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

Abstract

Pineoblastoma is a rare embryonal tumor of childhood that is conventionally treated with high-dose craniospinal irradiation (CSI). Multi-dimensional molecular evaluation of pineoblastoma and associated intertumoral heterogeneity is lacking. Herein, we report outcomes and molecular features of children with pineoblastoma from two multi-center, risk-adapted trials (SJMB03 for patients ≥ 3 years; SJYC07 for patients < 3 years) complemented by a non-protocol institutional cohort. The clinical cohort consisted of 58 patients with histologically diagnosed pineoblastoma (SJMB03 = 30, SJYC07 = 12, non-protocol = 16, including 12 managed with SJMB03-like therapy). The SJMB03 protocol comprised risk-adapted CSI (average-risk = 23.4 Gy, high-risk = 36 Gy) with radiation boost to the primary site and adjuvant chemotherapy. The SJYC07 protocol consisted of induction chemotherapy, consolidation with focal radiation (intermediate-risk) or chemotherapy (high-risk), and metronomic maintenance therapy. The molecular cohort comprised 43 pineal parenchymal tumors profiled by DNA methylation array (n = 43), whole-exome sequencing (n = 26), and RNA-sequencing (n = 16). Respective 5-year progression-free survival rates for patients with average-risk or high-risk disease on SJMB03 or SJMB03-like therapy were 100% and 56.5 ± 10.3% (P = 0.007); respective 2-year progression-free survival rates for those with intermediate-risk or high-risk disease on SJYC07 were 14.3 ± 13.2% and 0% (P = 0.375). Of patients with average-risk disease treated with SJMB03/SJMB03-like therapy, 17/18 survived without progression. DNA-methylation analysis revealed four clinically relevant pineoblastoma subgroups: PB-A, PB-B, PB-B-like, and PB-FOXR2. Pineoblastoma subgroups differed in age at diagnosis, propensity for metastasis, cytogenetics, and clinical outcomes. Alterations in the miRNA-processing pathway genes DICER1, DROSHA, and DGCR8 were recurrent and mutually exclusive in PB-B and PB-B-like subgroups; PB-FOXR2 samples universally overexpressed the FOXR2 proto-oncogene. Our findings suggest superior outcome amongst older children with average-risk pineoblastoma treated with reduced-dose CSI. The identification of biologically and clinically distinct pineoblastoma subgroups warrants consideration of future molecularly-driven treatment protocols for this rare pediatric brain tumor entity.

• Authors: Anthony P Y Liu, Brian Gudenas, Tong Lin, Brent A Orr, Paul Klimo Jr, Rahul Kumar, Eric Bouffet, Sridharan Gururangan, John R Crawford, Stewart J Kellie, Murali Chintagumpala, Michael J Fisher, Daniel C Bowers, Tim Hassall, Daniel J Indelicato, Arzu Onar-Thomas, David W Ellison, Frederick A Boop, Thomas E Merchant, Giles W Robinson, Paul A Northcott, Amar Gajjar
• Journal: Acta neuropathologica (Acta Neuropathol) Vol. 139 Issue 2 Pg. 259-271 (02 2020) ISSN: 1432-0533 [Electronic] Germany
• PMID: 31802236 (Publication Type: Clinical Trial, Phase II, Clinical Trial, Phase III, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Topics

• Adolescent
• Age Factors
• Brain Neoplasms (genetics, pathology, therapy)
• Child
• Child, Preschool
• Cohort Studies
• DNA Methylation
• Female
• Humans
• Male
• Pineal Gland
• Pinealoma (genetics, pathology, therapy)
• Proto-Oncogene Mas
• Risk Factors
• Survival Rate
• Young Adult