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 MethodsA 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. ConclusionBRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy. response to therapy and clinical outcome is still not known. As a result, as far as nonsurgical treatment is concerned, all patients with PLGGs receive similar treatment independent of their tumor's molecular alterations. 6 For deeply located tumors, such as hypothalamic/chiasmatic LGGs, the need for biopsy before treatment decisions are made for these children is still debated.The BRAF V600E mutation, which is observed in a variety of adult 7 and pediatric neoplasms, is thought to be present in only a small percentage of PLGGs.8 Controversy still exists as to whether BRAF V600E-mutant PLGG constitutes a unique subgroup with respect to natural history and outcome. 9,10 We have previously reported that PLGGs that transform to high-grade gliomas have a high incidence of BRAF V600E mutations in combination with CDKN2A deletion.11 CDKN2A is a tumor suppressor gene and a key regulator of the cell cycle. CDKN2A alterations act as a secondary hit, which allows for escape from cell cycle regulation and malignant behavior in multiple cancer types. 12,13 In PLGGs, CDKN2A loss has been reported to be associated with escape from oncogene-induced senescence, 14 especially when combined with BRAF mutations.To better define the clinical significance of BRAF V600E in these tumors, we performed a combined clinical and genetic analysis in an institutional discovery cohort of patients with PLGG who were diagnosed and treated in southern Ontario. 15 We then asse...

Adolescents and young adults with brain tumors in the context of molecular advances in neuro‐oncology

“…Since then multiple other activating alterations of RAS/MAPK pathway have been described in pediatric LGG, and it has been suggested that LGGs of childhood are a single pathway disease (Fig. ) …”

Histological and genetic analysis of anaplastic pleomorphic xanthoastrocytoma suspected of malignant progression over a 12‐year clinical course

“…Although biopsy of the initial cystic lesion was not performed, if these molecular abnormalities had been detected, the malignant transformation may have been predicted. In addition, our patient may have been able to be treated with BRAF inhibitors, which have a higher response rate for low‐grade gliomas with BRAF V600E mutation …”

Carboplatin and vincristine neurotoxicity in the treatment of pediatric low‐grade gliomas

“…We were not able to find a confounding factor, such as age or NF1 status, which could have accounted for this difference. It is possible that patients with BRAFV600E mutation, known to have a worse prognosis, could have been overrepresented in the dose‐reduced group . We were, however, limited by the retrospective nature of the study and it was not possible to test this hypothesis.…”

“…It is possible that patients with BRAFV600E mutation, known to have a worse prognosis, could have been overrepresented in the dose-reduced group. 24 We were, however, limited by the retrospective nature of the study and it was not possible to test this hypothesis. Since most dose reductions occurred during induction and the first maintenance cycle, it is also possible that vincristine plays a major role in initial tumor control.…”