Targeting BRAF V600E in Pediatric Cervicomedullary Ganglioglioma

Diana Osorio, MD, MPH, reviews the management of pediatric cervicomedullary ganglioglioma, emphasizing the challenges of treating tumors in a surgically inaccessible location and the importance of early biopsy and molecular profiling.

She discusses the clinical and prognostic significance of BRAF V600E and the rationale for BRAF/MEK inhibition with dabrafenib and trametinib. Dr Osorio also highlights practical considerations for managing treatment-related toxicities, adherence, and imaging findings during targeted therapy.

Review the case.

Transcript:

This was our case of a young girl, 12-year-old female, with a cervicomedullary tumor. And I found it interesting to present it here today because there are many challenges of a cervicomedullary location that are not always so intuitive for our practitioners.

Cervicomedullary tumors sit at the junction of the medulla and upper cervical cord, which is an eloquent and surgically inaccessible region. And gross total resection is generally not possible without unacceptable neurologic morbidity. So typically in these cases, you aim for a biopsy plus if there's symptoms that can be relieved by a slightly more partial resection, that is the maximum that a surgeon would probably do. And the point for the biopsy is to really get molecular characterization in our era of targeted therapy. And that's really the most important step and the reason to do the biopsy.

That said, tumors in this location are often gangliogliomas and historically are not very responsive to chemotherapy. So oftentimes these patients would require radiation therapy in the past. The presentation of this patient with progressive respiratory compromise is also classic and underappreciated manifestation. These tumors characteristically caused brainstem dysfunction, sleep disordered breathing, aspirations, cranial neuropathies, and failure to thrive, and respiratory symptoms that can be misattributed to a pneumonia. And that was how this patient, our patient presented initially being treated for a presumed pneumonia.

One suggestion from a recently published surgical series that only 45% underwent a subtotal resection and 39% biopsy alone and with most still requiring chemotherapy or radiotherapy and 45% recurrence. This quantifies why conventional local therapy is limited here and motivates the shift to targeted therapy, and that was published recently.

So the clinical significance of the BRAF V600E mutation, the frequency and the histology of this mutation is present in about 20% of pediatric low-grade gliomas overall, but is more frequently found in gangliogliomas, about 45% of patients. And this is consistent with this case, and it is best confirmed by sequencing as it was also done with our patient. Some centers can do it through immunohistochemistry, but again, sequencing is typically more robust. And the prognostic implications in pediatric low-grade gliomas with a V600E mutation has historically been associated with worse outcomes compared to those that are BRAF fused.

The SickKids cohort reported about 10-year progression-free survival of 27% for those pediatric low-grade gliomas that had the V600E mutation versus 60% for the wild type. And the lower overall survival was also noted. This is worth noting, because counterintuitively you think it's a grade 1 tumor, so they are likely going to have a good progression-free survival or overall survival. However, those V600E mutated tumors really is prognostic and also predictive of poor response to chemotherapy. And that is the rationale why we had to switch gears with our patient once we figured out that she did have the V600E mutation.

And so one other piece, the V600E is not the only molecular feature that we need to pay attention to. There's also prognostic significance with other alterations like CDKN2A/B deletions. So that is another important marker to look for in these patients, which it can also occur.

And so the rationale for the BRAF and the MEK inhibition in this case, so the V600E constitutively activates that MAPK pathway. Dabrafenib is one of the BRAF inhibitors on the market plus trametinib, which is the MEK inhibitor, provides that dual pathway blockade and improves the efficacy and mitigates the acquired resistance and the paradoxical MAPK reactivation that we see with single agent BRAF inhibition. In the randomized phase 2 first-line trial, and it was published in The New England Journal of Medicine by Dr Bouffet and team, dabrafenib and trametinib together was superior to carboplatin and vincristine on every axis. And so the median progression-free survival was much better, and that's the marker that we really use to determine that a treatment is more successful, is the progression-free survival. This led to the March 2023 FDA approval of this combination as first-line therapy for pediatric low-grade gliomas with the BRAF V600E mutation.

Now onto the management of treatment-related toxicity and those interruptions that our patient experienced. Interestingly, what we see with the double inhibitor therapy is that the skin side effects, those manifestations typically can be better tolerated than when you do monotherapy. Nonetheless, in our patient, she did have some significant skin manifestations, erythema nodosum and paniculitis is what she's been experiencing. And dermatology has been monitoring very, very closely and recently has made the conclusion that for her, she will need to be on chronic dapsone maintenance therapy throughout her treatment on the double inhibitor. And that's not the typical course that we have seen on patients with double inhibitor therapy. In fact, they tend to have less acne, less skin eruptions. But in our patient's case, it has been unique in the sense that she's had intermittent and recurring paniculitis. And finally, it's still present, but it is much better tolerated on the chronic dapsone therapy. And so this is an important strategy to keep in mind if you have a similar situation with a patient of yours in the future.

And with our patient, she did have a progression on her imaging even while she was on the inhibitor therapy, but through more clinical history taking, we realized that compliance was becoming an issue. And when we really figured out what were the barriers to compliance, and she was then eventually more on the right track. More recently, all her imaging has been very consistent with response and continued on the right dosing and compliant on her medication and symptomatically has improved as well.

Of note also, there is a different monitoring that has to occur on the double inhibitor therapy. Similar to when you're on monotherapy, you have to monitor the cardiotoxicities that can occur, LFTs, electrolyte imbalances, and renal monitoring for these patients. Our case nicely raises the interpretation difficulty of imaging when imaging worsens mid-therapy and really investigate why is the imaging getting worse. And in our case, we were able to hone in and figure out that it truly was a compliance issue and we held steady and she is now benefiting from the double inhibitor therapy in a very significant way.

The key takeaway is well aligned with the evidence. This early biopsy and molecular profiling of our patient in this eloquent location has enabled a targeted and lower morbidity therapy, avoiding those limitations that surgery and chemotherapy cannot offer in this location.

So back to the quiz, why was C correct? As we just went through, the BRAF V600E in this tumor is the targetable driver that qualifies this patient for the FDA approved targeted combination therapy strategy with dabrafenib trametinib and is a therapy that is markedly superior with regards to response and progression-free survival versus chemotherapy alone in this molecular subgroup. And additionally, I think in this case we can say versus radiation therapy. I think that the focal radiation therapy was not sufficient, and now over the course of the year and a half, we can see the difference between doing the double inhibitor therapy versus radiation therapy alone for her.

And why was answer A incorrect? BRAF V600E, although it can denote a more aggressive course for low-grade gliomas, it does not confirm high-grade glioma, and B does not predict radiation resistance because V600E has not been established as a predictor of radiation resistance. And also D is incorrect because unresectability here is driven by the cervicomedullary anatomy and not the BRAF V600E mutation.