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Ursula A. Matulonis, MD: Hello. I'm Dr Ursula Matulonis. Welcome to season two of the Medscape InDiscussion: Endometrial Cancer podcast series. Today, we'll discuss molecular classification and the genetics of endometrial cancer. First, I want to introduce my guest, Dr Katherine Fuh.
Dr Fuh is an associate professor of obstetrics and gynecology at the University of California, San Francisco (UCSF). She serves as the director of basic and translational research. She also serves as the John A. Kerner Chair in the Division of Gynecologic Oncology. Dr Fuh was also recently appointed as the community engagement liaison to the Molecular Oncology Program in the Office of Community Engagement at the Helen Diller Family Comprehensive Cancer Center.
Dr Fuh is a board-certified gynecologic oncologist and is a leading expert in the management and treatment of gynecologic cancers. She also serves on national committees for clinical trials and translational research, including serving as the translational co-chair for the Uterine Corpus Subcommittee for the NRG Clinical Trials Group. Dr Fuh is the principal investigator on multiple grants from various federal and foundation sources, and she also runs her own lab.
It's really an honor and a privilege to have Dr Fuh here today, as she is a leading expert in so many aspects of gynecologic oncology. Dr Fuh, welcome to the Medscape InDiscussion: Endometrial Cancer podcast.
Katherine Fuh, MD, PhD: Thank you, Dr Matulonis. That is very kind of you.
Matulonis: Well, you're fabulous, and it's great to have you here. We are going to talk about a lot of different topics today, including you and your incredible career so far and where you see your career going. Can you start off by telling us what you think about the molecular classification of endometrial cancer and how it informs treatment decisions for your patients?
Fuh: This is definitely a topic that we're all thinking about and talking about right now. Molecular classification is actually defined by The Cancer Genome Atlas (TCGA) and Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) molecular classifiers and also by immunohistochemical staining such as human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), and progesterone receptor (PR). The way TCGA was initially published in 2013 was really important. It laid the foundation for thinking about endometrial cancers more as molecular subtypes rather than histologic subtypes.
In this category, we really thought about DNA polymerase epsilon (POLE), which are these ultra-mutated mutations in the exonuclease domain of the POLE gene. The TCGA found that patients with tumors with POLE mutations had the highest survival. This really changed the way we approached and thought about this. There are clinical trials that I'm sure we'll talk about later that are really trying to understand how to use this information to become more clinically relevant. The second subtype is microsatellite instability-high (MSI-H), which is also hypermutated. The two remaining subtypes are copy number low, which actually correlated more with endometrioid histology, and copy number high, which is more serous-like.
The copy number low subtype was actually found to have increased PR expression, suggesting responsiveness to hormonal therapy. This is something that we're really looking at in clinical trials as well. The copy number high cluster was found to be a more serous subtype and actually might have more transcriptional activity of cell cycle deregulated genes like CCNE1 and PIK3CA MIC, as well as TP53. So, it really helps us to inform clinical care and clinical trial development, which we're really trying to move into the standard of care.
The ProMisE molecular classifier, as we think about it in terms of POLE, mismatch repair deficiency, and other subtypes, we think about it based on p53 immunohistochemistry (IHC) and separate that into the no specific molecular profile (NSMP) as well as p53 aberrant or mutant. This is the way that we can think about how we translate this to our patients. How do we use this to then think about chemotherapy plus immunotherapy? As we know from the four pivotal trials that have really helped us counsel our patients on including immunotherapy with mismatch repair deficiency or MSI-H tumors.
Matulonis: We've had a discussion with Gini Fleming about the role of checkpoint inhibition in mismatch repair–proficient tumors. Panos Konstantinopoulos spoke about targeting the ER for NSMP tumors. So, we've had a lot of discussions about therapies. As we move through this podcast, we'd love to hear what you think is exciting in endometrial cancer.
Focusing on the clinical aspects of genetic testing, how do you see ordering genetic testing? We all see patients who come in, and we can't find the sequencing. We can't find HER2 results. How do you order these different results? How do you organize them in the chart? And when do you order the molecular testing?
Fuh: Great questions because that really informs clinical care, and our patients are coming to us saying, gosh, you know, what is molecular testing–driven care?
