Oncotarget

Research Perspectives:

WNT-pathway medulloblastoma: what constitutes low-risk and how low can one go?

Shakthivel Mani, Abhishek Chatterjee, Archya Dasgupta, Neelam Shirsat, Sridhar Epari, Girish Chinnaswamy and Tejpal Gupta _

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Oncotarget. 2023; 14:105-110. https://doi.org/10.18632/oncotarget.28360

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Abstract

Shakthivel Mani1, Abhishek Chatterjee1, Archya Dasgupta1, Neelam Shirsat2, Sridhar Epari3, Girish Chinnaswamy4 and Tejpal Gupta1

1 Department of Radiation Oncology, ACTREC/TMH, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra 410210, India

2 Department of Neuro-Oncology Laboratory, ACTREC/TMH, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra 410210, India

3 Department of Pathology, ACTREC/TMH, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra 410210, India

4 Department of Pediatric Oncology, ACTREC/TMH, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra 410210, India

Correspondence to:

Tejpal Gupta, email: [email protected]

Keywords: de-intensification; medulloblastoma; molecular; survival; toxicity

Received: January 26, 2023     Accepted: January 31, 2023     Published: February 07, 2023

Copyright: © 2023 Mani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

Novel biological insights have established that medulloblastoma is a heterogenous disease comprising four broad molecular subgroups - WNT, SHH, Group 3, and Group 4 respectively, resulting in the incorporation of molecular/genetic information in 5th edition of WHO classification and contemporary risk-stratification. Concerns regarding therapy-related late toxicity in long-term survivors have led to systematic attempts at treatment de-intensification in good-risk medulloblastoma. Given the excellent survival (>90%) of WNT-pathway medulloblastoma, prospective clinical trials have focused on optimization of therapy to balance survival versus quality of survival. The currently accepted definition of low-risk WNT-pathway medulloblastoma includes children <16 years of age with residual tumour <1.5 cm2 and no evidence of metastases. This systematically excludes adolescents and young adults who have been perceived to have worse outcomes. We have previously reported long-term survival of our adolescent and young adult cohort that were largely comparable to childhood medulloblastoma. We now report on molecularly characterized WNT-subgroup patients treated between 2004–2020 with risk-stratified multi-modality therapy to identify differences between childhood (<15 years) versus adolescent and young adults (>15 years). Despite modest differences in disease status at presentation and treatment modality, there were no significant differences in patterns of failure or survival between childhood versus adolescent and young adult WNT-pathway medulloblastoma. Two de-intensification trials in low-risk WNT-pathway medulloblastoma – first testing omission of upfront craniospinal irradiation and second a primary chemotherapy approach after surgery – had to be terminated prematurely due to unacceptably high relapse rates suggesting that craniospinal irradiation remains an integral component of treatment. The presence of TP53 mutations and OTX2 gains have recently been reported as independent negative prognostic factors in a multi-institutional cohort of WNT-pathway medulloblastoma raising questions on eligibility of such patients for de-escalation trials. The definition of low-risk WNT-pathway medulloblastoma may need to be refined in light of recent clinical data and newer biological information.


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