Mutations to Medicine: Advances in Medical Management of Paediatric, Adolescent, and Young Adult Low-Grade Gliomas

Gliomas are the most common brain tumours in children, adolescents, and young adults. In children, paediatric-type low-grade gliomas (pLGG) predominate, while IDH-mutant low-grade gliomas (LGG) become more common in young adulthood. While outcomes with complete surgical resection are excellent, many pLGG patients with residual or unresectable tumours experience significant long-term functional impairment despite conventional medical treatment. IDH-mutant LGG have an unfavourable natural history, with high risk of malignant transformation. With the emergence of precision medicine, targeted therapies have offered hope as more effective treatments. For pLGG, favourable short-term outcomes have been demonstrated with MAPK inhibitors. Significant challenges remain, however, including designing treatment regimens that prevent regrowth, understanding mechanisms and biomarkers of response and resistance, and addressing treatment-related toxicities. Furthermore, pLGG manifest as a chronic disease, and it remains unclear whether targeted therapies can yield superior long-term functional outcomes relative to conventional chemotherapy. For IDH-mutant LGG, IDH inhibitors hold promise; however, it is unknown whether monotherapy will avert malignant transformation. Notably, adolescent and young adult patients have been excluded from many clinical trials, resulting in limited data on the efficacy and toxicity of pLGG-directed targeted therapies in this population. Clinical trials and patient care for LGG should be designed around tumour biology rather than patient age. Overall, the molecular era has transformed our understanding of LGG and facilitated the development of novel therapies. The next challenge is to translate new biological insights into patient- and tumour-specific treatment regimens that can improve long-term disease control and functional outcomes.