Discussion
PLGG encompass several entities characterized by different histopahtological features. During the last decade, molecular characterization of PLGG has identified a number of recurrent alterations, with the majority involving the MAPK pathway6. In children without NF1, the most common alterations in this pathway include theKIAA1549-BRAF fusion and the BRAFV600E mutation7. Both alterations can be targeted, and the use of MEK inhibitors in patients with PLGG harboring BRAF fusion or BRAF inhibitors in patients with PLGG harboring BRAFV600E mutation have shown promising response rate43.
Although PLGGs associated with BRAF mutation appear to have a more aggressive behavior 8, they show an excellent response to BRAF inhibitors. Hargrave et al conducted a trial of dabrafenib in children with BRAF mutated PLGG and reported a partial response in 19 of 27 evaluable patients, and a 1-year event free survival of 85%3. More recently, Nobre et al compared 2 cohorts of patients with BRAF mutated PLGG treated with chemotherapy or BRAF inhibitors (vemurafenib or dabrafenib) and demonstrated a clear advantage for targeted treatments, with an overall objective response rate of 28% and 71%, respectively5. Report on the combination of BRAF and MEK inhibitors in BRAF mutated LGG are pending. The rationale for this combination is based on superior outcome observed in patients with BRAF mutated melanomas randomized to either dabrafenib or dabrafenib and trametinib9.
However, the risk of developing resistance to BRAF inhibition exists and has been well documented in melanoma. In PLGG, there has been limited focus on this issue and the management of patients who show progression during treatment with BRAF inhibitors remains challenging. Mulcahy Levy et al recently described a patient with BRAFV600E mutated ganglioglioma who developed resistance to vemurafenib. The addition of chloroquine to vemurafenib was associated with durable clinical improvement as well radiographic response10. A clinical trial is ongoing to confirm these early data.
As the response rate of BRAFV600E PLGG is extremely high for BRAF inhibition, the fact that our patient had limited benefit of BRAF inhibition is intriguing. A plausible mechanism can be the additional FGFR1 N546K mutation. In contrast to FGFR gene fusions, point mutations in FGFR1 tend to be associated with other RAS/MAPK mutations and are showing less favorable outcome7.
Interestingly, the acute clinical deterioration of our patient within a week of discontinuation of the BRAF/MEK inhibition is not uncommon in BRAFV600E tumors. This precluded his inclusion in any clinical trial. Re-challenging with dabrafenib did not show any evidence of efficacy and the decision was made to proceed with chemotherapy, using the TPCV regimen. This regimen has been compared to the combination of vincristine and carboplatin in a randomized trial and has shown better event free survival at 5 years11. However, this trial did not include any molecular study and whether chemotherapy regimens have a better activity in specific molecular subgroups is unknown.
Our experience is intriguing and provides some evidence that salvage chemotherapy is still an option when targeted therapy fail. As most BRAFV600E PLGG recur rapidly after cessation of targeted therapies, the sustained tumor control, 2 years after completion of chemotherapy is encouraging, suggesting a different and potentially synergistic role for chemotherapy is such situations. Further studies will determine whether a combination of targeted and chemotherapy regimens are superior to each of these as a single modality.