Clinical, radiological and genomic features and targeted therapy in BRAF V600E mutant adult glioblastoma.

Abstract

PURPOSE:

Although uncommon, detection of BRAF V600E mutations in adult patients with glioblastoma has become increasingly relevant given the widespread application of molecular diagnostics and encouraging therapeutic activity of BRAF/MEK inhibitors.

METHODS:

We performed a retrospective study of adult glioblastoma patients treated at Dana-Farber Cancer Institute/Brigham and Women's Hospital or Massachusetts General Hospital from January 2011 to July 2019 with an identified BRAF V600E mutation by either immunohistochemistry or molecular testing. Patient characteristics, molecular genomics, and preoperative MRI were analyzed.

RESULTS:

Nineteen glioblastoma patients were included, with median age at diagnosis of 41-years-old (range 22-69). Only 1/18 was IDH1/2-mutant; 10/17 had MGMT unmethylated tumors. The most common additional molecular alterations were CDKN2A/2B biallelic loss/loss-of-function (10/13, 76.9%), polysomy 7 (8/12, 66.7%), monosomy 10 (5/12, 41.7%), PTEN biallelic loss/loss-of-function (5/13, 38.5%) and TERT promoter mutations (5/15, 33.3%). Most tumors were well-circumscribed (11/14) and all were contrast-enhancing on MRI. Twelve patients eventually developed subependymal or leptomeningeal dissemination. Six patients were treated with BRAF/MEK inhibition following disease progression after standard of care therapy, with 4/6 patients showing partial response or stable disease as best response. Median time to progression after BRAF/MEK inhibition was 6.0 months (95% CI 1.2-11.8). Grade 1 skin rash was present in 2 patients, but no other adverse events were reported. Median OS for the entire cohort was 24.1 months (95% CI 15.7-38.9).

CONCLUSION:

Understanding the natural history and features of BRAF V600E glioblastoma may help better identify patients for BRAF/MEK inhibition and select therapeutic strategies.

• Authors: Mary Jane Lim-Fat, Kun Wei Song, J Bryan Iorgulescu, Brian M Andersen, Deborah A Forst, Justin T Jordan, Elizabeth R Gerstner, David A Reardon, Patrick Y Wen, Isabel Arrillaga-Romany
• Journal: Journal of neuro-oncology (J Neurooncol) Vol. 152 Issue 3 Pg. 515-522 (May 2021) ISSN: 1573-7373 [Electronic] United States
• PMID: 33646525 (Publication Type: Journal Article)

Chemical References

• Protein Kinase Inhibitors
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• Mitogen-Activated Protein Kinase Kinases

Topics

• Adult
• Aged
• Female
• Genomics
• Glioblastoma (diagnostic imaging, drug therapy, genetics, radiotherapy)
• Humans
• Middle Aged
• Mitogen-Activated Protein Kinase Kinases
• Mutation
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins B-raf (genetics)
• Retrospective Studies
• Young Adult