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.