Abstract Background Atypical teratoid/rhabdoid (AT/RT) is an aggressive pediatric brain tumor, prevalent in children 3 years(Y) of age; methylation profiles subclassify AT/RTs into AT/RT-MYC (MYC), AT/RT-SHH (SHH), and AT/RT-TYR (TYR). At the molecular level, AT/RT shows alterations in SMARCB1 and SMARCA4. Despite treatment with surgery, radiation (RT), and chemotherapy, the cure rate remains suboptimal, and predictors of clinical outcome are unknown. Methods We studied the association between minimal residual disease (MRD), as measured by circulating tumor DNA (ctDNA) in CSF over multiple longitudinal time points on therapy, and outcomes in newly diagnosed, non-metastatic patients enrolled in phase 2 clinical trial SJATRT, stratum B1 (age 36 months). Whole-genome cell-free DNA methylomes were generated for copy number variation profiling and tumor classification by an integrative computational pipeline (M-PACT). Treatment consisted of postoperative induction chemotherapy till 12 months of age, and then focal RT followed by consolidation chemotherapy and maintenance with alisertib. Results There were 30 evaluable patients (SHH: 18, TYR: 7, MYC: 3, NC: 2); the 3Y progression free survival (PFS) and overall survival (OS) were 30.0% and 56.7%. Methylation class was not associated with outcome. A total of 94 CSF samples from 24 patients (SHH:12, TYR:7, MYC:3, NC: 2) were analyzed. The median number of CSF samples per patient was 4 (range: 1-8). Positive MRD as a time-dependent covariate was associated with worse PFS and OS (p = 0.041, 0.037). Furthermore, based on landmark analyses, positive MRD at the end of induction chemotherapy (n = 7/18) and focal RT (n = 8/14) were associated with worse PFS (p = 0.012, 0.047). Conclusion PFS and OS were not improved for patients enrolled in stratum B1 in SJATRT. Positive ctDNA in CSF, as a time-dependent covariate, was associated with worse PFS and OS in non-metastatic ATRT. Positive MRD at early time points may predict early relapse and serve as a biomarker for therapeutic intervention in future trials.
Bagchi et al. (Tue,) studied this question.