Cancers (Apr 2022)

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

  • Karolina Nemes,
  • Pascal D. Johann,
  • Mona Steinbügl,
  • Miriam Gruhle,
  • Susanne Bens,
  • Denis Kachanov,
  • Margarita Teleshova,
  • Peter Hauser,
  • Thorsten Simon,
  • Stephan Tippelt,
  • Wolfgang Eberl,
  • Martin Chada,
  • Vicente Santa-Maria Lopez,
  • Lorenz Grigull,
  • Pablo Hernáiz-Driever,
  • Matthias Eyrich,
  • Jane Pears,
  • Till Milde,
  • Harald Reinhard,
  • Alfred Leipold,
  • Marianne van de Wetering,
  • Maria João Gil-da-Costa,
  • Georg Ebetsberger-Dachs,
  • Kornelius Kerl,
  • Andreas Lemmer,
  • Heidrun Boztug,
  • Rhoikos Furtwängler,
  • Uwe Kordes,
  • Christian Vokuhl,
  • Martin Hasselblatt,
  • Brigitte Bison,
  • Thomas Kröncke,
  • Patrick Melchior,
  • Beate Timmermann,
  • Joachim Gerss,
  • Reiner Siebert,
  • Michael C. Frühwald

DOI
https://doi.org/10.3390/cancers14092185
Journal volume & issue
Vol. 14, no. 9
p. 2185

Abstract

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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.

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