Clinical outcome of pediatric medulloblastoma patients with Li-Fraumeni syndrome

Anna S. Kolodziejczak; Lea Guerrini-Rousseau; Julien Masliah Planchon; 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. Karajannis; 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 Tilburg; Olaf Witt; Gaëlle Bougeard; Kristian W. Pajtler; Stefan M. Pfister; Franck Bourdeaut; Till Milde

doi:10.1093/neuonc/noad114

Clinical outcome of pediatric medulloblastoma patients with Li-Fraumeni syndrome

Anna S. Kolodziejczak, Lea Guerrini-Rousseau, Julien Masliah Planchon, 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. CliffordEd C. Schwalbe, Luca Massimi, Matija Snuderl, Kristyn Galbraith, Matthias A. Karajannis, 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 Tilburg, Olaf Witt, Gaëlle Bougeard, Kristian W. Pajtler, Stefan M. Pfister, Franck Bourdeaut, Till Milde

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	2273-2286
Number of pages	14
Journal	Neuro-Oncology
Volume	25
Issue number	12
DOIs	https://doi.org/10.1093/neuonc/noad114
State	Published - 1 Dec 2023
Externally published	Yes

Keywords

Li–Fraumeni syndrome
medulloblastoma
survival
TP53
Prospective Studies
Humans
Cerebellar Neoplasms/therapy
Tumor Suppressor Protein p53/genetics
Medulloblastoma/therapy
Germ-Line Mutation
Retrospective Studies
Child
Li-Fraumeni Syndrome/complications

ASJC Scopus subject areas

Oncology
Clinical Neurology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/neuonc/noad114

Cite this

Kolodziejczak, A. S., Guerrini-Rousseau, L., Planchon, J. M., Ecker, J., Selt, F., Mynarek, M., Obrecht, D., Sill, M., Autry, R. J., Stutheit-Zhao, E., Hirsch, S., Amouyal, E., Dufour, C., Ayrault, O., Torrejon, J., Waszak, S. M., Ramaswamy, V., Pentikainen, V., Demir, H. A., ... Milde, T. (2023). Clinical outcome of pediatric medulloblastoma patients with Li-Fraumeni syndrome. Neuro-Oncology, 25(12), 2273-2286. https://doi.org/10.1093/neuonc/noad114

@article{19621b87051e4d6a9c441359d0fd6df6,

title = "Clinical outcome of pediatric medulloblastoma patients with Li-Fraumeni syndrome",

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.",

keywords = "Li–Fraumeni syndrome, medulloblastoma, survival, TP53, Prospective Studies, Humans, Cerebellar Neoplasms/therapy, Tumor Suppressor Protein p53/genetics, Medulloblastoma/therapy, Germ-Line Mutation, Retrospective Studies, Child, Li-Fraumeni Syndrome/complications",

author = "Kolodziejczak, {Anna S.} and Lea Guerrini-Rousseau and Planchon, {Julien Masliah} and Jonas Ecker and Florian Selt and Martin Mynarek and Denise Obrecht and Martin Sill and Autry, {Robert J.} and Eric Stutheit-Zhao and Steffen Hirsch and Elsa Amouyal and Christelle Dufour and Olivier Ayrault and Jacob Torrejon and Waszak, {Sebastian M.} and Vijay Ramaswamy and Virve Pentikainen and Demir, {Haci Ahmet} and Clifford, {Steven C.} and Schwalbe, {Ed C.} and Luca Massimi and Matija Snuderl and Kristyn Galbraith and Karajannis, {Matthias A.} and Katherine Hill and Li, {Bryan K.} and Mike Walsh and White, {Christine L.} and Shelagh Redmond and Loizou Loizos and Marcus Jakob and Kordes, {Uwe R.} and Irene Schmid and Julia Hauer and Claudia Blattmann and Maria Filippidou and Gianluca Piccolo and Wolfram Scheurlen and Ahmed Farrag and Kerstin Grund and Christian Sutter and Torsten Pietsch and Stephan Frank and Schewe, {Denis M.} and David Malkin and Myriam Ben-Arush and Astrid Sehested and Wong, {Tai Tong} and Wu, {Kuo Sheng} and Liu, {Yen Lin} and Fernando Carceller and Sabine Mueller and Schuyler Stoller and Taylor, {Michael D.} and Uri Tabori and Eric Bouffet and Marcel Kool and Felix Sahm and {Von Deimling}, Andreas and Andrey Korshunov and {Von Hoff}, Katja and Kratz, {Christian P.} and Dominik Sturm and Jones, {David T.W.} and Stefan Rutkowski and {Van Tilburg}, {Cornelis M.} and Olaf Witt and Ga{\"e}lle Bougeard and Pajtler, {Kristian W.} and Pfister, {Stefan M.} and Franck Bourdeaut and Till Milde",

note = "{\textcopyright} The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.",

