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Jacob Sands, MD: Hello. I'm Dr Jacob Sands. Welcome to Season 3 of the Medscape InDiscussion: Lung Cancer podcast series. Today we'll discuss NUT carcinoma, but first let me introduce my guest, Dr Jia Luo. Dr Luo is an instructor in medicine at Harvard Medical School. She's a thoracic medical oncologist at Dana-Farber Cancer Institute, and her research focuses on developing better treatments, particularly related to genetic and immune characteristics of lung cancers. She leads and develops clinical trials, testing anticancer medicines that target cancers driven by these changes. As part of that work, she has also developed particular expertise related to NUT carcinoma. Dr Luo, welcome to the Medscape InDiscussion: Lung Cancer podcast.
Jia Luo, MD: Thank you so much for having me on the podcast, Dr Sands.
Sands: I think NUT carcinoma is a generally underappreciated diagnosis. This is something that I see sometimes, where the initial stains didn't really lead to a NUT carcinoma diagnosis, and it has actually taken the medical oncologist recognizing that clinically this could be a NUT carcinoma and then directing pathology to go back and evaluate that. Can you help us tease apart where we should be considering and specifically thinking about NUT carcinoma as a diagnosis?
Luo: Absolutely. We're doing an investigation to really figure out the reason this is being underdiagnosed. It turns out that the pathologists actually do quite a good job picking this up, but you're absolutely right, Dr Sands, that sometimes it does take additional clinical intuition from a medical oncologist or another clinician.
The reason it's hard to diagnose NUT carcinoma is that it is ultimately a molecular diagnosis. That means the cancer itself is driven by a bromodomain and extraterminal (BET) protein family member, such as BRD4, BRD3, and NSD3, among others, fused to a gene known as NUTM1. NUTM1 stands for nuclear protein in testis–1. It's a protein that really should be expressed only in the developing testes and ovaries. It should not be a protein that is expressed in other parts of the body in an adult, such as the lung, as a lung primary or head and neck primary.
We think this is purely bad luck. I always tell my patients, "There's nothing that you did or did not do to have a diagnosis of NUT carcinoma." There is likely a random genetic event that caused a double-strand break to happen, both in the NUTM1 gene as well as the BET family member. These two genes become fused together, and ultimately, DNA becomes RNA becomes protein, so transcription translation, and you end up with this NUTM1::BRD fusion that generates this oncoprotein. This protein binds to acetylated histones. You may recall that DNA is wound into histones and compressed into chromatin; you really need to acetylate and unwind DNA from histones in order to complete a transcription, translation, and gene expression. When this oncoprotein binds acetylated histones, it recruits another protein that's also an epigenetic reader, known as P300, and all three of those proteins come together into a complex that leads to massive histone acetylation and forms these mega-domains, which are large areas of open DNA that's being translated and transcribed. This ultimately leads to upregulation of genes like MYC, SOX2, and other oncogenes and ultimately drives NUT carcinoma. NUT carcinoma is tough because it's a fusion oncogene-oncoprotein, and it's a molecular diagnosis of very specific fusions that drive this. When something is a molecular diagnosis and it's a fusion, it's not generally picked up on your standard next-generation sequencing panels that we like to send.
That's ultimately one of the reasons I would think about this specifically in the context of lung cancer. In anyone who is younger, doesn't have much of a smoking history — 10 pack-year or less — and then has a poorly differentiated or squamous histology, you really should discuss with your pathology colleagues whether someone has thought about NUT carcinoma.
Sands: That's very helpful, to get that outline to the genomics in particular around the diagnosis. Can you also specify what scans would look like in typical NUT carcinoma diagnosis, which we should really consider in those younger patients, as you outline, with less of a smoking history and poorly differentiated squamous pathology? What else would we see on scans or anything else related to the diagnosis?
Luo: Great point, Dr Sands, because you're right that, clinically, we have to think about this. Contrary to popular belief, we're trying to overturn this myth; the term "midline" has actually been removed from the name of this cancer. We now just call it NUT carcinoma. Initially it was thought that this cancer only developed in the midline, but we actually do clinically see NUT carcinoma — at least from a lung cancer perspective — like a squamous cell lung cancer. I would think about getting what you usually get for someone with squamous cell lung cancer: cross-sectional imaging, generally CT, of chest, abdomen, pelvis. I would get a PET scan. If there's back pain, I would consider getting an MRI of the total spine, and then I would get a baseline brain MRI as well. I would approach it quite similarly to someone with a new diagnosis of a garden-variety squamous cell lung cancer. We often do see a lung mass. There could be postobstructive pneumonia. There do tend to be enlarged mediastinal lymph nodes, and the sites of metastasis — because this is such an aggressive cancer — tend to be where you would see squamous lung cancers: bone, liver, lymph nodes, and organs like that.
