Age and DNA-methylation subgroup as potential independent risk factors for treatment stratification in children with Atypical Teratoid/Rhabdoid Tumors (ATRT)

BACKGROUND: Controversy exists as to what may be defined as standard of care (including markers for stratification) for patients with Atypical Teratoid Rhabdoid Tumors (ATRT). The European Rhabdoid Registry, EU-RHAB, recruits uniformly treated patients and offers standardized genetic and DNA methylation analyses.

METHODS: Clinical, genetic and treatment data of 143 patients from 13 European countries were analyzed (2009 - 2017). Therapy consisted of surgery, anthracycline-based induction and either radiotherapy or high dose chemotherapy following a consensus among European experts. FISH, MLPA and sequencing were employed for assessment of somatic and germline mutations in SMARCB1. Molecular subgroups (ATRT-SHH, -TYR and -MYC) were determined using DNA-methylation arrays resulting in profiles of 84 tumors.

RESULTS: Median age at diagnosis of 67 girls and 76 boys was 29.5 months. 5-year overall survival (OS) and event-free survival (EFS) were 34.7±4.5% and 30.5±4.2%. Tumors displayed allelic partial/whole gene deletions (66%; 122/186 alleles) or single nucleotide variants (34%; 64/186 alleles) of SMARCB1. Germline mutations were detected in 26% of ATRT (30/117). The patient cohort consisted of 47% ATRT-SHH (39/84), 33% ATRT-TYR (28/84), and 20% ATRT-MYC 17/84). Age <1 year, non-TYR signature (ATRT-SHH or -MYC), metastatic or synchronous tumors, germline mutation, incomplete remission and omission of radiotherapy were negative prognostic factors in univariate analyses (p<0.05). An adjusted multivariate model identified age <1 year and a non-TYR signature as independent negative predictors of OS: high risk (<1 year + non-TYR; 5-year OS = 0%), intermediate risk (<1 year + ATRT-TYR or ≥1 year + non-TYR; 5-year OS = 32.5±8.7%) and standard risk (≥1 year + ATRT-TYR, 5-year OS = 71.5±12.2%).

CONCLUSIONS: Age and molecular subgroup status are independent risk factors for survival in children with ATRT. Our model warrants validation within future clinical trials.