Clinical, surgical, and molecular characteristics and outcomes of adult patients with diffuse midline glioma, H3 K27-altered, treated with surgical resection.
Summary
This retrospective study investigated the clinical, surgical, and molecular characteristics and outcomes of 52 adult patients with H3 K27-altered diffuse midline glioma (DMG) treated with surgical resection. The median overall survival was 17.8 months. Genomic profiling revealed a distinct molecular landscape dominated by H3F3A mutations, frequently co-occurring with TP53 mutations, and a significant enrichment of mutations within the RTK/RAS/PI3K signaling pathway, involving NF1, FGFR1, and PIK3CA. Postoperative adjuvant radiotherapy combined with temozolomide emerged as the sole independent protective factor for overall survival. While maximal safe resection is considered essential, molecular targeted therapies did not achieve independent statistical significance.
Analysis
CLINICAL: This retrospective study provides important data on the management of H3 K27-altered diffuse midline glioma in adults. It confirms the irreplaceable role of postoperative adjuvant radiotherapy combined with temozolomide, which emerged as the sole independent protective factor for overall survival (HR = 0.12, P < 0.001). While maximal safe surgical resection is considered an essential cytoreductive foundation, the study did not demonstrate an independent benefit for the extent of resection or targeted therapies, suggesting that the latter require further investigation in well-designed clinical trials. These findings could influence future treatment guidelines by integrating resection and targeted agents into adult-tailored, multi-modal frameworks, with a potential clinical impact in the medium term (3-5 years). BIOMOL: Molecular analysis using next-generation sequencing (NGS) on a subset of patients allowed for the characterization of the unique genomic landscape of these tumors. It highlighted a predominance of H3F3A mutations, often associated with TP53 mutations, and notably a significant enrichment of mutations in the RTK/RAS/PI3K signaling pathway, specifically involving NF1, FGFR1, and PIK3CA genes. This discovery of new alterations and potential resistance or sensitivity mechanisms opens avenues for the development of predictive biomarkers and targeted therapies. The use of NGS on tumor samples (likely FFPE, though not specified) enabled this characterization, and its validation could lead to clinical tests to identify patients eligible for targeted treatments.