MEDB-14. Clinical outcome of pediatric medulloblastoma patients with Li-Fraumeni syndrome

Abstract

PURPOSE: The prognosis for SHH-medulloblastoma (MB) patients with Li-Fraumeni syndrome (LFS) is poor. Due to lack of comprehensive data for these patients, it is challenging to establish effective therapeutic recommendations. We here describe the largest retrospective cohort of pediatric LFS SHH-MB patients to date and their clinical outcomes. PATIENTS AND METHODS: N=31 patients with LFS SHH-MB were included in this retrospective multicenter study. TP53 variant type, clinical parameters including treatment modalities, event-free survival (EFS) and overall survival (OS), as well as recurrence patterns and incidence of secondary neoplasms, were evaluated. RESULTS: All LFS-MBs were classified as SHH subgroup, in 30/31 cases based on DNA methylation analysis. The majority of constitutional TP53 variants (72%) represented missense variants, and all except two truncating variants were located within the DNA-binding domain. 54% were large cell anaplastic, 69% gross totally resected and 81% had M0 status. The 2-(y)ear and 5-(y)ear EFS were 26% and 8,8%, respectively, and 2y- and 5y-OS 40% and 12%. Patients who received post-operative radiotherapy (RT) followed by chemotherapy (CT) showed significantly better outcomes (2y-EFS:43%) compared to patients who received CT before RT (30%) (p<0.05). The 2y-EFS and 2y-OS were similar when treated with protocols including high-dose chemotherapy (EFS:22%, OS:44%) compared to patients treated with maintenance-type chemotherapy (EFS:31%, OS:45%). Recurrence occurred in 73.3% of cases independent of resection or M-status, typically within the radiation field (75% of RT-treated patients). Secondary malignancies developed in 12.5% and were cause of death in all affected patients. CONCLUSIONS: Patients with LFS-MBs have a dismal prognosis. This retrospective study suggests that upfront RT may increase EFS, while intensive therapeutic approaches including high-dose chemotherapy did not translate into increased survival of this patient group. To improve outcomes of LFS-MB patients, prospective collection of clinical data and development of treatment guidelines are required.

Current practice of cancer predisposition testing in pediatric patients with CNS tumors in the United States

“…This preference toward pathology‐specific guidelines parallels the integration of molecular tumor testing into care for pediatric patients with CNSTs. The recent expansion of more elaborate molecular tumor analysis in these patients, particularly with high‐grade gliomas and MBLs, has significant implications for treatment and management with germline findings as an important component of the overall diagnosis 25–29 …”

“…The recent expansion of more elaborate molecular tumor analysis in these patients, particularly with high-grade gliomas and MBLs, has significant implications for treatment and management with germline findings as an important component of the overall diagnosis. [25][26][27][28][29] Conversely, more genetics providers selected universal testing for all patients with CNSTs than neuro-oncologists and pediatric oncologists. This parallels the shift in adult hereditary cancer testing toward universal GT for certain diagnoses rather than restricted by specific criteria.…”