Evolution of Neurofibromatosis and Schwannomatosis Care

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepherd, a Medical Oncologist and Co-Director of the Sarcoma Program at Cleveland Clinic. Today, I'm happy to be joined by Dr. Mina Lobbous, a Neuro-Oncologist at the Brain Tumor Center and Medical Director of the Adult Neurofibromatosis and Schwannomatosis Clinic here at Cleveland Clinic. He's here today to talk about the evolution of the management of neurofibromatosis and schwannomatosis. So welcome.

Mina Lobbous, MD, MSPH: Thanks for having me.

Dale Shepard, MD, PhD: Give me a little idea what you do here at the Cleveland Clinic.

Mina Lobbous, MD, MSPH: At Cleveland Clinic, I co-lead the adult neurofibromatosis and schwannomatosis program, which is focused specifically on caring for adult patients with NF1, NF2-related schwannomatosis and other forms of schwannomatosis. And as you know, historically, these conditions have largely been managed in pediatric settings, and what we are increasingly recognizing is that the disease burden in adulthood is different, and in many way, has been under addressed for years. As you know, adult face evolving tumor risks, higher risk of cancer, including malignant peripheral nerve sheath tumors, cumulative neurologic complications, chronic pain, as well as other secondary malignancies.

Our program brings together neuro-oncology, medical oncology, sarcoma specialist, geneticist, neurosurgery, pain management, and a coordinated model. Takes a village to care for those patients. And our care go beyond clinical care, building prospective databases, collaborate on imaging and molecular studies, work to expand the access to novel therapeutics. Our goal is not to simply treat tumors as they arise, but help define adult NF biology, accelerate therapeutic development for a population that has historically had limited systemic options.

Dale Shepard, MD, PhD: So, it sounds fantastic. We'll dive into a few of those points and flesh that out. A lot of different people might be listening in. So let's start really basic. What are these diseases that some people may not even be familiar with?

Mina Lobbous, MD, MSPH: Neurofibromatosis and schwannomatosis are genetic tumor predisposition syndromes that primarily affect the nervous system, central and peripheral, but they are biologically distinct entities. So we'll start with neurofibromatosis type one, or NF1, which is one of the most common tumor suppressor syndromes caused by a mutation in the NF1 gene, which encodes neurofibroma at tumor suppressors that negatively regulate the RAS-MAPK pathway. Loss of neurofibroma results in a hyperactive RAS signaling, which drive tumor formation, particularly neurofibromas, plexiform neurofibromas, glioma in the brain, and importantly, also confers a risk of malignant peripheral nerve sheath tumor, or NPNST, which are aggressive soft tissue sarcomas.

NF2-related schwannomatosis, that's a different disorder and it involved mutation in the NF2 gene, which includes Merlin, a protein involved in contact inhibition and cytoskeletal regulation. These patients often develop bilateral vestibular hearing nerve schwannomas, meningiomas, ependymomas, and other tumors.

The other forms of schwannomatosis, such as SMARCB and LZTR, these are more rare. These patients often have several of those schwannomas. They rarely have the hearing nerve ones and they often have chronic, can be disabling pain.

Dale Shepard, MD, PhD: I guess just relatively speaking, how common are these?

Mina Lobbous, MD, MSPH: NF1 is one in 3,000 live births. NF2 is like one in 30,000, so it's less common. And then the other type of schwannomatosis are more rare.

Dale Shepard, MD, PhD: So, one thing I picked up and this sometimes happens with these genetic conditions, you said that a lot of patients don't necessarily get treated by adult specialists. So, you have an adult clinic. Tell us a little bit about how the management of adults is different than management of children and that transition, which sometimes a little awkward sometimes going from pediatric specialists to adult specialists.

Mina Lobbous, MD, MSPH: That's one of the major challenges, I believe, in the field, is this transitions, a critical period when patients go from the pediatric setting to adult settings, sometimes things kind of fall in cracks. You know, the patients move. They get out of their parents' insurance. They're busy. So they may not seek medical care and years and years can go by and disease working in the background and then the unfortunately may reenter the system after bad complication have happened.