Sands: You've described NUT carcinoma as generally having a poor prognosis. This has been a challenging diagnosis to treat. Before we dive into some of the initial discussion, I just want to give our listeners a look ahead and say that Dr Luo will be going over some clinical trial options that are currently available. I just want to make sure people are aware; they are particularly important in this disease setting, and so we'll get to that in a moment. Dr Luo, can you describe for us what general first-line treatment looks like, particularly in the metastatic setting?
Luo: When considering first-line treatment, I would think about squamous cell lung cancer–directed regimens. We did a recent large case series of over 100 patients within what's known as the International NUT Carcinoma Registry. Feel free to visit that website, nc-registry.org, where individuals who have NUT carcinoma are contributing their patient data anonymously.
We looked at the primary medical records and looked into what were treatments that they were receiving. It does seem like, in general, it's a squamous cell cancer–derived regimen such as platinum doublet chemotherapy. And I would consider checkpoint inhibitors right now, partly because about a quarter of these individuals are PD-L1, tumor proportion score (TPS) positive. This is quite aggressive. To be honest, a fair number of people don't make it to the second line. I would consider adding the checkpoint blockade and consider treating it like you would treat squamous cell lung cancer.
One question we had in this particular analysis was that some people have ifosfamide-based treatments, and that's because this cancer also resembles Ewing sarcoma in some ways. There's a younger patient population, and there are some sarcoma features to this cancer. What we have learned from this analysis is that potentially there may be a benefit in a very small subset of young, generally pediatric patients in the nonmetastatic setting, to really try to cytoreduce before a multimodal therapy. In general, we didn't see a significant benefit with ifosfamide-based regimens. So I would think about squamous lung cancer–directed treatment for these individuals.
Sands: You've mentioned potentially seeing a benefit with ifosfamide in the younger-patient subset. Are there data for that in early-stage treatment?
Luo: Great question, Dr Sands. As you can imagine, this is a pretty aggressive cancer. The most common presentation is in the metastatic setting, especially with a lung primary, similar to lung squamous cancers, but a select number of individuals present a little bit earlier. We looked at this with our limited dataset and identified only a handful of individuals. This will obviously need further investigation with larger patient populations, but of individuals that we know who lived for 3 years or longer, all of them presented with nonmetastatic disease — disease that hadn't spread beyond the thorax or the head and neck. They all had surgery. They also, for the most part, had radiation therapy around the time of surgery as well. All of them received perioperative systemic therapy. Within this group, there were a few individuals who had ifosfamide-based therapy, but they were all younger than age 15. I think this generally speaks to that there could be a subset of individuals, probably pediatric patients, who would benefit from ifosfamide-based treatment, but as a population overall in NUT carcinoma, especially for us adult medical oncologists, I would actually consider a more traditional squamous-driven regimen. I think the big take-home here, in this nonmetastatic patient setting, is really engaging your colleagues in thoracic surgery and radiation oncology, considering referral to a major academic center that performs a lot of these lung surgeries, and having that multidisciplinary discussion for these patients. I think that's critical, to maximize our ability to eradicate the cancer early on.
Sands: That's interesting. With a pediatric population, I would assume that they are generally going to end up at the larger centers with more specialized surgeons for those kinds of cases, where you mentioned the handful of individuals that had more than 3-year survival. Are there any older patients in that dataset that had more than 3-year survival? When I say "older," I'm talking about patients even in their forties, which I know for this diagnosis is a bit older. What is the age range where you're seeing some of the benefits, those durable, disease-control cases?
Luo: Once again, this is limited by not having a large dataset. We are trying to more consistently have individuals consent to the registry so we can increase our numbers, but in the limited number of individuals, we saw that the age range of the 3-year-or-longer survivors was 13 up to the sixties. The median age of NUT carcinoma, we think, is in the twenties to thirties, based on internal data of all the patients we've ever seen with NUT carcinoma; but they actually range from less than 1 year old to — the oldest patient we have in the registry — 82 years old. Even though we think of it more in the young patient population, I would say that you can be any age. Within that, this report also looked at gender as well as self-reported race and ethnicity. NUT carcinoma affects both genders and across races and ethnicities. So you really have to think about it in all individuals presenting with thoracic primary–looking cancer that's largely poorly differentiated or squamous. I would really think about this cancer diagnosis.
Sands: This really highlights the importance of this registry, in that much of our knowledge about these cases, and what's working and what's not, really comes at this point largely (but not entirely) from this registry. You said that registry was nc-registry.org?
Luo: Exactly. If you google NUT carcinoma registry, it should be the first hit.
