efficacy. These results may in part be explained by data from preclinical models showing significant activity only at higher concentrations compared to those achieved with current dosing regimens. In the current pediatric trial, we applied an intra-patient dose escalation design. The purpose of this trial was to determine a safe dose recommendation (SDR) of single-agent vorinostat for intra-patient dose escalation, pharmacokinetic analyses (PK), and activity evaluation in children (3-18 years) with relapsed or therapy-refractory malignancies. Results: A phase I intra-patient dose (de)escalation was performed until individual maximum tolerated dose (MTD). The starting dose was 180 mg/m(2)/day with weekly dose escalations of 50 mg/m(2) until DLT/maximum dose. After MTD determination, patients seamlessly continued in phase II with disease assessments every 3 months. PK and plasma cytokine profiles were determined. Fifty of 52 patients received treatment. n = 27/50 (54%) completed the intra-patient (de)escalation and entered phase II. An SDR of 130 mg/m(2)/day was determined (maximum, 580 mg/m(2)/day). n = 46/50 (92%) patients experienced treatment-related AEs which were mostly reversible and included thrombocytopenia, fatigue, nausea, diarrhea, anemia, and vomiting. n = 6/50 (12%) had treatment-related SAEs. No treatment-related deaths occurred. Higher dose levels resulted in higher C-max. Five patients achieved prolonged disease control (> 12 months) and showed a higher C-max (> 270 ng/mL) and MTDs. Best overall response (combining PR and SD, no CR observed) rate in phase II was 6/27 (22%) with a median PFS and OS of 5.3 and 22.4 months. Low levels of baseline cytokine expression were significantly correlated with favorable outcome. Conclusion: An SDR of 130 mg/m(2)/day for individual dose escalation was determined. Higher drug exposure was associated with responses and long-term disease stabilization with manageable toxicity. Patients with low expression of plasma cytokine levels at baseline were able to tolerate higher doses of vorinostat and benefited from treatment. Baseline cytokine profile is a promising potential predictive biomarker

Genotype–phenotype associations within the Li-Fraumeni spectrum: a report from the German Registry

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by pathogenic TP53 variants. The condition represents one of the most relevant genetic causes of cancer in children and adults due to its frequency and high cancer risk. The term Li-Fraumeni spectrum reflects the evolving phenotypic variability of the condition. Within this spectrum, patients who meet specific LFS criteria are diagnosed with LFS, while patients who do not meet these criteria are diagnosed with attenuated LFS. To explore genotype–phenotype correlations we analyzed 141 individuals from 94 families with pathogenic TP53 variants registered in the German Cancer Predisposition Syndrome Registry. Twenty-one (22%) families had attenuated LFS and 73 (78%) families met the criteria of LFS. NULL variants occurred in 32 (44%) families with LFS and in two (9.5%) families with attenuated LFS (P value < 0.01). Kato partially functional variants were present in 10 out of 53 (19%) families without childhood cancer except adrenocortical carcinoma (ACC) versus 0 out of 41 families with childhood cancer other than ACC alone (P value < 0.01). Our study suggests genotype–phenotype correlations encouraging further analyses. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13045-022-01332-1

ATRT–SHH comprises three molecular subgroups with characteristic clinical and histopathological features and prognostic significance

Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive central nervous system tumor characterized by loss of SMARCB1/INI1 protein expression and comprises three distinct molecular groups, ATRT–TYR, ATRT–MYC and ATRT–SHH. ATRT–SHH represents the largest molecular group and is heterogeneous with regard to age, tumor location and epigenetic profile. We, therefore, aimed to investigate if heterogeneity within ATRT–SHH might also have biological and clinical importance. Consensus clustering of DNA methylation profiles and confirmatory t-SNE analysis of 65 ATRT–SHH yielded three robust molecular subgroups, i.e., SHH-1A, SHH-1B and SHH-2. These subgroups differed by median age of onset (SHH-1A: 18 months, SHH-1B: 107 months, SHH-2: 13 months) and tumor location (SHH-1A: 88% supratentorial; SHH-1B: 85% supratentorial; SHH-2: 93% infratentorial, often extending to the pineal region). Subgroups showed comparable SMARCB1 mutational profiles, but pathogenic/likely pathogenic SMARCB1 germline variants were over-represented in SHH-2 (63%) as compared to SHH-1A (20%) and SHH-1B (0%). Protein expression of proneural marker ASCL1 (enriched in SHH-1B) and glial markers OLIG2 and GFAP (absent in SHH-2) as well as global mRNA expression patterns differed, but all subgroups were characterized by overexpression of SHH as well as Notch pathway members. In a Drosophila model, knockdown of Snr1 (the fly homologue of SMARCB1) in hedgehog activated cells not only altered hedgehog signaling, but also caused aberrant Notch signaling and formation of tumor-like structures. Finally, on survival analysis, molecular subgroup and age of onset (but not ASCL1 staining status) were independently associated with overall survival, older patients (> 3 years) harboring SHH-1B experiencing relatively favorable outcome. In conclusion, ATRT–SHH comprises three subgroups characterized by SHH and Notch pathway activation, but divergent molecular and clinical features. Our data suggest that molecular subgrouping of ATRT–SHH has prognostic relevance and might aid to stratify patients within future clinical trials. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00401-022-02424-5

