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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're going to discuss hormonal therapy updates for metastatic endometrial cancer and different ways to target and treat estrogen receptor–positive (ER+) metastatic endometrial cancer. Let me introduce my guest, Dr Panos Konstantinopoulos. Welcome, Panos.
Panagiotis A. Konstantinopoulos, MD, PhD: Thank you so much for having me.
Matulonis: Panos, it's great to have you. Dr Konstantinopoulos is the director of translational research and an attending medical oncologist in the Division of Gynecologic Oncology at the Dana-Farber Cancer Institute. He's my wonderful colleague. Panos is an associate professor of medicine at Harvard Medical School. Congratulations on receiving the Velma Eisenson Chair for Clinical and Translational Research at Dana-Farber. You are the inaugural recipient. Today, Panos and I are going to focus on the use of hormonal therapies for metastatic endometrial cancer.
Dr Konstantinopoulos will cover the different types of therapies available, when and in what clinical circumstances to use them, what are some of the key biomarkers when using these therapies, and what the future holds for new hormonal therapies. We have a lot to cover.
Panos, let's start off by having you talk about the status of hormonal therapy for endometrial cancer. What therapies are used prior to the use of CDK4/6 inhibitors? Also, maybe a little bit about CDK4/6 inhibitors as well.
Konstantinopoulos: When we talk about hormonal therapy and endometrial cancer, we prioritize endometrioid tumors. Endometrioids are the most common endometrial cancer histology; these tumors are considered to be hormonally driven. Estrogen signaling through the estrogen receptor acts as an oncogenic driver for endometrioid tumors. Approximately 84% of these tumors that are grade 1 and 2, and 50% of grade 3 endometrioid tumors, express estrogen receptors.
Other, more rare endometrial cancer histologies, such as serous, clear cell, and carcinosarcomas, are not considered hormonally driven. I want to say that there is a small fraction of carcinosarcomas that have an endometrioid epithelial component, and some of these rare carcinosarcomas may still respond to hormonal therapy.
We usually prioritize hormonal therapy in endometrial cancer as an alternative option after progression through chemotherapy and immunotherapy or as an alternative, less toxic option for those patients who have more indolent or minimally symptomatic disease. We can think about either monotherapy endocrine therapy, or we can think about combinations. In terms of monotherapy choices, we can think about progestins, which have been used as early as the 1950s and have shown objective responses in the range of 15%-20%. There seems to be no dose-response relationship. In other words, higher doses of these drugs do not give better outcomes. So, either medroxyprogesterone acetate at a dose of 200 mg/d or megestrol acetate (Megace), at a dose of 160 mg/d, are monotherapy progestins that can be used.
Single-agent tamoxifen is the only selective estrogen receptor modulator that has shown some activity. But personally, when I want to use monotherapy endocrine therapy, I use aromatase inhibitors like letrozole or anastrozole. These drugs have shown objective response rates of around 9%, but they have shown clinical benefit in the PARAGON study. Anastrozole has shown a clinical benefit of 44% at 3 months, with a median duration of clinical benefit of 5.6 months. I personally like to use these agents, particularly for small-volume, low-burden disease, minimally symptomatic. I want to mention that fulvestrant, which is a selective estrogen receptor degrader (SERD), has also shown activity in two small phase 2 studies with an objective response of about 15%. It is included as monotherapy in the National Comprehensive Cancer Network (NCCN) guidelines.
In terms of combinations, the combination of progestins with tamoxifen is a commonly used regimen in GOG studies; a megestrol acetate daily for 3 weeks, alternating with tamoxifen, 40 mg/d for 3 weeks, showed an objective response rate of 27% with a median progression-free survival (PFS) of 2.7 months.
It's important to highlight that this regimen showed activity in 22% among grade 3 tumors. The rationale there is that it's possible that tamoxifen induces progesterone receptors, thereby explaining why we use the sequential alternating progestin and tamoxifen schedule. This is one of the NCCN guidelines, and it's listed as a preferred regimen. One thing to be careful about with this regimen is that it can cause thromboembolic events, including deep vein thrombosis and pulmonary embolism. It's about 9% in that study, so it's good to be aware of that complication. The combination of letrozole with the mammalian target of rapamycin (mTOR) inhibitor everolimus was also studied, and it is listed as a preferred regimen in the NCCN guidelines. It was studied in a phase 2 trial in patients with up to two prior cytotoxic therapies, regardless of estrogen receptor status. It showed an objective response of 32% and a median PFS of 3 months. Serous histology was the best predictor of lack of response. So, only endometrioid tumors responded.
And as I said, this is listed as a preferred regimen for recurrent or metastatic endometrial cancer. Now, these two regimens, the everolimus/letrozole vs the alternating tamoxifen and progestin, were compared in GOG 3007. This study showed that both regiments had activity, with objective response rates of 22% and 25%, respectively.
But what was interesting is that when we looked at chemotherapy-naive patients, these patients experienced PFS of 28 months on everolimus/letrozole and only 5 months on megestrol acetate and tamoxifen. So, it is possible that when thinking about chemotherapy-naive patients, in patients who have never had chemotherapy before for whom we want to use a combinatorial strategy, this study does support the use of everolimus/letrozole compared with the combination of progestin and tamoxifen.
