Patients with Group 4 medulloblastomas survived longer postrelapse than those with other subgroups.

  • Major Finding: Patients with Group 4 medulloblastomas survived longer postrelapse than those with other subgroups.

  • Concept: In this retrospective study, molecular features and, rarely, even subgroup sometimes changed upon relapse.

  • Impact: This work suggests that repeating molecular profiling of medulloblastomas after relapse is critical.

Medulloblastoma is clinically defined by the existence of four subgroups: WNT, Sonic Hedgehog (SHH), Group 3, and Group 4. Despite treatment by surgical resection with craniospinal irradiation and chemotherapy, medulloblastoma fatally recurs in nearly one third of patients. In an effort to better understand the clinical outcomes and molecular features mediating medulloblastoma recurrence, Kumar and colleagues retrospectively compared clinical outcomes of patients with relapsed medulloblastoma of different subgroups from two clinical trials, one enrolling 72 patients and the other enrolling 52 patients. WNT subgroup medulloblastomas were not represented in either trial. Comparison of time to relapse in the larger of the clinical studies showed that patients with Group 4 tumors tended to survive longer postrelapse (2.79 years) than patients with tumors of other subgroups (0.91 years for Group 3; 1.23 years for SHH; 2.07 years for unclassified), and similar results were seen in the smaller trial, suggesting that subgroup is a critical prognostic determinant. Furthermore, in the larger trial, patients with Group 4 tumors had longer survival times after relapse (2.27 years) compared with the other subgroups (0.44 years for Group 3; 1.06 years for SHH; 1.07 years for unclassified), but this trend was not observed in the smaller trial. Additionally, DNA methylation profiling and next-generation sequencing of paired patient samples from initial medulloblastoma tumors and recurrent tumors showed that subgroup stabilities were largely maintained after recurrence. However, further analysis of these tissues revealed driver gene alterations, and chromosome copy number varied in the patient-matched initial and relapsed medulloblastoma tumors. Surprisingly, methylation-based classification of some of the matched patient samples showed that some Group 4 tumors switched molecular profiles to that of Group 3 at relapse, suggesting that subgroup plasticity is sometimes present in recurrent medulloblastomas. Taken together, these findings encourage the use of molecular profiling in future clinical studies of relapsed medulloblastoma, as this may provide insight into underlying molecular and clinical features of medulloblastoma recurrence and mortality.

Kumar R, Smith KS, Deng M, Terhune C, Robinson GW, Orr BA, et al. Clinical outcomes and patient-matched molecular composition of relapsed medulloblastoma. J Clin Oncol 2021 Jan 27 [Epub ahead of print].

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