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Integrated molecular and clinical analysis of BRAF-mutant glioma in adults

      Background: The significance of BRAF alterations in adult glioma is increasingly acknowledged given their potential therapeutic implications. While the spectrum of BRAF alterations in pediatric glioma is well-characterized, the implications of BRAF alterations on the clinical course and response to treatment in adult glioma remain unclear. In this study, we characterize a large (300 patient) multi-institutional, retrospective cohort of adults with BRAF-mutated gliomas by functional class. We identify the clinical phenotypes, genomic signatures, and molecular features associated with each BRAF alteration functional class to assess prognostic implications and guide therapeutic approaches.
      Materials and Methods: 206 adults with BRAF-mutated gliomas—along with a pediatric sub-cohort—were identified from Dana-Farber/Brigham Cancer Center, Johns Hopkins Hospital, GENIE, and TCGA. Patients were grouped into cohorts based on the putative activation mechanism of their BRAF alteration: Class I (RAS-independent/ dimerization-independent), II (RAS-independent/ dimerization-dependent), III (RAS-dependent/ dimerization-dependent), as well as rearrangements, amplifications, and other unclassified alterations.
      Results: Adult BRAF-mutant gliomas harbor distinct clinical and molecular features from pediatric, with a higher prevalence of BRAFV600E(Class I) and BRAF-fusions in pediatric tumors. Class II/III, gains and unclassified alterations are almost exclusively present in adult glioma. Other genomic associations observed within functional classes (NF1 loss with Class II/III; EGFR with unclassified) are consistent with their putative mechanism of ERK-activation. BRAFV600E alterations are associated with improved survival in adults with glioma compared with other BRAF alterations, though not in glioblastoma, while increased age is associated with inferior survival. A subset of additional alterations is associated with better (KIAA1549 HR 0.48; p < 0.02) or worse (CDKN2A/B loss, TERT-promoter, PTEN; p < 0.01) survival. Moreover, glioma with BRAFV600E alterations expressed higher levels of transcripts associated with MEK inhibitor sensitivity. In 13 patients treated with targeted therapy (6 PXA, 4 GBM, 2 PA, 1 other astrocytoma), 6 had a clinical benefit. Median time to progression was 5 months and overall survival was 165 months (53 months in glioblastoma).
      Conclusions: This large cohort of BRAF-altered adult glioma demonstrates a broad range of alterations. Molecular alterations and clinical outcomes varied across BRAF classes, suggesting distinct biological characteristics.
      Conflict of interest:
      Corporate-sponsored Research: Dr. Schreck’s laboratory receives research support from Springworks Therapeutics.