year = "2023",

month = dec,

day = "1",

doi = "10.1093/neuonc/noad114",

language = "אנגלית",

volume = "25",

pages = "2273--2286",

number = "12",

}

Kolodziejczak, AS, Guerrini-Rousseau, L, Planchon, JM, Ecker, J, Selt, F, Mynarek, M, Obrecht, D, Sill, M, Autry, RJ, Stutheit-Zhao, E, Hirsch, S, Amouyal, E, Dufour, C, Ayrault, O, Torrejon, J, Waszak, SM, Ramaswamy, V, Pentikainen, V, Demir, HA, Clifford, SC, Schwalbe, EC, Massimi, L, Snuderl, M, Galbraith, K, Karajannis, MA, Hill, K, Li, BK, Walsh, M, White, CL, Redmond, S, Loizos, L, Jakob, M, Kordes, UR, Schmid, I, Hauer, J, Blattmann, C, Filippidou, M, Piccolo, G, Scheurlen, W, Farrag, A, Grund, K, Sutter, C, Pietsch, T, Frank, S, Schewe, DM, Malkin, D, Ben-Arush, M, Sehested, A, Wong, TT, Wu, KS, Liu, YL, Carceller, F, Mueller, S, Stoller, S, Taylor, MD, Tabori, U, Bouffet, E, Kool, M, Sahm, F, Von Deimling, A, Korshunov, A, Von Hoff, K, Kratz, CP, Sturm, D, Jones, DTW, Rutkowski, S, Van Tilburg, CM, Witt, O, Bougeard, G, Pajtler, KW, Pfister, SM, Bourdeaut, F & Milde, T 2023, 'Clinical outcome of pediatric medulloblastoma patients with Li-Fraumeni syndrome', Neuro-Oncology, vol. 25, no. 12, pp. 2273-2286. https://doi.org/10.1093/neuonc/noad114

TY - JOUR

T1 - Clinical outcome of pediatric medulloblastoma patients with Li-Fraumeni syndrome

AU - Kolodziejczak, Anna S.

AU - Guerrini-Rousseau, Lea

AU - Planchon, Julien Masliah

AU - Ecker, Jonas

AU - Selt, Florian

AU - Mynarek, Martin

AU - Obrecht, Denise

AU - Sill, Martin

AU - Autry, Robert J.

AU - Stutheit-Zhao, Eric

AU - Hirsch, Steffen

AU - Amouyal, Elsa

AU - Dufour, Christelle

AU - Ayrault, Olivier

AU - Torrejon, Jacob

AU - Waszak, Sebastian M.

AU - Ramaswamy, Vijay

AU - Pentikainen, Virve

AU - Demir, Haci Ahmet

AU - Clifford, Steven C.

AU - Schwalbe, Ed C.

AU - Massimi, Luca

AU - Snuderl, Matija

AU - Galbraith, Kristyn

AU - Karajannis, Matthias A.

AU - Hill, Katherine

AU - Li, Bryan K.

AU - Walsh, Mike

AU - White, Christine L.

AU - Redmond, Shelagh

AU - Loizos, Loizou

AU - Jakob, Marcus

AU - Kordes, Uwe R.

AU - Schmid, Irene

AU - Hauer, Julia

AU - Blattmann, Claudia

AU - Filippidou, Maria

AU - Piccolo, Gianluca

AU - Scheurlen, Wolfram

AU - Farrag, Ahmed

AU - Grund, Kerstin

AU - Sutter, Christian

AU - Pietsch, Torsten

AU - Frank, Stephan

AU - Schewe, Denis M.

AU - Malkin, David

AU - Ben-Arush, Myriam

AU - Sehested, Astrid

AU - Wong, Tai Tong

AU - Wu, Kuo Sheng

AU - Liu, Yen Lin

AU - Carceller, Fernando

AU - Mueller, Sabine

AU - Stoller, Schuyler

AU - Taylor, Michael D.

AU - Tabori, Uri

AU - Bouffet, Eric

AU - Kool, Marcel

AU - Sahm, Felix

AU - Von Deimling, Andreas

AU - Korshunov, Andrey

AU - Von Hoff, Katja

AU - Kratz, Christian P.

AU - Sturm, Dominik

AU - Jones, David T.W.

AU - Rutkowski, Stefan

AU - Van Tilburg, Cornelis M.

AU - Witt, Olaf

AU - Bougeard, Gaëlle

AU - Pajtler, Kristian W.

AU - Pfister, Stefan M.

AU - Bourdeaut, Franck

AU - Milde, Till

PY - 2023/12/1

Y1 - 2023/12/1

N2 - 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.

AB - 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.

KW - Li–Fraumeni syndrome

KW - medulloblastoma

KW - survival

KW - TP53

KW - Prospective Studies

KW - Humans

KW - Cerebellar Neoplasms/therapy

KW - Tumor Suppressor Protein p53/genetics

KW - Medulloblastoma/therapy

KW - Germ-Line Mutation

KW - Retrospective Studies

KW - Child

KW - Li-Fraumeni Syndrome/complications

UR - http://www.scopus.com/inward/record.url?scp=85179853525&partnerID=8YFLogxK

U2 - 10.1093/neuonc/noad114

DO - 10.1093/neuonc/noad114

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 37379234

AN - SCOPUS:85179853525

SN - 1522-8517

VL - 25

SP - 2273

EP - 2286

JO - Neuro-Oncology

JF - Neuro-Oncology

IS - 12

ER -

Clinical outcome of pediatric medulloblastoma patients with Li-Fraumeni syndrome

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