Infants and Newborns with Atypical Teratoid Rhabdoid Tumors (ATRT) and Extracranial Malignant Rhabdoid Tumors (eMRT) in the EU-RHAB Registry: A Unique and Challenging Population

Malignant rhabdoid tumors (MRT) predominantly affect infants and young children. Patients below six months of age represent a particularly therapeutically challenging group. Toxicity to developing organ sites limits intensity of treatment. Information on prognostic factors, genetics, toxicity of treatment and long-term outcomes is sparse. Methods: Clinical, genetic, and treatment data of 100 patients (aged below 6 months at diagnosis) from 13 European countries were analyzed (2005–2020). Tumors and matching blood samples were examined for SMARCB1 mutations using FISH, MLPA and Sanger sequencing. DNA methylation subgroups (ATRT-TYR, ATRT-SHH, and ATRT-MYC) were determined using 450 k / 850 k-profiling. Results: A total of 45 patients presented with ATRT, 29 with extracranial, extrarenal (eMRT) and 9 with renal rhabdoid tumors (RTK). Seventeen patients demonstrated synchronous tumors (SYN). Metastases (M+) were present in 27% (26/97) at diagnosis. A germline mutation (GLM) was detected in 55% (47/86). DNA methylation subgrouping was available in 50% (31 / 62) with ATRT or SYN; for eMRT, methylation-based subgrouping was not performed. The 5-year overall (OS) and event free survival (EFS) rates were 23.5 ± 4.6% and 19 ± 4.1%, respectively. Male sex (11 ± 5% vs. 35.8 ± 7.4%), M+ stage (6.1 ± 5.4% vs. 36.2 ± 7.4%), presence of SYN (7.1 ± 6.9% vs. 26.6 ± 5.3%) and GLM (7.7 ± 4.2% vs. 45.7 ± 8.6%) were significant prognostic factors for 5-year OS. Molecular subgrouping and survival analyses confirm a previously described survival advantage for ATRT-TYR. In an adjusted multivariate model, clinical factors that favorably influence the prognosis were female sex, localized stage, absence of a GLM and maintenance therapy. Conclusions: In this cohort of homogenously treated infants with MRT, significant predictors of outcome were sex, M-stage, GLM and maintenance therapy. We confirm the need to stratify which patient groups benefit from multimodal treatment, and which need novel therapeutic strategies. Biomarker-driven tailored trials may be a key option

Infants and newborns with Atypical Teratoid Rhabdoid Tumors (ATRT) and Extracranial Malignant Rhabdoid Tumors (eMRT) in the EU-RHAB registry: a unique and challenging population

SIMPLE SUMMARY: Malignant rhabdoid tumors (MRT) are deadly tumors that predominantly affect infants and young children. Even when considering the generally young age of these patients, the treatment of infants below the age of six months represents a particular challenge due to the vulnerability of this patient population. The aim of our retrospective study was to assess the available information on prognostic factors, genetics, toxicity of treatment and long-term outcomes of MRT. We confirmed that, in a cohort of homogenously treated infants with MRT, significant predictors of outcome were female sex, localized stage, absence of a GLM and maintenance therapy, and these significantly favorably influence prognosis. Stratification-based biomarker-driven tailored trials may be a key option to improve survival rates. ABSTRACT: Introduction: Malignant rhabdoid tumors (MRT) predominantly affect infants and young children. Patients below six months of age represent a particularly therapeutically challenging group. Toxicity to developing organ sites limits intensity of treatment. Information on prognostic factors, genetics, toxicity of treatment and long-term outcomes is sparse. Methods: Clinical, genetic, and treatment data of 100 patients (aged below 6 months at diagnosis) from 13 European countries were analyzed (2005–2020). Tumors and matching blood samples were examined for SMARCB1 mutations using FISH, MLPA and Sanger sequencing. DNA methylation subgroups (ATRT-TYR, ATRT-SHH, and ATRT-MYC) were determined using 450 k / 850 k-profiling. Results: A total of 45 patients presented with ATRT, 29 with extracranial, extrarenal (eMRT) and 9 with renal rhabdoid tumors (RTK). Seventeen patients demonstrated synchronous tumors (SYN). Metastases (M+) were present in 27% (26/97) at diagnosis. A germline mutation (GLM) was detected in 55% (47/86). DNA methylation subgrouping was available in 50% (31 / 62) with ATRT or SYN; for eMRT, methylation-based subgrouping was not performed. The 5-year overall (OS) and event free survival (EFS) rates were 23.5 ± 4.6% and 19 ± 4.1%, respectively. Male sex (11 ± 5% vs. 35.8 ± 7.4%), M+ stage (6.1 ± 5.4% vs. 36.2 ± 7.4%), presence of SYN (7.1 ± 6.9% vs. 26.6 ± 5.3%) and GLM (7.7 ± 4.2% vs. 45.7 ± 8.6%) were significant prognostic factors for 5-year OS. Molecular subgrouping and survival analyses confirm a previously described survival advantage for ATRT-TYR. In an adjusted multivariate model, clinical factors that favorably influence the prognosis were female sex, localized stage, absence of a GLM and maintenance therapy. Conclusions: In this cohort of homogenously treated infants with MRT, significant predictors of outcome were sex, M-stage, GLM and maintenance therapy. We confirm the need to stratify which patient groups benefit from multimodal treatment, and which need novel therapeutic strategies. Biomarker-driven tailored trials may be a key option