Therapeutic implications of improved molecular diagnostics for rare CNS embryonal tumor entities: results of an international, retrospective study

Abstract

Background: Only few data are available on treatment-associated behavior of distinct rare CNS embryonal tumor entities previously treated as "CNS-primitive neuroectodermal tumors" (CNS-PNET). Respective data on specific entities, including CNS neuroblastoma, FOXR2 activated (CNS NB-FOXR2), and embryonal tumors with multilayered rosettes (ETMR) are needed for development of differentiated treatment strategies.

Methods: Within this retrospective, international study, tumor samples of clinically well-annotated patients with the original diagnosis of CNS-PNET were analyzed using DNA methylation arrays (n = 307). Additional cases (n = 66) with DNA methylation pattern of CNS NB-FOXR2 were included irrespective of initial histological diagnosis. Pooled clinical data (n = 292) were descriptively analyzed.

Results: DNA methylation profiling of "CNS-PNET" classified 58 (19%) cases as ETMR, 57 (19%) as high-grade glioma (HGG), 36 (12%) as CNS NB-FOXR2, and 89(29%) cases were classified into 18 other entities. Sixty-seven (22%) cases did not show DNA methylation patterns similar to established CNS tumor reference classes. Best treatment results were achieved for CNS NB-FOXR2 patients (5-year PFS: 63% ± 7%, OS: 85% ± 5%, n = 63), with 35/42 progression-free survivors after upfront craniospinal irradiation (CSI) and chemotherapy. The worst outcome was seen for ETMR and HGG patients with 5-year PFS of 18% ± 6% and 22% ± 7%, and 5-year OS of 24% ± 6% and 25% ± 7%, respectively.

Conclusion: The historically reported poor outcome of CNS-PNET patients becomes highly variable when tumors are molecularly classified based on DNA methylation profiling. Patients with CNS NB-FOXR2 responded well to current treatments and a standard-risk CSI-based regimen may be prospectively evaluated. The poor outcome of ETMR across applied treatment strategies substantiates the necessity for evaluation of novel treatments.

Keywords: CNS NB-FOXR2; CNS embryonal tumor; CNS-PNET; DNA methylation profiling; ETMR.

Fig. 1

Cohort description. A. Patients were included either based on a historical diagnosis of CNS-PNET (CNS-PNET re-evaluation cohort) or on the results of DNA methylation profiles according to CNS NB-FOXR2 (extended cohort). B. Pie chart of entities diagnosed by DNA methylation profiling within the CNS-PNET re-evaluation cohort. C. t-SNE analysis of DNA methylation profiles from all included. D. Further subspecification of DNA methylation profiles of HGG and other diagnoses. Abbreviations: CNS-PNET, CNS-primitive neuroectodermal tumors; HGG, high-grade gliomas; t-SNE, t-distributed stochastic neighbor embedding.

Fig. 2

CNS NB-FOXR2: Molecular characteristics, clinical information, and treatment. A. Overview of copy number profiles of CNS NB-FOXR2. Bars indicating gain, balanced, or loss add up to 100% for each chromosome arm. B. The pie chart depicts the nearly balanced sex ratio. C. The bar chart shows the age distribution of age at first diagnosis (information available for 89/102 patients). D. Tumor location is specified for 87 patients with CNS NB-FOXR2, with each dot corresponding to one single tumor, or multiple tumors with the respective number of cases given. E. Overview of applied treatment and documented response for patients with CNS NB-FOXR2. Overall, 41 of 63 patients remained event-free (EF). Of 22 patients with event, 12 patients were alive at last follow-up with evidence of disease (AWD₂), or in second complete remission (CR₂). Numbers indicated with the symbol * refer to patients with previous evidence of disease (ED) and documented response to treatment. Abbreviations: CCR, continuous complete response; CR, complete response; CSI, craniospinal irradiation; CT, chemotherapy; DOD, death of disease; DUR, death of unknown reason; HDCT, high-dose chemotherapy; M+, metastatic disease; M0, localized disease, M0R0, with complete resection, M0R+, with incomplete resection, and M0Rx, with unknown resection status; na, not annotated; OR, objective response; PD, relapse or progression; PR, partial response; RT, radiotherapy; SD, stable disease; Tx, treatment.

Fig. 3

ETMR: Molecular characteristics, clinical information, and treatment. A. Overview of copy number profiles of ETMR. Bars indicating gain, balanced, or loss add up to 100% for each chromosome arm. B. Pie charts depict that 55/58 ETMR carry the characteristic C19MC amplification. The sex ratio was nearly balanced. C. The bar chart shows the age distribution of age at first diagnosis (information available for 55/58 patients). D. Tumor location is specified with each dot corresponding to one single tumor, or multiple tumors with the respective number of cases given. E. Overview of applied treatment and documented response for patients with ETMR. Overall, 9 of 52 patients remained event-free (EF). Of 43 patients with event, 3 died postoperatively, 38 progressed/relapsed while on treatment, and 2 relapsed after the end of treatment. The symbol § indicates the number of patients with relapse or progression (PD) as first documented response, which differs from overall number of PD after the respective treatment element due to initial continuous complete response (CCR), complete response (CR), partial response (PR), or stable disease (SD) and later PD before the onset of next treatment element; Further explanations and abbreviations: see Figure 2. Abbreviations: ETMR, embryonal tumor with multilayered rosettes; OR, objective response; SD, stable disease.

Fig. 4

Kaplan-Meier plots of survival. PFS (A) and OS (B) for the re-evaluation cohort. Respective PFS (C) and OS (D) for this same cohort with patients grouped according to the result of DNA methylation profiles: CNS NB-FOXR2, ETMR, HGG, other, and unclassified. Survival according to postoperative staging for the pooled cohort of patients with CNS NB-FOXR2: PFS (E) and OS (F) (n = 1 patient with missing information on initial staging is not regarded for this analysis), and for patients with ETMR: PFS (G) and OS (H). Patients without postoperative treatment were excluded from survival analyses. Abbreviations: ETMR, embryonal tumor with multilayered rosettes; HGG, high-grade gliomas; OS, overall survival; PFS, progression-free survival.