So in adult care, we focus on having this seamless transition from pediatric to adult. We work very closely with our colleagues in the children NF program. We have frequent meetings ensuring, again, a seamless transition. We focus on counseling and how the disease is different than adults. We educate our patients on risk of cancer. You know, we talk about surveillance imaging. We talk about fertility as well, fertility as well with those patients. And we bring on the different specialists who play key role in caring for those patients, as I listed earlier, from medical oncology, geneticists, dermatologists, plastic surgery, all these different experts.

So it is different than pediatric settings, but we're making this process as seamless as it can be.

Dale Shepard, MD, PhD: I guess um as a sarcoma guy, I unfortunately see these malignant peripheral nerve sheet tumors and patients that oftentimes have a lot of neurofibromas from a surveillance standpoint. How do you approach that? I normally see them after they've been diagnosed, but how do you keep an eye on people who already have things like neurofibromas, they get new nodules and things? And ultimately, I see them when they get a sarcoma, but what does surveillance look like in those patients?

Mina Lobbous, MD, MSPH: It's an excellent question. So we know from the natural history studies that plexiform neurofibroma, you know can progress in adults, and the average growth rate is about, or the median is about 16% per year. So we know it can continue to grow. It's a little bit slower in adults than it's in kids, for example. We educate our patients about the alarming symptoms. If there is rapid growth, if the lesion is becoming more hard, more tender, more painful, that's a red flag that need urgent evaluation and advanced imaging.

In term of surveillance, there are guidelines for surveillance. We have protocols working with our radiology colleagues on having total body, whole body MRI imaging, as well as PET imaging. The frequencies, the intervals differ, but we have these protocols and we customize based on the patient, what I would call disease burden. Also, there are a lot of studies that looked at genotype, phenotype correlation. So we know that certain pathogenic variant carry a higher risk of developing these cancers. So those patients require even more close follow-up.

As you know, the risk of cancer in this patient range from 15, 20%. And majority of this is coming from plexiform neurofibroma turning into MPNST, but also breast cancer. So talking about screening and surveillance. So we know that women with NF1, they have a higher risk of breast cancer. So we start with if our women with NF1 or high risk breast cancer clinics, they start mammogram, breast MRI screening at age of 30 instead of the age of 40.

Dale Shepard, MD, PhD: Yeah, makes sense. How has management changed over time? You mentioned before about new targets and things. Historically, there were surgical options. How has the landscape changed?

Mina Lobbous, MD, MSPH: It has been quite transformative in the last decade or so. As you said, historically, it has been surveillance, surgical interventions when it's needed, and the transition from largely surgical supportive care to more molecularly targeted systemic therapy. So now we understand the central rule of the RAS-MPK signaling in NF1, and we have therapies that directly target that pathway. It started with the landmark SPRINT trial in children. With NF1, associated plexiform neurofibromas that led to the FDA approval of the first MEK inhibitor in NF1 selumetinib in 2020. And then subsequently, mirdametinib showed positive outcomes in both pediatric and adult with NF1 plexiform neurofibroma that led to the FDA approval last year in pediatric and adult with inoperable plexiform neurofibroma. And more recently, the FDA approval of selumetinib in adults was NF1 based on the phase three randomized control trial, KOMET, in adult with NF1 and inoperable plexiform neurofibroma.

So in parallel, advanced in molecular characterization have clarified the genetic and epigenetic events, also underlying malignant transformation. Imaging has improved, volumetric assessment have become more refined, and also collaborative trial network have expanded. So the mindset has shifted from reactive management to more biology-driven intervention.

Dale Shepard, MD, PhD: And then with the onset of these systemic therapies, how much of a role is surgery at this point?

Mina Lobbous, MD, MSPH: It continue to play a role in some patients. Talk about plexiform neurofibroma, for example, these are highly vascular. They're wrapped around nerves. They can cross multiple tissue planes. So surgery can be complicated, but still, if the surgeon is able to achieve gross total resection or at least meaningful debulking without causing permanent motor or sensory damage, we still evaluate this in our multidisciplinary clinic working with soft tissue, plastic surgeon, neurosurgeon. So it still does have a role, but now with the MEK inhibitor, we have other treatment to offer to our patients.

Dale Shepard, MD, PhD: Anytime there's systemic therapy, everyone wants to go toward immunotherapy. So has there been a role of immunotherapy at this point?

