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PURPOSE

We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors.

METHODS

Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing.

RESULTS

A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving , , and . Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms.

CONCLUSION

Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.

目的

我们旨在研究复发性髓母细胞瘤的临床结果，并比较患者匹配的诊断和复发肿瘤之间的分子特征。

方法

在 SJMB03（NCT00085202）或 SJYC07（NCT00602667）试验中入组的经历髓母细胞瘤复发的儿童和婴儿，对其临床结果进行了分析，包括复发的解剖和时间模式以及复发后的生存情况。通过 DNA 甲基化阵列和下一代测序分析了一个主要独立的配对分子队列。

结果

SJMB03 中有 72 例（22%）和 SJYC07 中有 52 例（66%）患者发生了复发，其中包括 3 组和无翅肿瘤的大量代表性。尽管大多数患者表现出一些远处疾病（79%），但 38%的 sonic hedgehog 肿瘤患者仅出现局部复发。复发时间和复发后生存因分子亚组而异，具有 4 组肿瘤的患者潜伏期较长。在 SJYC07 中之前未接受放疗的患者中，复发后放疗与长期生存相关。SJMB03 患者的再放疗只是暂时缓解。在 127 例具有患者匹配肿瘤对的患者中，有 9 例（7%）随后发生了非髓母细胞瘤 CNS 恶性肿瘤。其余患者的亚组（96%）和亚型（80%）稳定性基本保持。观察到少数亚组从 4 组到 3 组肿瘤的分歧，这与涉及、和的遗传改变相一致。鉴定出驱动基因和染色体臂的亚组特异性改变模式。