RESUMEN
Glioblastoma, IDH-wild type, the most common malignant primary central nervous system tumor, represents a formidable challenge in clinical management due to its poor prognosis and limited therapeutic responses. With an evolving understanding of its underlying biology, there is an urgent need to identify prognostic molecular groups that can be subject to targeted therapy. This study established a cohort of 124 sequential glioblastomas from a tertiary hospital and aimed to find correlations between molecular features and survival outcomes. Comprehensive molecular characterization of the cohort revealed prevalent alterations as previously described, such as TERT promoter mutations and involvement of the PI3K-Akt-mTOR, CK4/6-CDKN2A/B-RB1, and p14ARF-MDM2-MDM4-p53 pathways. MGMT promoter methylation is a significant predictor of improved overall survival, aligned with previous data. Conversely, age showed a marginal association with higher mortality. Multivariate analysis to account for the effect of MGMT promoter methylation and age showed that, in contrast to other published series, this cohort demonstrated improved survival for tumors harboring PTEN mutations, and that there was no observed difference for most other molecular alterations, including EGFR amplification, RB1 loss, or the coexistence of EGFR amplification and deletion/exon skipping (EGFRvIII). Despite limitations in sample size, this study contributes data to the molecular landscape of glioblastomas, prompting further investigations to examine these findings more closely in larger cohorts.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Isocitrato Deshidrogenasa , Humanos , Glioblastoma/genética , Glioblastoma/mortalidad , Glioblastoma/patología , Persona de Mediana Edad , Masculino , Femenino , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Anciano , Adulto , Isocitrato Deshidrogenasa/genética , Mutación , Estudios de Cohortes , Pronóstico , Biomarcadores de Tumor/genética , Metilación de ADN/genética , Adulto Joven , Anciano de 80 o más Años , Regiones Promotoras Genéticas/genética , Análisis de SupervivenciaRESUMEN
Glioblastoma IDH wild type (GBM) is a very aggressive brain tumour, characterised by an infiltrative growth pattern and by a prominent neoangiogenesis. Its prognosis is unfortunately dismal, and the median overall survival of GBM patients is short (15 months). Clinical management is based on bulk tumour removal and standard chemoradiation with the alkylating drug temozolomide, but the tumour invariably recurs leading to patient's death. Clinical options for GBM patients remained unaltered for almost two decades until the encouraging results obtained by the phase II REGOMA trial allowed the introduction of the multikinase inhibitor regorafenib as a preferred regimen in relapsed GBM treatment by the National Comprehensive Cancer Network (NCCN) 2020 Guideline. Regorafenib, a sorafenib derivative, targets kinases associated with angiogenesis (VEGFR 1-3), as well as oncogenesis (c-KIT, RET, FGFR) and stromal kinases (FGFR, PDGFR-b). It was already approved for metastatic colorectal cancers and hepatocellular carcinomas. The aim of the present review is to focus on both the molecular and clinical knowledge collected in these first three years of regorafenib use in GBM.
Asunto(s)
Antineoplásicos , Glioblastoma , Neoplasias Hepáticas , Compuestos de Fenilurea , Piridinas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Resultado del Tratamiento , Neoplasias Hepáticas/tratamiento farmacológicoRESUMEN
INTRODUCTION: Despite aggressive treatment, glioblastoma invariably recurs. The optimal treatment for recurrent glioblastoma (rGBM) is not well defined. Stereotactic radiosurgery (SRS) for rGBM has demonstrated favorable outcomes for selected patients; however, its efficacy in molecular GBM subtypes is unknown. We sought to identify genetic alterations that predict response/outcomes from SRS in rGBM-IDH-wild-type (IDH-WT). METHODS: rGBM-IDH-WT patients undergoing SRS at first recurrence and tested by next-generation sequencing (NGS) were reviewed (2009-2018). Demographic, clinical, and molecular characteristics were evaluated. NGS interrogating 205-genes was performed. Primary outcome was survival from GK-SRS assessed by Kaplan-Meier method and multivariable Cox proportional-hazards. RESULTS: Sixty-three lesions (43-patients) were treated at 1st recurrence. Median age was 61-years. All patients were treated with resection and chemoradiotherapy. Median time from diagnosis to 1st recurrence was 8.7-months. Median cumulative volume was 2.895 cm3 and SRS median marginal dose was 18 Gy (median isodose-54%). Bevacizumab was administered in 81.4% patients. PFS from SRS was 12.9-months. Survival from SRS was 18.2-months. PTEN-mutant patients had a longer PFS (p = 0.049) and survival from SRS (p = 0.013) in multivariable analysis. Although no statistically significant PTEN-mutants patients had higher frequency of radiation necrosis (21.4% vs. 3.4%) and lower in-field recurrence (28.6% vs. 37.9%) compared to PTEN-WT patients. CONCLUSIONS: SRS is a safe and effective treatment option for selected rGBM-IDH-WT patients following first recurrence. rGBM-IDH-WT harboring PTEN-mutation have improved survival with salvage SRS compared to PTEN-WT patients. PTEN may be used as a molecular biomarker to identify a subset of rGBM patients who may benefit the most from SRS.