As we're thinking about this molecular testing, I think about it in three broad categories. Most providers are used to having in-house testing in terms of pathology performing the IHC for mismatch repair proteins. I remember, as a fellow, that was something that was just getting started and really being launched, and now it's universal. One way to think about molecular testing is IHC. With mismatch repair protein, IHC is also ER, PR, then, in some places, HER2 IHC. So that is one category.
The other molecular testing we talk about a lot is next-generation sequencing (NGS), DNA and RNA sequencing, whether or not it's in-house, but for most, it's commercially based, right? So, we send that out.
The third category is whether or not it's all-inclusive, including both the protein and the NGS together, the DNA and RNA. Whether done in-house or commercially.
When someone comes to us, either as a newly diagnosed patient, just having had surgery, and has, let's say, advanced-stage disease, what's next? Do we do the comprehensive, or do we do the DNA, RNA, and protein? I do this for the advanced-stage patients. That's something where we can really have biomarker-informed care, especially if someone's mismatch repair–deficient. We know that combining with immunotherapy is critical.
Let's say someone comes in with recurrent disease, they were treated somewhere else, or they were initially early-stage and now recurrent. That's another category because we know the clinical trials also correlate with improved response, with knowing the molecular profile, especially again with mismatch repair deficiency or MSI-H. With the other biomarkers, HER2, for example, we know that DESTINY-PanTumor trials also correlate with response to trastuzumab deruxtecan and ER/PR. That also can inform.
What can help patients get into clinical trials? This also helps not just with the standard of care, but what are the other options? With early stage, there are some trials that we're still waiting for reading out. GY020 looked at high intermediate risk early-stage cancers with mismatch repair deficiency. If you combine pembrolizumab with radiation therapy, is that better than radiation alone? We're still waiting for the early-stage cancers. Then how do we use POLE to inform us? And that's really more in the clinical trial right now. What can we do in terms of sequencing in the here and now? How can we inform clinical care with advanced-stage recurrent cancer patients? Certainly, having that molecular testing, both DNA and RNA and also protein is really important. And then, certainly, there is more to come for the other subtypes and stages.
Matulonis: What do you do about high-risk stage I patients, like a stage I carcinosarcoma or a stage IB? I'm using the old classification now, but basically, muscle invasion, serous carcinoma. Do you get testing on those patients, or do you say, okay, let's give them a break, and hopefully, they'll do okay, before ordering if they do recur?
Fuh: I counsel and talk about it with the patient, but I do tend to want to test. I do tend to want to have more information. It's important to have information to be able to help guide. Especially with the histologic subtypes, we know they can be more aggressive because they also have molecular aggressiveness in terms of the carcinosarcomas and the serous cancers that have more p53-driven tumors. That can help us guide HER2 expression. We know that p53-mutated tumors tend to also have HER2 expression, whether or not that can also help inform the sequencing of treatment options. So, for those, I would say like stage IA, grade 1 endometrioid histology, endometrial cancer, I think we have sufficient data that those tend to do quite well with surgery, but certainly, keeping our ears and eyes open for surveillance and making sure. Still, yes, I would say the more aggressive subtypes are the ones that I would also lean toward molecular testing.
Matulonis: Do you order germline testing on any patients if we are looking for BRCA1 or 2 or other?
Fuh: I would say Lynch is where we think about it more, especially in the young patients with endometrial cancer, who are 40 and younger. Even if they have risk factors that can lead to endometrial cancer, we still test for hereditary and germline. For BRCA, we know that certainly, it is possible. So certainly, with family history (we would order germline testing), but the way we do our panel testing is a panel test. So, if we're going to test for Lynch, we're also going to test for BRCA and other possible genetic germline genes. So, yes, that's also what we would consider.
Matulonis: Do you have a special place where you store all this information? I was just seeing a patient yesterday, and in the chart, from the outside notes, the tumor was described as HER2-negative, which always drives me crazy without any kind of quantification around it. Then, there is a lack of source data for the sequencing. How do you store that information so it's easy for you and your colleagues to find?
Fuh: That is a universal question, and I'm glad to hear it's a universal issue as well. I store the information in my progress notes. Still, until it gets to that progress note, it is a lot of trying to put everything together, which is what needs to be improved for our patients and for patient care, as patients may be seeking other opinions and trying to understand.
