Podcast: Oncogenic Drivers of Pediatric Low-Grade Glioma (pLGG)

Eugene Hwang, MD: Hi, my name is Eugene Hwang. I'm a pediatric neuro-oncologist at Children's National Hospital in Washington, DC. Today, I am honored to talk a little bit about pediatric low-grade gliomas, and first we'll start about some of the epidemiology and the drivers that we've come to understand about pLGGs. So, as you most likely know, pLGGs are the most common type of childhood brain tumor, occurring in roughly 30 to 40% of all CNS tumors.

Moderator: What is the general prognosis for patients with pediatric low-grade gliomas?

Eugene Hwang, MD: Unlike many of our pediatric brain cancers and brain tumors, pLGGs tend to have a pretty good prognosis, with a 10-year overall survival of over 95% for pilocytic astrocytomas, and 80 to 90% for other low-grade gliomas under that bucket. And we think that that actually is true passed into adulthood as well as 30- and 40-year survival studies still demonstrate an above 90% overall survival for these patients. So, they don't tend to upgrade to malignant cancers—also, that can happen—and otherwise we have many nice treatments that we've developed today.

Moderator: How would you describe the common trajectory of disease?

Eugene Hwang, MD: So, when there is a child with a pediatric low-grade glioma, we have an understanding about what that trajectory of disease progression is going to be. Most children will, as we just said, survive this tumor, but also most children will likely need a lot of treatment to do so. Now, if you can gross-totally-resect a low-grade glioma, then you have a really excellent chance of not having to need any other treatment during that patient's lifetime. Although some of those patients will recur—and those patients who cannot attain GTRs, which are the majority of patients, will likely need not just one, but more treatments.

Moderator: Can you describe the treatment process for pediatric low-grade gliomas?

Eugene Hwang, MD: When we think about what treatments those patients get, historically that's really been chemotherapy-related, and so we have a really great understanding that about a third of the kids who require medical management will survive that tumor and not have a recurrence. That does mean, of course, that the majority of patients—two-thirds—will recur, and when you have a situation that post chemotherapy or tumor has come back, then in large part we really view those children as having more of a chronic disease. What that means is that that tumor is likely going to re-respond to additional therapy that you provide, but when that therapy stops, or even during it sometimes, that that tumor will likely regrow and it's kind of a waxing and waning or relapsing or remitting disease course until that child hits an area that we think of occurring roughly in the post-adolescent phase, this timeframe that we think that these tumor just turn off, they senesce and they don't grow again. So, in large part for those patients, which do make up the bulk of the practice of a pediatric neuro-oncology practice, will have a series of treatments that they'll undergo until their tumor senesces.

Moderator: What about surgery?

Eugene Hwang, MD: Well, we think about gross total resection, as you know, that that can actually achieve cure by itself. I think that one of the challenges, though, is many of the tumors that occur in childhood that are low-grade gliomas occur in places where gross total resection is very difficult to attain, and if you do attain, it can lead to actually long-term or permanent morbidity that will affect that child for the rest of their lives. Now, the most common places for sporadic tumors to occur that are low-grade gliomas are in the posterior fossa where, one could argue, you have a larger arena that one could attain gross total resection. But also of course, in that posterior fossa is the brainstem, which often is involved with some of these pLGGs. And of course doing aggressive surgery in that area can be pretty devastating to that patient. And then the other places in the optic pathway tract, and as we know, an aggressive resection in those areas can lead to permanent visual impairment, which we really try to avoid because we expect these kids to survive and live long and fruitful lives.

Moderator: So, what is the first step for nonresectable tumors?

Eugene Hwang, MD: So chemotherapy, as I said, was really the previous mainstay of treatment and remains the sort of accepted standard of care today. And the upfront context, that chemotherapy, there's probably like three or four different kinds that are widely accepted, although really they come down to either vinblastine-based backbone or a carbo-vincristine-based backbone and each of those requires IV infusions on a weekly basis, which is pretty impactful to that patient's and that family's fiscal health and their ability to engage in all their childhood.

Moderator: What have we learned from the latest research on pediatric low-grade gliomas?

Eugene Hwang, MD: In the last 10 years, we've really learned a ton about pLGGs and, perhaps the biggest breakthrough is the idea about the oncogenic drivers, which characterize pLGGs in general. So, unlike many of the other pediatric brain cancers where we don't have a lot of new interventions that are effective and pLGGs, we've really come to understand that they tend to be single-driver tumors, which of course opens an immense opportunity for targeted therapy. When I talk about single drivers, we are really talking about genetic alterations, such as a mutation or fusion that really directly contribute to the development and progression of that cancer. And in fact, that has actually made its way into the most recent WHO criteria with the updated 2021 classification dividing low-grade gliomas into a circumscribed and a diffuse cohort. But each of them really characterized by different kinds of molecular alterations, including the BRAF fusion, the ^V600E point mutation, and then some slightly less common alterations, like FR mutations, or the MYBL1, or other MAP kinase alterations. Now, still taken together, almost all of these drive through the MAP kinase pathway. So, these still remain, although a little bit heterogeneous, single-driver tumors, which again, allows us to potentially target those tumors quite well.

Moderator: Does the specific mutation seem to impact a tumor's treatment response?

Eugene Hwang, MD: When we talk about the most common two, we're really talking about the BRAF proto-oncogene, the KIAA1549 fusion, or the ^V600E mutation. And it's also true that fusions tend to be characterized in pilocytic astrocytomas, whereas ^V600E alterations are seen, unfortunately, in both low- and high-grade tumors. But when they're in the low-grade context, they're gangliogliomas, pleomorphic xanthoastrocytomas, and a couple of other types. So again, nearly three quarters of these low-grade gliomas are driven by these MAP kinase pathway oncogenic drivers, which again provides a great susceptibility for us. So let's cone in on BRAF for a second. So, we already mentioned that the first, the two most common BRAF alterations are that KIAA1549 fusion and the ^V600 point mutation. I should take a moment to mention that without knowing that these exist in the tumor—meaning if you have a low-grade glioma that isn't driven by something that we already know, like an NF1 predisposition or one of these alterations or something else—then it becomes much more challenging to use targeted therapy at all.

In general, I just want to think about the fusions, which again occur mostly in the pilocytic astrocytomas. They've really, I think, been incredibly responsive to targeted therapy, which we'll talk about a little bit later, as have the ^V600E mutations, which as I said, are enriched in certain kinds of tumors. But in large part because of the prevalence of the ^V600E alteration and a wider range of grades for low- and high-grade gliomas, and also the possibility of acquiring secondary mutations like the CDKN2A/B deletions. These tend to have slightly worse prognoses, although still fall nicely within the bucket of pLGGs. And so overall we hope we'll have good long-term overall survival.

Moderator: Are there any other common mutations?

Eugene Hwang, MD: FGFR mutations—that's probably the third most common alteration in pLGGs, primarily the FGFR1:TACC fusion. That's something that I think is really begging to be targeted with targeted therapy as well. Although FGFR inhibitors, as we'll talk about in another video, also have been a more challenging for us to directly target when thinking about the see-saw of toxicity and efficacy. In conclusion, what we have learned in the last decade is that this big group, the largest group of pediatric CNS tumors, which again have typically had a relatively good outcome, are in fact driven by, in general, single-driver MAP kinase alterations. And that's really opened the door for us to think outside the box of our standard or typical radiation, surgery, and chemotherapy alterations.