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 highdose 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. DNAmethylation 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.Liu et al.

ETMR: a tumor entity in its infancy

“…Cancers associated to the DICER1 predisposition syndrome, both benign and malignant, primarily have biallelic loss of function mutations and mutations affecting an RNASE III domain of DICER1 (reviewed in [28]). However, there are also tumors such as Wilms tumor or pineoblastoma that recurrently have mutations leading to a complete loss of function of DICER1 or that have mutations in other members of the miRNA processing pathway such as mutations in DROSHA and DGCR8 [82,84,109,128,135]. These tumors rarely have mutations in the RNase IIIa or RNase IIIb domain of DICER1, suggesting that a general lack of miRNA processing, rather than biased loading of 3p miRNAs, is the driving mechanism in the majority of these tumors [113].…”

“…These tumors rarely have mutations in the RNase IIIa or RNase IIIb domain of DICER1, suggesting that a general lack of miRNA processing, rather than biased loading of 3p miRNAs, is the driving mechanism in the majority of these tumors [ 113 ]. Interestingly, two cases initially histologically diagnosed as pineoblastoma and harbouring RNase IIIb domain mutations in DICER1 were by DNA methylation profiling reclassified as ETMRs [ 84 ]. Together with earlier findings that ETMRs could present with a pineoblastoma-like histology this opens the possibility that the type of aberration affecting DICER1 could influence what type of tumor develops.…”

Clinical and molecular heterogeneity of pineal parenchymal tumors: a consensus study

“…It is possible that reported benefit of more aggressive resection in previous studies was confounded by higher rates for total tumor removal in patients with localized disease. 6,32 The recognition of heterogeneity within PB is key to enhancing patient outcome, as the effect of adjuvant treatment could be scrutinized in the context of subgroup tumor biology. Accordingly, treatment intensity could be adapted and use of experimental therapy prioritized.…”

“…Differential expression and gene-set enrichment analysis (GSEA) was performed as previously described. 6…”

“…17 Gross tumor removal is often advocated on the basis of medulloblastoma studies, although evidence supporting the value of aggressive resection for patients with PB is inconsistent. 4,6,14,17-19 Furthermore, CSI with tumor boost, a critical prognostic modality for patients with embryonal tumors including PB, is not an option for infants due to adverse neuro-cognitive effects in survivors. 20 The benefit of high-dose chemotherapy with autologous stem cell rescue versus standard-dose chemotherapy is also unknown.…”