I also agree with you that we should use our language better. Instead of saying HER2-low or -negative, what is that percentage, and who did the testing? And also, was it breast or gastric? We want to get into the details that may help us in the future. But, for now, as an institution, we are trying to figure out how we can better store this information so it's more accessible for everyone, especially as folks are going through clinical trials and trying to understand what the options are based on trying to find the information quickly.
Matulonis: You wrote a really nice commentary in gynecologic oncology in 2024 about whether we should be rebiopsying our patients with endometrial cancer at the time of progression to see if the molecular profiling has changed. Can you talk about what you recommend?
Fuh: Yes, absolutely. This was a wonderful commentary that Dr Beryl Manning-Geist, who's now at Emory, and I wrote together. It was from a case report from Dr Britta Weigelt's group written by Dr Sushmita Gordhandas. It really looked at two recurrent endometrial cancer cases and tried to answer the question that we ask quite often. Someone presents with either early stage or advanced stage, and this case report actually showed two cases. One was early endometrioid. One was an advanced stage, IVB grade 3 endometrioid. Both had standard-of-care treatment. Both had recurrences, one at 38 months and one at 6 months. They were able to biopsy and test the primary tumor as well as the recurrent metastatic tumor. They found that along with their typical POLE wild type or mismatch repair–proficient, they also found a subclonal beta-catenin mutation or CTNNB1 mutation in the primary. Subclonal. So subclonal, meaning that it probably doesn't do much. It's just sort of sitting there. But then, in the recurrent metastatic tumor, they actually found that it became clonal. The recurrences were in the lung for the patient with early-stage disease, and for the advanced-stage patient, it was in the brain. There are areas that can be difficult to treat as well. This highlights the idea that there is evolution, and these subclonal mutations can become clonal. We're now wondering how we actually target and treat these clonal mutations. That's where we are in the process of identifying these specific biomarkers that may drive these tumors to become more aggressive and more metastatic and recurrent. But now, let's find the therapy that we can pair with this and actually treat this. This was a really nice example of how rebiopsy might actually be really informative.
Matulonis: Do you have any sense, from what you've done, that there's any change in HER2 expression, ER, PR expression? I know breast cancer doctors talk a lot about that. Obviously, we're going to be using more antibody-drug conjugates (ADCs) in endometrial cancer, and whether or not receptor alpha changes or any of those other markers change over time.
Fuh: Exactly. We ask about this and talk about it all the time. We're waiting for that information. As we are being able to accrue, either retrospectively or prospectively, I know there certainly are studies underway right now trying to understand if you have HER2, that is a tumor that does express HER2 at the primary tumor. Let's say 5 years, 8 years down the line, is it still going to be HER2-expressing, or is something going to happen? And what are the treatments in between actually to help guide that? Hopefully, we can all work toward this goal to understand that because it's really important for our patients.
We are currently using baseline tumors for most of what we're doing because that is what we have access to in terms of coverage. Sometimes, we can't cover that second biopsy. Therefore, it's difficult to do that, or it's in a unique location that's difficult to have. Having a large-scale study where we can answer that question would be really useful for our patients.
Matulonis: I want to move on to some of your research. Congratulations on the Route 66 Endometrial Cancer SPORE grant, the Specialized Programs of Research Excellence grant that you share with the University of New Mexico and the University of Oklahoma. You were involved in Project 2 of that grant, which is entitled Inhibiting AXL to Improve Treatment Response in Endometrial Cancer.
I've heard you talk about a phase 3 study that you ran of the AXL inhibitor AVB-500 combined with weekly paclitaxel vs weekly paclitaxel alone in platinum-resistant ovarian cancer. You also published a really fantastic paper in Cancers a few years ago that tested preclinically whether inhibiting the receptor tyrosine kinase AXL with AVB-500 combined with bevacizumab would improve the response in uterine serous cancer. Can you tell us about AXL? What happens when it's inhibited, the results of this phase 3 trial in ovary cancer, and how those clinical trial results may have informed the clinical trial in the endometrial SPORE grant?
