Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas

Abstract

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively ( P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy.

Fig 1.

Survival of patients from the SickKids cohort with pediatric low-grade glioma stratified by BRAF V600E status. (A) Progression-free survival (PFS) of the SickKids cohort according to BRAF V600E status. (B) Overall survival (OS) for the entire SickKids cohort according to BRAF V600E status. (C) PFS of the SickKids cohort comparing BRAF V600E with KIAA1549-BRAF. (D) OS of the SickKids cohort comparing BRAF V600E with KIAA1549-BRAF. P values were determined by using the log-rank test. WT, wild type.

Fig 2.

Survival of patients with BRAF V600E pediatric low-grade glioma according to the extent of resection and CDKN2A deletion. (A) Progression-free survival (PFS) of the BRAF V600E SickKids cohort according to the extent of resection. (B) PFS for the BRAF V600E independent cohort according to the extent of resection. (C) PFS for the BRAFV 600E SickKids cohort according to CDKN2A status. (D) PFS for the BRAF V600E independent cohort according to CDKN2A status. P values were determined using the log-rank test. GTR, gross total resection. bal, balanced; del, deleted.

Fig 3.

Response of patients with BRAF V600E pediatric low-grade glioma to chemotherapy and BRAF V600E inhibition. Waterfall plot of response to chemotherapy at 6 months. Note the response to BRAF V600E inhibitors in gray. PFS, progression-free survival.

Fig A1.

Progression-free survival (PFS) of patients from the SickKids cohort who were treated with conventional therapies. (A) PFS for patients with BRAF V600E from the SickKids cohort who were treated with radiation. (B) PFS for patients with BRAF V600E from the SickKids cohort who were treated with chemotherapy.

Fig A2.

Survival of SickKids patients stratified by CDKN2A status. (A) Progression-free survival (PFS) and (B) overall survival (OS) for all patients from the SickKids cohort according to CDKN2A status. (C) PFS and (D) OS for patients from the SickKids cohort with wild-type pediatric low-grade glioma (PLGG) according to CDKN2A status. (E) PFS and (F) OS for patients from the SickKids cohort with BRAF V600E PLGG according to CDKN2A status. P values were determined by using log-rank test.

Fig A3.

(A) Progression-free survival (PFS) for the BRAF V600E independent cohort. (B) Overall survival (OS) for the BRAF V600E independent cohort.