Risk-adapted therapy and biological heterogeneity in pineoblastoma: integrated clinical-molecular analysis from the prospective, multi-center SJMB03 and SJYC07 trials

Abstract

Background/Objectives: Pineoblastoma is an aggressive embryonal tumor conventionally treated with high‐dose CSI. We report outcome and molecular analysis of patients with pineoblastoma from two multi‐center risk‐adapted trials (SJMB03 for ≥3y, SJYC07 for <3y) and a non‐protocol SJMB03‐equivalent cohort (SJMB03‐like). Design/Methods: Fifty‐three patients with pineoblastoma treated on SJMB03 (N=30), SJMB03‐like (N=11), and SJYC07 (N=12) were included. High‐risk (HR) disease was defined by metastasis (M+) (SJMB03/SJMB03‐like/SJYC07) and/or residual tumor ≥1.5cm2 (R+) (SJMB03/SJMB03‐like). The SJMB03 protocol comprised risk‐adapted CSI (non‐HR=23.4Gy, HR=36Gy) with boost and chemotherapy (cisplatin/cyclophosphamide/vincristine); the SJYC07 protocol consisted of induction (methotrexate/cisplatin/cyclophosphamide/vincristine), consolidation (non‐HR=focal radiation, HR=cyclophosphamide/topotecan) and metronomic maintenance therapy. Available samples were profiled on MethylationEPIC array and analyzed with a reference brain tumor dataset. WES and RNA‐seq were performed in a subset. Results: Among SJMB03/SJMB03‐like patients, 18 were non‐HR and 23 HR (M+=17; R+ only=6). In SJYC07, 7 were non‐HR and 5 HR (M+). 5y‐PFS in patients on SJMB03/SJMB03‐like therapy with non‐HR and HR disease were 100% and 59.1±10.5% respectively (p=0.012). Patients on SJYC07 with non‐HR and HR disease had 5y‐PFS of 14.3±13.2% and 0% respectively (p=0.23). Unsupervised clustering of 40 methylation profiles resulted in 4 subgroups. Subgroup‐1 (N=7) patients were younger (median=1.2y; range=0.5‐5.7y), often metastatic (71%), and had epigenetic profiles that either associated with RB1‐driven pineoblastoma (“PB_A”) or formed a related cluster. Tumors in subgroup‐2 (N=9; median=1.9y; range=0.4‐14.4y) were heterogeneous and clustered with diverse reference classes. Subroups‐3 (N=6) and 4 (N=18) patients were older (median=8.4y; range=3.3‐17y) and less frequently metastatic (subgroup‐3=0%; subgroup‐4=44%). Profiles from subgroup‐3 formed a distinct cluster while those from subgroup‐4 overlapped with pineoblastoma methylation‐class “PB_B”. Pathogenic alterations in the microRNA processing pathway were enriched in subgroups‐3 and 4. Conclusions: Children ≥3y with non‐HR pineoblastoma can be successfully treated with 23.4Gy CSI and chemotherapy. Moreover, molecular analysis uncovers a biologically diverse disease, with subgroup‐specific differences in patient age and propensity for metastasis.