Mina Lobbous, MD, MSPH: Immunotherapy has been explored, but responses to checkpoint inhibitors have generally been modest, likely reflecting the immunologically cold tumor microenvironment. Ongoing trials are examining combinatorial immunotherapy approaches, including strategies to modulate the myeloid microenvironment. So the future likely lies in rational combination therapies rather than just single agents, informed by deeper molecular profiling and biomarker development. For example, a trial through the NF clinical trial consortium that will open soon study MEK inhibitor plus immunotherapy and a promo domain inhibitor in NF1 in PNSD.

Dale Shepard, MD, PhD: And so certainly the biomarkers might help define which treatments people might respond better to. You also mentioned genomics could play into risk stratification. Is that correct? In terms of people being more likely to develop cancers and things like that?

Mina Lobbous, MD, MSPH: There are wealth of data on the genotype, phenotype correlations. And also, we know from the MPNST data in NF1, usually when this malignant transformation happen, tumors pick up more mutation outside the RAS pathway, like the CDKN2A loss. PRC2 complex inactivation, leading to epigenetic dysregulation, which again has opened new avenues for therapeutic exploration through combining MEK inhibitor with other targeted therapy and immunotherapy as well.

Dale Shepard, MD, PhD: As we've started using systemic therapies, is the quest to get better therapies, is it mostly because of poor response rates or not having a durable response, little bit of both?

Mina Lobbous, MD, MSPH: It's a little bit of both. And talking about the plexiform neurofibroma, we have seen durable responses from MEK inhibitor. The question, does it change the disease natural history? Does it decrease the risk of transformation to MPNST or other atypical lesions? That's yet to be known. Do MEK inhibitors work for other tumors driven from the same mutation, like NF1 associated glioma? There is a phase three clinical trial for that. Does it work for cutaneous neurofibroma? There are other clinical trial also looking at that. So I do believe it's more complex than just a single agent cover all tumors that come with this disorder.

Dale Shepard, MD, PhD: If you think about where we've been, where we are now, what are the greatest needs? What do we still need to make the most progress with?

Mina Lobbous, MD, MSPH: Great question. So I do believe it's the combinatorial therapy approaches for this higher grade tumor, MPNST, higher grade glioma in neurofibromatosis type one, and having prognostic markers, imaging markers, tumor biomarker that can predict which tumors have even higher chance of malignant transformation. So we can customize the monitoring. And perhaps if research show that MEK inhibitor does change tumor natural history, we may even initiate these treatment sooner than later in what we call higher risk groups.

Dale Shepard, MD, PhD: We talked at the beginning about people being seen by pediatric specialists in your adult clinic. Just in general, people might be listening in, who should get referred to a specialty center? Everyone with this disease? With a rare disease, you have to be faced with people who don't live next to a center like ours. How do you sort of co-manage? Who should be seen here? How do you co-manage?

Mina Lobbous, MD, MSPH: I think any patients with these disorder should be referred, if possible, to a comprehensive neurofibromatosis and schwannomatosis centers, surveillance, patient education, access to treatment. And we work very closely with our community oncology colleagues, for example, on co-managing those patients, so to decrease the burden of traveling and all these logistics on our patients. But I do believe that having this multidisciplinary evaluation for this patient is quite important.

Dale Shepard, MD, PhD: It's exciting to see how much has happened in the field over a short period of time. Well done having an adult clinic that can address this in a multidisciplinary way. Appreciate your insights.

Mina Lobbous, MD, MSPH: Thank you so much for having me today. Neurofibromatosis and schwannomatosis are no longer conditions defined solely by surveillance and surgery. Now molecular understanding is shaping targeted therapy, combination of strategy and risk stratification. So while MEK inhibition was a critical breakthrough, a significant unmet needs remain, particularly in adult patients in the management of malignant peripheral nerve shift tumor and other high-grade neoplasms. So the future of this field is in the biomarker-driven care, rational therapeutic combination and strong multidisciplinary centers that can integrate research directly into clinical practice. And if we continue to collaborate across institutions and different specialties, these rare tumor syndromes have the potential to become models for precision oncology and complex genetic disease.

Dale Shepard, MD, PhD: Fantastic. Thank you for what you do.

Mina Lobbous, MD, MSPH: Thank you.

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