Fuh: Thank you so much. Your group has really led the way with these multiple SPORE grants as well, which are really important for Gyn cancers and really give us the opportunity to expand from the bench to the bedside. So yes, this project with the AXL inhibition to improve response in endometrial cancer started when I was at Washington University and is now carrying forward at UCSF.
We developed this SPORE endometrial cancer project using our preclinical data. The preclinical data showed that when we inhibit AXL in endometrial cancers, we can improve sensitivity to paclitaxel. And we have some mechanisms to show that. Michael Toboni, who's now at the University of Alabama, worked on inhibiting AXL and combining it with bevacizumab and showed in uterine serous cancers that it improved response and decreased tumor burden in preclinical models.
In parallel to all this, I was leading the phase 3 clinical trial you mentioned in platinum-resistant ovarian cancer. This was a really important trial because we looked at standard of care, weekly paclitaxel vs standard-of-care paclitaxel with the AVB-500, which we now call batiraxcept in platinum-resistant ovarian cancer. At the time, similar to uterine cancer or ovarian cancer, you think about the AXL protein by IHC as a biomarker. We found that a majority of the tumors expressed as biomarkers. So, we included everyone in this platinum-resistant ovarian cancer trial. What was informative was that, when we looked at AXL-high tumors, those patients actually really responded well and had improved both progression-free survival and overall survival in ovarian cancer when they received paclitaxel with batiraxcept, the AXL inhibitor in ovarian cancer.
This was happening at the same time that we had the SPORE grant open and developed this uterine serous cancer trial. This trial is going to move forward soon. It will hopefully open at four sites: Washington University, UCSF, University of New Mexico, and University of Oklahoma. It will really give our patients the opportunity to receive an AXL inhibitor with paclitaxel. Because of the ovarian cancer trial, we're now working with Exelixis for their AXL inhibitor, zanzalintinib, just based on the timing of everything. We're excited to see how we can bring a new pathway or inhibit a new pathway in Gyn cancers to give additional options to our patients.
Matulonis: Yeah, that's great. I remember hearing you talk about this. Has the trial started?
Fuh: Yes, it's going to start. We're in the final phases of the Investigational New Drug at the FDA. That was submitted in early February. So, if everything goes as scheduled and planned, we're hoping that we will be able to open in the spring. So, we'll see how that goes.
Matulonis: Good luck. It's great work, and it is really exciting to hear about the project. Certainly, we still need really great therapies for endometrial serous cancer. Because you're involved in so much at UCSF and elsewhere, I also want you to talk about the SPORE grant and the National Cancer Institute. Can you talk about other novel and noteworthy projects that you're working on at UCSF right now?
Fuh: Thank you so much. We're really looking at the tumor microenvironment and trying to understand how fibroblasts, usually thought to be very supportive cells, can actually, with expression of either AXL or another receptor tyrosine kinase, discoidin domain receptor 2 (DDR2), influence tumor cells. By inhibiting AXL or DDR2 in the fibroblasts, we can actually lead tumor cells to be more responsive to treatments such as poly (ADP-ribose) polymerase (PARP) inhibitors. We have some data that's going to be hopefully published soon where we can actually show and highlight that by manipulating the fibroblasts, we can actually regulate tumor cells to become more sensitive to PARP inhibitors because they are suppressed by these fibroblasts expressing either DDR2 or AXL. So, that's one angle that we're looking at.
Another is working with a collaborator at the Innovative Genomics Institute at Berkeley, Alan Ashworth, where we're trying to deliver cytokines specifically to the tumors through lipid nanoparticles. We already have some data in our preclinical models where we can focus this on the tumors themselves and actually look at the tumor-infiltrating lymphocytes to see more immune-activating T cells in these tumors. And so, of course, we're now going to pair it with other immunotherapy and see if we can offer additional options for patients who have tumors that, typically, are not responsive. You've led these big clinical trials looking at this already in ovarian cancer, but they're trying to really figure out a different angle and more tumor-specific possibly.
Matulonis: Well, that's exciting. You have so many hats and roles. You're the director of translational research at UCSF. You run trials in gynecologic oncology, which you've just talked about. You have a lab. Importantly, you operate on patients as a gynecologic oncology surgeon. I also imagine that you mentor junior faculty. How do you do it all? How do you run your day? And what advice would you give to junior faculty fellows who precede you to be as successful as you are?
