Extensive Molecular and Clinical Heterogeneity in Patients With Histologically Diagnosed CNS-PNET Treated as a Single Entity: A Report From the Children's Oncology Group Randomized ACNS0332 Trial

Abstract

Purpose: Children with histologically diagnosed high-risk medulloblastoma, supratentorial primitive neuroectodermal tumor of the CNS (CNS-PNET), and pineoblastoma (PBL) have had poor survival despite intensive treatment. We included these patients in this Children's Oncology Group trial. Molecular profiling later revealed tumor heterogeneity that was not detectable at protocol inception. Enrollment of patients with CNS-PNET/PBL was subsequently discontinued, and outcomes for this part of the study are reported here.

Patients and methods: In this phase III, four-arm prospective trial, consenting children age 3-22 years with newly diagnosed CNS-PNET were randomly assigned (1:1) to receive carboplatin during radiation and/or adjuvant isotretinoin after standard intensive therapy. Primary outcome measure was event-free survival (EFS) in the intent-to-treat population. Molecular tumor classification was retrospectively completed using DNA methylation profiling.

Results: Eighty-five participants with institutionally diagnosed CNS-PNETs/PBLs were enrolled. Of 60 patients with sufficient tissue, 31 were nonpineal in location, of which 22 (71%) represented tumors that were not intended for trial inclusion, including 18 high-grade gliomas (HGGs), two atypical teratoid rhabdoid tumors, and two ependymomas. Outcomes across tumor types were strikingly different. Patients with supratentorial embryonal tumors/PBLs exhibited 5-year EFS and overall survival of 62.8% (95% CI, 43.4% to 82.2%) and 78.5% (95% CI, 62.2% to 94.8%), respectively, whereas patients with molecularly classified HGG had EFS and overall survival of 5.6% (95% CI, 0% to 13.0%) and 12.0% (95% CI, 0% to 24.7%), respectively. Neither carboplatin, nor isotretinoin significantly altered outcomes for all patients. Survival for patients with HGG was similar to that of historic studies that avoid craniospinal irradiation and intensive chemotherapy.

Conclusion: For patients with CNS-PNET/PBL, prognosis is considerably better than previously assumed when molecularly confirmed HGGs are removed. Identification of molecular HGGs may spare affected children from unhelpful intensive treatment. This trial highlights the challenges of a histology-based diagnosis for pediatric brain tumors and indicates that molecular profiling should become a standard component of initial diagnosis.

Figures

Fig 1.

Methylation profiling identifies disparate molecular diagnoses in tumors pathologically classified institutionally as supratentorial primitive neuroectodermal tumor of the CNS (CNS-PNET) and pineoblastoma (PBL). Tumors were molecularly classified on the basis of unsupervised cluster analyses of the 60 CNS-PNET/PBL methylation profiles, together with the methylation profiles of 216 reference cases that represented 27 distinct molecular brain tumor entities. AD, adult; ATRT, atypical teratoid rhabdoid tumor; BCOR, bcl6 corepressor; CNS EFT-CIC, Ewing sarcoma family tumor with CIC alteration; CIC, capicua transcriptional repressor; CNS NB-FOXR2, forkhead box R2; CPC, choroid plexus carcinoma; CPP, choroid plexus papilloma; EPN, ependymoma: ET, embryonal tumor; GBM, glioblastoma multiforme; HGNET-MN1, high-grade neuroepithelial tumor with MN1 alteration; INF, infant; MB, medulloblastoma; MELCYT, melanocytoma; MNG, meningioma; NOS, not otherwise specified; PB, pineoblastoma; PXA, pleomorphic xanthoastrocytoma; RELA, v-rel avian reticuloendotheliosis viral oncogene homolog A; SHH, Sonic Hedgehog; TSNE, stochastic neighbor embedding (tSNE) method; WNT, Wingless; YAP, yes-associated protein 1.

Fig 2.

Outcome of molecularly classified high-grade glioma versus supratentorial embryonal tumor (sET)/pineoblastoma (PBL) tumors. (A) Event-free survival (EFS). Estimated EFS at 5 years for molecularly defined high-grade glioma (HGG) was 5.6% (95% CI, 0% to 13.0%)%, whereas 5-year EFS for supratentorial ET/PBL tumors was 62.8% (95% CI, 43.4% to 82.2%; P < .001). (B) Overall survival (OS). Estimated OS at 5 years for molecularly defined high-grade glioma was 12.0% (95% CI, 0% to 24.7%), whereas 5-year OS for supratentorial ET/PBL tumors was 78.5% (95% CI, 62.2% to 94.8%; P < .001).

Fig 3.

Outcome of patients with molecularly classified supratentorial embryonal tumor (ET)/pineoblastoma (PBL) tumors randomly assigned to receipt of (A and B) carboplatin (n = 36) and (C and D) isotretinoin. (A) Event-free survival (EFS) at 5 years for patients with molecularly defined supratentorial ET/PBL who received carboplatin was 67.5% (95% CI, 40.8% to 94.2%), whereas patients who did not receive carboplatin had 5-year EFS of 59.1% (95% CI, 32.8% to 85.4%) at 5 years, which was not significantly different from those who received carboplatin (P = .73). (B) Overall survival (OS) at 5 years for patients with molecularly defined supratentorial ET/PBL tumors who received carboplatin was 87.5% (95% CI, 67.3% to 100%), whereas patients who did not receive carboplatin had 5-year OS of 71.8% (95% CI, 49.3% to 94.3%; P = .46). (C) EFS at 5 years for patients with molecularly defined supratentorial ET/PBL tumors who received isotretinoin was 51.9% (95% CI, 28.4% to 75.4%), whereas patients who did not receive isotretinoin had 5-year EFS of 80.0% (95% CI, 53.5% to 100%; P = .15). (D) OS at 5 years for patients with molecularly defined supratentorial ET/PBL tumors who received isotretinoin was 73.1% (95% CI, 50.8% to 95.4%), whereas lack of isotretinoin conferred 5-year OS of 86.7% (95% CI, 66.1% to 100%; P = .63).

Fig 4.

Impact of residual disease on overall survival (OS) for patients with molecularly classified supratentorial embryonal tumor (ET)/pineoblastoma (PBL) tumors. Estimated OS at 3 years for patients with molecularly defined supratentorial ET/PBL tumors who had minimal residual disease was 93.8% (95% CI, 81.5% to 100%) compared with and OS of 75.0% (95% CI, 47.2% to 100%) for patients with > 1.5 cm2 of residual disease (P = .012).