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BRAF V600E worsens outcomes in pediatric low-grade gliomas
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BRAF V600E mutations defined a distinct subset of pediatric low-grade gliomas that had poor outcomes after conventional therapy, according to a combined clinical and genetic analysis.
“In recent years, the genetic background of pediatric low-grade gliomas has begun to be unraveled,” Uri Tabori, MD, principal investigator at The Arthur and Sonia Labatt Brain Tumor Research Center and physician at The Hospital for Sick Children at University of Toronto, and colleagues wrote.
Although pediatric low-grade gliomas are “genetically quiet,” they harbor a few alterations in the RAS/MAPK pathway, researchers wrote.
“The scarcity of other genetic alterations in pediatric low-grade gliomas is in keeping with the generally benign behavior; however, the role, if any, that these alterations play in predicting response to therapy and clinical outcome is still not known,” the researchers added. “As a result, as far as nonsurgical treatment is concerned, all patients with pediatric low-grade gliomas receive similar treatment independent of their tumor’s molecular alterations.”
BRAF V600E mutations — observed in a variety of neoplasms, but which may be present in only a small percentage of pediatric low-grade gliomas — could be highly targetable in this setting.
To better define the clinical significance of BRAF V600E in these tumors, Tabori and colleagues conducted a combined clinical and genetic analysis of 510 children with low-grade gliomas diagnosed and treated at The Hospital for Sick Children between January 1985 to December 2015.
Of 405 children (50.6% male, median age, 8.52 years) treated between 2000 and 2015, 69 (17%) harbored the BRAF V600E mutation.
The BRAF V600E mutation appeared most common in midline tumors (33%) — including optic pathway, brainstem and spinal cord tumors — which are not often routinely biopsied in clinical practice.
The researchers analyzed long-term survival data from the full cohort of 510 patients (median follow-up, 7 years), 99 of whom harbored BRAF V600E mutations.
Unlike other tumors in the cohort, BRAF V600E-mutated tumors continued to progress without reaching a plateau.
After conventional therapies, a smaller proportion of patients with BRAF V600E-mutated low-grade gliomas achieved 5-year PFS than patients with BRAF wild-type low-grade gliomas (50.1% vs. 72.8%). This difference reached statistical significance at 10 years (27% vs. 60.2%; HR = 2.04; 95% CI, 1.45-2.88).
Rates of 10-year OS were 83.9% in patients with BRAF V600E mutations and 92.1% in patients with wild-type tumors (HR = 1.57; 95% CI, 0.8-3.14).
“Continuous late progression was associated with late deaths in patients with the BRAF V600E pediatric low-grade gliomas,” Tabori and colleagues wrote. “Of importance, late deaths related to tumor progression were observed in BRAF V600E pediatric low-grade gliomas even at 25 years of follow-up.”
A multivariable Cox proportional hazards regression model revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E-mutated patients. Further, interaction between BRAF V600E and CDKN2A deletion predicted recurrence (HR = 3.2; 95% CI, 1.12-9.35).
To further examine the poor outcomes in this setting, the researchers assembled an independent cohort of 180 children with BRAF V600E-mutated low-grade gliomas from 18 collaborating institutions.
Results showed similarly poor PFS and OS. In addition, researchers again linked poor outcomes with a lack of complete resection (P = .001) and CDKN2A deletion (P = 0.02).
Six patients who experienced progression after conventional treatment received BRAF inhibitors.
At 6 months, only 23% of tumors had shown an objective response to chemotherapy and up to 24% of tumors progressed while on therapy. However, all six tumors demonstrated a significant response to V600E-targeted therapy, with 49% to 80% cytoreduction. All six patients remained on V600E inhibitors at the time of the analysis (median follow-up, 18.5 months).
“Although longer follow-up is required to determine emerging resistance and long-term adverse effects of these drugs, the rapid responses observed with these therapies in patients with BRAF V600E pediatric low-grade gliomas are encouraging and can potentially prevent ongoing sequelae, such as visual loss and neurologic deterioration, which are commonly observed with current therapies,” Tabori and colleagues wrote.
The researchers noted these data show BRAF V600E-mutated pediatric low-grade gliomas are a distinct disease subtype that require different short- and long-term therapeutic approaches.
“Upfront diagnosis of these tumors is needed to define prognosis and a decision whether to include aggressive surgery and early targeted therapies for these patients,” they added.
“Finally, this study highlights the need for a change in our overall approach to pediatric low-grade gliomas. Consideration for upfront biopsy and molecular diagnosis of deeply located midline tumors that are commonly treated without histologic confirmation will allow for better tailoring of therapeutic interventions and better outcome for these children in the era of precision medicine. – by Kristie L. Kahl
Disclosures: Tabori reports he has no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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