Clinical outcome of pediatric medulloblastoma patients with Li–Fraumeni syndrome

• DOI: 10.1093/neuonc/noad114
• Publication Date: 2023-06-28T16:47:24Z
• Authors: Anna S Kolodziejczak; Lea Guerrini-Rous...; Julien Masliah Pl...; Jonas Ecker; Florian Selt; Martin Mynarek; Denise Obrecht; Martin Sill; Robert J Autry; Eric Stutheit-Zhao; Steffen Hirsch; Elsa Amouyal; Christelle Dufour; Olivier Ayrault; Jacob Torrejon; Sebastian M Waszak; Vijay Ramaswamy; Virve Pentikainen; Haci Ahmet Demir; Steven C Clifford; Ed C Schwalbe; Luca Massimi; Matija Snuderl; Kristyn Galbraith; Matthias A Karaja...; Katherine Hill; Bryan K Li; Mike Walsh; Christine L White; Shelagh Redmond; Loizou Loizos; Marcus Jakob; Uwe R Kordes; Irene Schmid; Julia Hauer; Claudia Blattmann; Maria Filippidou; Gianluca Piccolo; Wolfram Scheurlen; Ahmed Farrag; Kerstin Grund; Christian Sutter; Torsten Pietsch; Stephan Frank; Denis M Schewe; David Malkin; Myriam Ben-Arush; Astrid Sehested; Tai-Tong Wong; Kuo-Sheng Wu; Yen-Lin Liu; Fernando Carceller; Sabine Mueller; Schuyler Stoller; Michael D Taylor; Uri Tabori; Eric Bouffet; Marcel Kool; Felix Sahm; Andreas von Deimling; Andrey Korshunov; Katja von Hoff; Christian P Kratz; Dominik Sturm; David T W Jones; Stefan Rutkowski; Cornelis M van Ti...; Olaf Witt; Gaëlle Bougeard; Kristian W Pajtler; Stefan M Pfister; Franck Bourdeaut; Till Milde
• Keywords: MESH: Humans; [SDV]Life Sciences [q-bio]; 610; MESH: Retrospective Studies; medulloblastoma; survival; MESH: Prospective Studies; 3. Good health; Li–Fraumeni syndrome; MESH: Child; MESH: Germ-Line Mutation; TP53; MESH: Li-Fraumeni Syndrome; MESH: Tumor Suppressor Protein p53; MESH: Cerebellar Neoplasms; MESH: Medulloblastoma

Abstract

Background The prognosis for Li–Fraumeni syndrome (LFS) patients with medulloblastoma (MB) is poor. Comprehensive clinical data for this patient group is lacking, challenging the development of novel therapeutic strategies. Here, we present clinical and molecular data on a retrospective cohort of pediatric LFS MB patients.

Methods In this multinational, multicenter retrospective cohort study, LFS patients under 21 years with MB and class 5 or class 4 constitutional TP53 variants were included. TP53 mutation status, methylation subgroup, treatment, progression free- (PFS) and overall survival (OS), recurrence patterns, and incidence of subsequent neoplasms were evaluated.

Results The study evaluated 47 LFS individuals diagnosed with MB, mainly classified as DNA methylation subgroup “SHH_3” (86%). The majority (74%) of constitutional TP53 variants represented missense variants. The 2- and 5-year (y-) PFS were 36% and 20%, and 2- and 5y-OS were 53% and 23%, respectively. Patients who received postoperative radiotherapy (RT) (2y-PFS: 44%, 2y-OS: 60%) or chemotherapy before RT (2y-PFS: 32%, 2y-OS: 48%) had significantly better clinical outcome then patients who were not treated with RT (2y-PFS: 0%, 2y-OS: 25%). Patients treated according to protocols including high-intensity chemotherapy and patients who received only maintenance-type chemotherapy showed similar outcomes (2y-PFS: 42% and 35%, 2y-OS: 68% and 53%, respectively).

Conclusions LFS MB patients have a dismal prognosis. In the presented cohort use of RT significantly increased survival rates, whereas chemotherapy intensity did not influence their clinical outcome. Prospective collection of clinical data and development of novel treatments are required to improve the outcome of LFS MB patients.