Sands: This is great. All of our listeners can hopefully contribute and really make sure that, as we see cases, they end up in this registry so that our discussion can be more plentiful in the years ahead. Part of that is also going to be advancing treatment options. Before we get into some of the clinical trials that I know you're involved with, what about second-line treatment and beyond? Is that also something that we think of more as traditional squamous cell treatments? Or is there anything different as we get into second line and beyond when talking about treating NUT carcinoma?
Luo: I wish I had a good answer for that. I think it just speaks to the aggressiveness of this cancer that we really don't. For instance, one question that we're actively trying to address is, who are the patients who benefit from immunotherapy-based treatments? Not based on a lot of data, I would think that squamous regimens would help these patients. But I would say that in the second line, and even in the first line, really think about considering a clinical trial. I know most listeners here are based in the United States. We have several clinical trials that we'll dive right into. But I'm also aware of clinical trials in Europe. The other thing that I would bring up is to think about not just trials and treatment derived at shrinking the cancer; getting early palliative care involved in these individuals is extremely important. I'm not talking about palliative care from a hospice perspective. Most patients present with metastatic disease. They can have bone metastasis. It's a common site of spread. So really thinking about engaging your palliative care colleagues is quite important, as is thinking about palliative radiation to sites that are painful. Because there is a bias toward young-adult patient populations, if there is social work or other supportive care within your institution, such as a young-adult program, thinking about things like fertility preservation — that's something that we don't traditionally think about in lung cancer, but we actually should think about it in this patient population. The prognosis is not great, and so I do think an early conversation — at least mentioning to the patient, "What do you know about the prognosis of this cancer?" — is important, almost as a routine informed-consent discussion. It is super-important to be upfront about this.
Sands: These are some very important points that you're bringing up in the complexities of caring for particularly younger patients. For our listeners, I'll direct you back to a conversation I had with Dr Rosenstein around interacting with patients. That's more broad in oncology care, but some of the things he brought up in that discussion are really going to be of particular interest when dealing with this population of patients as well. Dr Luo is also mentioning something he had said, starting with patients' understanding of things, and really diving a bit more into how best to interact with these patients, considering that this is going to have some unique challenges in younger patients. This is all in our effort to provide individual care to each patient that we're treating. This is a tough setting, though. We're talking about younger patients and a poor prognosis. We've talked about first-line therapy being a squamous treatment that you highly recommend giving with a checkpoint inhibitor. Recognizing that a decent percentage of patients are not ever going to get to second-line therapy, when talking about second line and beyond, it sounds like the data we have are somewhat limited. We know that prognosis is poor. You mentioned earlier that the majority of patients don't live 3 years from the registry data. Clinical trials now sound overwhelmingly important in this setting. Give us some good news. What are some of the trials you'd like to highlight?
Luo: Absolutely. Early consideration of clinical trials for this cancer is absolutely necessary because there are limited treatments and there's no FDA-approved treatment. What I think is potentially a large vulnerability of this cancer is that, ultimately, it is largely an oncogene-driven form of non–small cell lung cancer. We've seen successes over and over again in oncogene-driven, non–small cell lung cancer. I do think that focusing on that does hold some promise in this cancer. We currently have four clinical trials that are available. The history of this is, there are these medicines called BET bromodomain inhibitors and they are a therapeutic vulnerability in this cancer. These drugs are oral. They're small molecules that ultimately internalize into cancer cells and competitively inhibit and evict these BET proteins, including NUT oncoprotein. The first-generation drugs were rather nonspecific for BET family members and they were limited by toxicity. We had some responses. The monotherapy objective response rate is around a quarter. Most individuals did not have a prolonged duration of response. And so all of the trials that we have available now are really trying to be combination studies that are potentially more tolerable. We actually do have a first-line trial, CTEP ETCTN 10507. It's a combination of chemotherapy — in this case, cisplatin and etoposide with a BET bromodomain inhibitor, ZEN-3694. We have several second-line studies. These can all be found on clinicaltrials.gov as active and enrolling. The three that are in the metastatic setting include CTEP ETCTN 10509, which is BET bromodomain inhibitor ZEN-3694 plus abemaciclib, which is a CDK4/6 inhibitor. This is derived from preclinical data out of our institution in Stephen Elledge's lab, noting that CDK4/6 inhibition is synthetically lethal with that bromodomain inhibition. At our institution, we also have the Kronos Bio CDK9 inhibitor study open. That's also an oral therapy in the second-line or metastatic setting that's inhibiting CDK9, which is not a cell-cycle CDK but one that regulates epigenetic machinery associated with BRD4 NUT, and that is enrolling patients. And then finally, there is a dual BET CBP/p300 inhibitor from Epigenetix that's also enrolling. I should mention that all of these trials are enrolling at multiple sites across the United States, so patients don't have to necessarily relocate to Boston. They're open in Houston, Texas, as well, with Dr Sarina Piha-Paul. The ETCTN trials are open with Dr Robert Hsu at University of Southern California. Industry-sponsored trials are also open at other sites. I would absolutely consider these trials. Within our pediatric patient population, we also have a BET bromodomain inhibitor trial open with Steve DuBois, here with our pediatrics group.
