Relevance of molecular groups in children with newly diagnosed atypical teratoid rhabdoid tumor: Results from prospective St. Jude multi-institutional trials

Purpose: Report relevance of molecular groups to clinicopathologic features, germline SMARCB1/SMARCA4 alterations (GLA), and survival of children with atypical teratoid rhabdoid tumor (ATRT) treated in two multi-institutional clinical trials. Materials and Methods: Seventy-four participants with newly diagnosed ATRT were treated in two trials: infants (SJYC07: age < 3 years; n 52) and children (SJMB03: age 3–21 years; n 22), using surgery, conventional chemotherapy (infants), or dose-dense chemotherapy with autologous stem cell rescue (children), and age- and risk-adapted radiotherapy [focal (infants) and craniospinal (CSI; children)]. Molecular groups ATRT-MYC (MYC), ATRT-SHH (SHH), and ATRT-TYR (TYR) were determined from tumor DNA methylation profiles. Results: Twenty-four participants (32%) were alive at time of analysis at a median follow-up of 8.4 years (range, 3.1–14.1 years). Methylation profiling classified 64 ATRTs as TYR (n 21), SHH (n 30), and MYC (n 13), SHH group being associated with metastatic disease. Among infants, TYR group had the best overall survival (OS; P 0.02). However, outcomes did not differ by molecular groups among infants with nonmetastatic (M0) disease. Children with M0 disease and <1.5 cm² residual tumor had a 5-year progression-free survival (PFS) of 72.7 12.7% and OS of 81.8 11%. Infants with M0 disease had a 5-year PFS of 39.1 11.5% and OS of 51.8 12%. Those with metastases fared poorly [5-year OS 25 12.5% (children) and 0% (infants)]. SMARCB1 GLAs were not associated with PFS. Conclusions: Among infants, those with ATRT-TYR had the best OS. ATRT-SHH was associated with metastases and consequently with inferior outcomes. Children with nonmetastatic ATRT benefit from postoperative CSI and adjuvant chemotherapy.