Dual inhibitor therapy using dabrafenib (a selective oral inhibitor of several mutated forms of BRAF kinase) and trametinib (a reversible inhibitor of MEK1 and MEK2) has been used successfully for treatment of metastatic melanoma, anaplastic thyroid cancer, and other tumor types, but has been reported in only a few patients with primary brain tumors and none with pleomorphic xanthoastrocytoma.
We find that PXAs are genetically defined by the combination of CDKN2A biallelic inactivation and RAF alterations that were present in all 19 cases, most commonly as CDKN2A homozygous deletion and BRAF p.V600E mutation but also occasionally BRAF or RAF1 fusions or other rearrangements.
Dual inhibitor therapy using dabrafenib (a selective oral inhibitor of several mutated forms of BRAF kinase) and trametinib (a reversible inhibitor of MEK1 and MEK2) has been used successfully for treatment of metastatic melanoma, anaplastic thyroid cancer, and other tumor types, but has been reported in only a few patients with primary brain tumors and none with pleomorphic xanthoastrocytoma.
Because mutations of FANCA and BRAF and copy number variations of CDKN2A/B are more frequent in PXA than in glioblastoma, they might be used to distinguish the 2 tumors.
The tumor was negative for the V600E mutation, but 2 RNA sequencing platforms detected a QKI-RAF1 fusion (t(6; 3)(q26; p25)), which has not been previously reported in PXAs.
In post-hoc subgroup analysis, hypermutator tumors (mismatch repair deficiency and somatic POLE/POLD1 mutations) and those biologically resembling pleomorphic xanthoastrocytoma ([PXA]-like, driven by BRAF_V600E or NF1 mutation) had significantly more CD8<sup>+</sup> tumor-infiltrating lymphocytes, and longer survival with the addition of BEV.
In post-hoc subgroup analysis, hypermutator tumors (mismatch repair deficiency and somatic POLE/POLD1 mutations) and those biologically resembling pleomorphic xanthoastrocytoma ([PXA]-like, driven by BRAF_V600E or NF1 mutation) had significantly more CD8<sup>+</sup> tumor-infiltrating lymphocytes, and longer survival with the addition of BEV.
Immunohistochemical and molecular biological assessment for isocitrate dehydrogenases 1 and 2 (IDH1/2), α-thalassemia/mental-retardation-syndrome-X-linked gene (ATRX), p53, BRAF, telomere reverse transcriptase promoter (TERT-p), H3F3A, and integrase interactor 1 (INI1) were performed. eGBM tended to lack the degenerative changes characteristic for PXA.
Immunohistochemical and molecular biological assessment for isocitrate dehydrogenases 1 and 2 (IDH1/2), α-thalassemia/mental-retardation-syndrome-X-linked gene (ATRX), p53, BRAF, telomere reverse transcriptase promoter (TERT-p), H3F3A, and integrase interactor 1 (INI1) were performed. eGBM tended to lack the degenerative changes characteristic for PXA.
Both components were positive for the mutant IDH1 R132H and showed loss of ATRX expression, whereas BRAF V600E was restricted to the PXA-like component.
A valine-to-glutamic acid substitution at position 600 of the serine/threonine-protein kinase BRAF (BRAF V600E) mutation, which is commonly found in PXA, has recently been detected in approximately 50% of all epithelioid glioblastoma (GBM) cases.
A valine-to-glutamic acid substitution at position 600 of the serine/threonine-protein kinase BRAF (BRAF V600E) mutation, which is commonly found in PXA, has recently been detected in approximately 50% of all epithelioid glioblastoma (GBM) cases.
A valine-to-glutamic acid substitution at position 600 of the serine/threonine-protein kinase BRAF (BRAF V600E) mutation, which is commonly found in PXA, has recently been detected in approximately 50% of all epithelioid glioblastoma (GBM) cases.
A valine-to-glutamic acid substitution at position 600 of the serine/threonine-protein kinase BRAF (BRAF V600E) mutation, which is commonly found in PXA, has recently been detected in approximately 50% of all epithelioid glioblastoma (GBM) cases.
A valine-to-glutamic acid substitution at position 600 of the serine/threonine-protein kinase BRAF (BRAF V600E) mutation, which is commonly found in PXA, has recently been detected in approximately 50% of all epithelioid glioblastoma (GBM) cases.
A valine-to-glutamic acid substitution at position 600 of the serine/threonine-protein kinase BRAF (BRAF V600E) mutation, which is commonly found in PXA, has recently been detected in approximately 50% of all epithelioid glioblastoma (GBM) cases.
A valine-to-glutamic acid substitution at position 600 of the serine/threonine-protein kinase BRAF (BRAF V600E) mutation, which is commonly found in PXA, has recently been detected in approximately 50% of all epithelioid glioblastoma (GBM) cases.