Fuh: Thank you. That's very kind of you. It's looking at role models like yourself and having excellent mentorship early on. I attribute that a lot to the time at Washington University and the mentorship there, giving the time to build and establish this foundation for the lab, especially with the lab-based research. You really need that mentorship. Greg Longmore was integral. He is actually a medical oncologist and a molecular oncologist. Dave Mudge, Matt Powell, and Pramod Thakur all really helped to carve out that time to establish the lab base. There is a really wonderful, supportive team. We had a PhD, Deb Frank. And just really feeling that team spirit, which is really important.
For the young folks who are coming through the pipeline, it is important to figure out your motivation for all this. For me, it's the same motivation that I had that got me into Gyn oncology or these patients and seeing how we do need more therapies. That really helps to prioritize what is important in your day and how to get through everything.
I want to highlight the clinical trial mentorship with Katie Moore specifically, who helped guide this bench to bedside transition and all of her time and effort. Also, the GOG Foundation, in terms of Tom Herzog, Rob Coleman, and Dave O'Malley, helped me make this transition.
The transition from the bench to the bedside is not easy, and it definitely takes a team of support. Role models like yourself and others have really also helped make me feel like I can do this because you've done this. I appreciate all that support.
Matulonis: Well, that's very kind, but you are a star, and you've accomplished so much. I really look forward to seeing your career and your continued success. I want to finish up on a clinical note. From a therapeutic and clinical care standpoint, what recent research and findings in endometrial cancer do you think are noteworthy for our audience to know and learn about?
Fuh: We didn't talk much about ADCs. You have other episodes that address this with Katie Moore in the previous season. I think that is an important field, and we're really going to try to understand how we can sequence and utilize ADCs in endometrial cancer, whether or not they're really biomarker-driven, or are they just agnostic to the biomarkers and thinking about when and where to use it.
I am also thinking about other ways of maintenance therapy. I am thinking about p53 wild-type tumors and how we actually have maintenance strategies. Are they ER-positive, PR-positive? Can we utilize the maintenance strategy based on that expression level or through selinexor or with p53 wild-type tumor?
That's noteworthy as well. We're thinking about how to deal with the tumor that's measurable in there, but then also how to maintain it, especially for those that are mismatch repair–proficient, that don't have the immunotherapy as an option for maintenance.
Matulonis: Katie Moore spoke during the first series about ADCs, and coming up, we are having a discussion with Leif Ellison from Massachusetts General Hospital. He's a breast cancer researcher, and we will explore what the breast cancer doctors have learned about ADC after ADC, which we're really experiencing right now in gynecologic oncology but really don't have great answers to. You pointed out really great research that's going on and very exciting findings. Thank you so much. Dr Fuh, it's been great to have you on this podcast. Thank you so much for joining.
Fuh: Great. Thank you so much. I appreciate it.
Matulonis: Today, we've talked to Dr Fuh about the molecular classification of endometrial cancer, new and exciting research that she's been working on, as well as others, and what's to come in the future. We also learned about how she's become so successful in her career, really holding on to multiple different hats in terms of administrative hats, research hats, mentoring hats, etc.
Thank you all for tuning in. Please take a moment to download the Medscape app to listen and subscribe to this podcast series on endometrial cancer. This is Dr Ursula Matulonis for the Medscape InDiscussion: Endometrial Cancer podcast.
Listen to additional seasons of this podcast.
Resources
Molecular Testing for Endometrial Cancer: An SGO Clinical Practice Statement
TCGA Molecular Prognostic Groups of Endometrial Carcinoma: Current Knowledge and Future Perspectives
Histopathological Characterization of ProMisE Molecular Groups of Endometrial Cancer
Testing Strategies for Lynch Syndrome in People With Endometrial Cancer
Endometrial Cancer at Recurrence: To Re-Sequence or Not to Re-Sequence
Route 66 Endometrial Cancer SPORE
Project 2: Inhibiting AXL to Improve Treatment Response in Endometrial Cancer
Inhibition of AXL and VEGF-A Has Improved Therapeutic Efficacy in Uterine Serous Cancer
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Cite this: Endometrial Cancer: Molecular Classification, Genetics, When to Rebiopsy, and What's New in the Research - Medscape - Mar 12, 2025.
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