Therapeutic Strategies and Molecular Insights in Pediatric Low-Grade Gliomas
Mohamed Shebl Abdelbaki, MD, St. Louis Children’s Hospital, Washington University of Medicine in St Louis, Missouri, explores current therapeutic strategies and molecular drivers of pediatric low-grade gliomas (pLGGs).
In this video, Dr Abdelbaki emphasizes the importance of maximal safe surgical resection for pLGGs and discusses the role of chemotherapy when surgery is not complete or feasible. Lastly, he reviews key molecular drivers of pLGGs and underscores the importance of integrating molecular data into treatment plans.
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Transcript:
If we start discussing an important topic, which is how should we treat our patients? We talked about surgery being the mainstay of therapy, making sure that this is a maximal safe resection. I lead an international tumor board and we have cases from different parts of the world, and unfortunately for a case from a high-income country, the child walked in to the OR and came out with significant weakness, quadriparesis, because of the surgeon trying to achieve a maximum resection for a tumor that's supposed to be a low-grade glioma, turned out to be a paralytic astrocytoma. Which left the child with permanent weakness, for a tumor that could have been only biopsied and we could have treated with other modalities.
Chemotherapy, target therapy, we'll discuss. Radiation therapy is we typically leave as a last resort, but we have to still keep in mind for some of our patients who may be older and having progressive, rapid progressive visual decline or rapid progressive weakness, we have to keep that in mind for those patients and not exclude that possibility in our mind or our discussions.
Chemotherapy options, I think all of us are aware of what's out there. There are many chemotherapy options. I will discuss only the most common. Carboplatin-vincristine, as we see on the left, Joann Ater published this, the A9952 Children’s Oncology Group study that has shown that it has shown similar effects to TPCV, but the side effect profile is better with carboplatin-vincristine and that's why so many of our institutions consider this as the standard of care for patients with pLGGs, specifically for newly diagnosed BRAF fusion, as we are going to talk about. Vinblastine is another viable option. Eric Bouffet has spearheaded these efforts and the top graph is NF1, which will not be the focus of our conversations today. NF1 patients typically have better outcomes in terms of if they have pLGGs, but as we can see the progression-free survival for vinblastine is pretty similar to what we see with TPCV or carboplatin-vincristine, so definitely another excellent option to consider as first-line in the recurrent setting of course.
There are many benefits to the chemotherapy options. We know that there are no resistant mechanisms for them and if you use chemotherapy, you can use it across different histologies and molecular subgroups. We are very much aware of their side effect profiles, so very rarely there will be surprises regarding a new side effect that we're not aware of. All of our institutions have supportive care protocols for chemotherapy. But nothing's perfect in life, and with chemotherapy you have bone marrow suppression, the need for central line, you have to visit the emergency room at midnight if your child has a fever. Then there are hypersensitivity reactions, like up to 40% with carboplatin. Vincristine can cause neurological toxicities. Side effects to chemotherapy exists.
We are very fortunate that we've been treating patients with pediatric low-grade gliomas for a long period of time and they are commonly in locations that we’re able to resect and to gain tissue, and therefore many researchers around the world were able to identify how these tumors grow, It typically happens through a single driver alteration within the MAP kinase pathway, most commonly, and less commonly in the PI3 kinase pathway. And this is the RAS/RAF/MEK/ERK pathway, we're going to talk about this more. In rare cases, especially young adults where you may have more drivers, FGFR alterations may be associated with other drivers, but in general and most commonly, we're going to see 1 alteration that's driving the growth of these tumors.
We all hear about the KIAA1549-BRAF, in other terms and that's how we're going to refer to it afterwards, which is a BRAF fusion. So that's the most common alteration in patients with pLGG followed by BRAF V600E mutation in 15% to 20%, I would say. NF alterations, as well as other alterations along the MAP kinase pathway or the transmembrane receptors that we're going to refer to during this presentation. And as you can see, less commonly the PI3 kinase pathway.
The histologies, for someone who has not done or has not seen pediatric brain tumor patients before, the histologies may be a bit intimidating, but what I would urge you to do is look up the names because the names may be complicated, but what you have to think about is this a grade 1, is this a grade 2. Grade 1 and 2 are pLGGs as we discussed. If you look up something, and this is an anaplastic astrocytoma at grade 3, no, that's not pediatric low glioma. This would not apply to what we're discussing. And the BRAF fusions and mutations differ according to the type of histology. So that it would not be confusing: BRAF mutations can happen in high-grade gliomas as well. It’s not necessarily that you see a BRAF mutation, that means that this is definitely pediatric low-grade glioma. No, you may have this happen in higher-grade tumors, so if you do not know the nomenclature, please look it up. If it's a grade 1 or 2, that means it's a low-grade glioma.
How does it work? In general, and our focus will be the BRAF fusions and the BRAF V600E mutations, because these are the most common. When you have a BRAF V600E mutation, you're going to have an alteration that leads to the downstream phosphorylation and then the cell proliferation and survival.
If you have a BRAF fusion, it will be the dimerization of these 2 molecules that would lead to the downstream phosphorylation. This is very important that we're going to show this slide again, including the names of the drugs so that it would be very clear.
Identifying these BRAF alterations was very important in our ability to understand what are the drivers for pLGGs, how we're going to be treating them as you're going to see, but also allowed us to be able to identify which ones may be associated with poorer prognosis in terms of the progression-free survival. Which may be the case for patients with BRA V600E mutation, where they are more prone to have progression compared to those who have BRAF fusions. In addition to if you have less than a complete resection and BRAF V600E mutation, you may have lesser progression-free survival and if you have BRAF V600E mutation and CDKN2A deletions, this means that there is a higher chance that the tumor will come back or progress.
How would that be important? I think, it's informing the families making. We're not identifying the therapies for those patients yet, but making sure that we are following these patients closely if they have BRAF V600E mutation and CDKN2A deletions so that we would keep a close eye on these tumors. If you're going to space out the imaging for a patient with a completely resected BRAF fusion, I may think differently, if you're treating a patient with less than a complete resection, BRAF V600E mutation, and CDKN2A deletions. In addition to those with a V600E mutation and CDKN2A deletions, may be at risk for malignant transformation later on. It’s very important to inform the families and keep that in mind so that we would follow these patients closely.
