MEDB-14. Clinical outcome of pediatric medulloblastoma patients with Li-Fraumeni syndrome
Authors: Kolodziejczak Anna , Guerrini-Rousseau Lea , Planchon Julien Masliah , Ecker Jonas , Selt Florian , Mynarek Martin , Obrecht Denise , Sill Martin , Hirsch Steffen , Sturm Dominik , Waszak Sebastian M , Ramaswamy Vijay , Pentikainen Virve , Demir Haci Ahmet , Clifford Steven C , Schwalbe Ed , Massimi Luca , Snuderl Matija , Galbraith Kristyn , Karajannis Matthias A , Hill Katie , Li Bryan , White Christine L , Redmond Shelagh , Loizos Loizou , Jakob Marcus , Kordes Uwe , Schmid Irene , Hauer Julia , Blattmann Claudia , Filippidou Maria , Scheurlen Wolfram , Kontny Udo , Grund Kerstin , Sutter Christian , Pietsch Torsten , van Tilburg Cornelis M , Frank Stephan , Schewe Denis M , Malkin David , Taylor Michael D , Tabori Uri , Bouffet Eric , Kool Marcel , Sahm Felix , von Deimling Andreas , Korshunov Andrey , Von Hoff Katja , Kratz Christian , Jones David T W , Rutkowski Stefan , Witt Olaf , Bougeard Gaelle , Pajtler Kristian W , Pfister Stefan M , Bourdeaut Franck , Milde Till 
Published: June 2022

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&lt;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.