Sands: In many ways it feels like we're just starting the discussion, but that's all the time we have for today. I look forward to advances in the field. Today we talked with Dr Luo about NUT carcinoma, and I'm going to outline some of that discussion. Dr Luo highlighted that this is a molecular diagnosis and it really comes from fusion, which makes it a little tougher to diagnose in next-generation sequencing panels. Those panels are better at picking up mutations. Fusions are a little bit tougher. The population of patients that get NUT carcinoma is generally younger with a lower or no smoking history. At first glance, NUT carcinoma typically looks like a poorly differentiated squamous cell lung cancer. Although this used to be called "midline," Dr Luo highlighted that "midline" is no longer a part of the diagnosis and that NUT carcinoma really is not limited to a central location. Although, if there's a lung mass, then often there are mediastinal lymph nodes, and there can be bulky disease within the mediastinum. Part of the initial workup should be much like that for squamous cell carcinoma, with a brain MRI and CT of chest, abdomen, and pelvis. The treatment in the first-line setting, as far as standard of care, is broadly the squamous cell treatments with chemotherapy plus a checkpoint inhibitor. About 25% of patients do have PD-L1–positive disease, hence the importance of using a checkpoint inhibitor. Dr Luo highlighted that a substantial number of patients don't make it to second-line therapy, and so that first-line treatment is important. Much of this discussion about data comes from nc-registry.org, a collection of cases that have been submitted. To all of our listeners, if you have patients with NUT carcinoma, I really urge you to go to that site and contribute to the patient data. This is how we're able to really talk about the diagnosis and come up with better treatments. Dr Luo highlighted that from that data, we see some ifosfamide use, but usually when there are benefits with that, it's in particularly young patients; broadly across the population, ifosfamide does not show particularly promising results, but there may be a subset of patients where it is promising, particularly the younger subset. There are some cases of early-stage disease and the outcomes reported in there, although, again, it's a limited number of cases. Those that have lived at least 3 years are broadly limited stage and have typically had surgery, radiation, and perioperative systemic therapy as well. In the second-line setting, there's really very limited data. Although Dr Luo highlighted that other squamous regimens are probably the ones to choose outside of clinical trials, there really are some important clinical trials to discuss. She highlighted, with optimism, that this is largely an oncogene-driven non–small cell lung cancer, and we've seen some great success in our treatment in oncogene-driven cancers, particularly over the past decade or so. We've highlighted that in other episodes in our series on lung cancer treatments; there are a lot of oncogene-driven cancers that we've discussed and an array of treatments. Hopefully this is a diagnosis where we'll have some of that success to report out further in future discussions. The BET bromodomain inhibitors are oral regimens and right now are some of the most promising. Dr Luo highlighted a first-line trial of cisplatin and etoposide and the BET bromodomain inhibitor ZEN-3694. There are also second-line (and beyond) trials with abemaciclib and ZEN-3694, a CDK9 inhibitor — that is also an oral drug; and then a combination, a dual BET and CBP/p300 inhibitor.
Although this is a particularly challenging diagnosis with a poor prognosis in what is generally a young population, there are some regimens that are showing some promise, and there are some clinical trial options available. I would just like to underscore a few things from the discussion: nc-registry.org has a site where you can contribute data, but also recognize that there are important clinical trials to consider for each patient being treated for this diagnosis. Please take a moment to download the Medscape app to listen and subscribe to this podcast series on lung cancer. This is Dr Jacob Sands for the Medscape InDiscussion: Lung Cancer podcast.
Listen to additional seasons of this podcast.
Resources
NUT Carcinoma: Clinicopathologic Features, Molecular Genetics and Epigenetics
The MYC Oncogene — The Grand Orchestrator of Cancer Growth and Immune Evasion
Next-Generation Sequencing in Cancer
Initial Chemotherapy for Locally Advanced and Metastatic NUT Carcinoma
International NUT Carcinoma Registry
Improving Lung Cancer Patient Care Through Collaboration, Psychology, and Communication
BET Bromodomain Inhibitors: Novel Design Strategies and Therapeutic Applications
Development of CDK4/6 Inhibitors: A Five Years Update
Dual BET and CBP/p300 Inhibitor in Patients With Targeted Advanced Solid Tumors
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Cite this: NUT Carcinoma: Diagnostic Challenges, Emerging Treatments, and Clinical Trials - Medscape - Jul 09, 2024.
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