There was also a triplet combination of letrozole, everolimus, and metformin that was evaluated in endometrioid histology. That showed an objective response of 28% and a median PFS of 5.7 months. This study showed that having no negative PR expression was associated with less benefit to this agent.
Now we have the CDK4/6 inhibitors. We can talk more about them. The combination of hormonal therapy with CDK4/6 inhibitors has shown activity, particularly in the no–specific molecular profile (NSMP) and mismatch repair–proficient (MMRP) tumors, and not in the p53-mutated tumors. The way I personally try to prioritize this is when talking about estrogen receptor-negative (ER-) tumors, I would favor either the letrozole/everolimus or the megestrol acetate and tamoxifen regimen, mainly because all the data on the CDK4/6 inhibitor combinations were done in tumors that are ER+. Because we don't have data on ER- for CDK4/6 inhibitors, I would prioritize the letrozole/everolimus or the megestrol acetate and tamoxifen regimen. If the patients are chemotherapy-naive, I would use letrozole/everolimus.
If the tumors are NSMP or MMRP, and not p53 mutated and ER+, I would consider a CDK4/6 inhibitor regimen. We can talk about estrogen receptor 1 (ESR1) mutations later, but there, we could consider a combination with a SERD or a SERD alone. With p53-mutated tumors, the data on letrozole/everolimus and megestrol acetate and tamoxifen — we don't have data on whether there is a response or not. But because we don't have evidence of response, we actually know that p53 mutation is associated with a lack of response to CDK4/6 inhibitors For p53-mutated tumors. I would, again, prioritize a letrozole/everolimus or a megestrol acetate and tamoxifen regimen there. Now, if patients have a small burden of disease, low volume, and indolent, and people want to use a single agent, then I would personally use an aromatase inhibitor, and if patients have an ESR1 mutation, I would use a SERD like fulvestrant. Both of these are in the NCCN guidelines.
Matulonis: Panos, that's a great review of systemic treatment. I think a lot of clinicians will turn to the guidelines as well. And if you look at the hormonal therapy for recurrent, metastatic endometrial cancer, there are multiple possibilities. As you mentioned, the preferred regimens are megestrol acetate and tamoxifen alternating, and then everolimus/letrozole. But that other recommended middle category includes lots of different progestational agents, and obviously the aromatase inhibitors, tamoxifen, and fulvestrant.
I think that is a challenge when a patient comes to a clinician and they've got a low-grade endometrioid, endometrial cancer, and sometimes the estrogen receptor status is known and sometimes it's not known, but a lot of times that metastatic disease is asymptomatic lung metastases. I do think that prioritization of an aromatase inhibitor [is right], which is probably one of the simpler therapies that we have. It's not totally simple, but that would make perfect sense. The other thing to think about for low-volume, ER+ disease is, of course, surgical resection. I think you mentioned the isolated, metastatic focus or one or two foci, and then even radiation therapy. You talked about some of the — I would say biomarkers — for selection of patients, but then also for understanding response and resistance. I'm going to break those biomarkers into two categories. One is clinical biomarkers. What are some of the clinical biomarkers that you use, or clinical scenarios that you use, to help you make that decision? Okay, I'm going to use an estrogen receptor, targeted therapy vs chemotherapy, or something else. And then secondly, what are some of the immunohistochemistry biomarkers, genetic or genomic biomarkers, that you might use, or, from a research standpoint, that might be important for understanding mechanisms of resistance and response?
Konstantinopoulos: Regarding histology, we think of hormonal therapy. As I mentioned, endometrioid histology, particularly grade 1 and 2 tumors, 84% of these tumors express estrogen receptor and 50% of grade 3 express estrogen receptor. I do not use hormonal therapy in serous clear cell and carcinosarcomas. I mentioned the exception of the carcinosarcomas with endometrioid epithelial component, which may sometimes respond to hormonal therapy. But generally, I focus on endometrioid histology. Now, we have to keep in mind that the standard of care is chemotherapy and immunotherapy, so we obviously need to consider the standard of care. But if patients have progressed to standard-of-care treatment or they're not eligible for standard-of-care treatment, either because they have more indolent or minimally symptomatic disease, then it's certainly reasonable to consider the use of hormonal therapy.
And now we have the molecular stratification of endometrial cancer. So we know we have the NSMP tumors, which are the nonspecific molecular profile, which are not p53 mutated, not DNA polymerase epsilon (pole), and not mismatch repair deficient. We do know these tumors are hormonally driven, and they do respond very well to hormonal therapy.
We actually now know that there is a substratification of those. If we look at ER- NSMP tumors, they do very, very poorly, but those that are ER+ are certainly great candidates for response to hormonal therapy. And particularly CDK4/6 inhibitors, because there is evidence that cyclin D1 is overexpressed in these tumors because of the beta-catenin and the KRAS mutations. That shows there is some dependency on the CDK4/6 blockade.
If we look at the study of letrozole and abemaciclib, we have a 50% objective response in NSMP tumors. There was a 58% response rate in the fulvestrant abemaciclib study. So, clearly, among the NSMP tumors, I think consideration of hormonal therapy should be made, especially after progression through prior chemoimmunotherapy.
Also, we did see responses to CDK4/6 blockade with mismatch repair–deficient tumors, which are obviously very sensitive to immunotherapy and chemoimmunotherapy. Two of them had an objective response. One had a clinical benefit. In the fulvestrant and abemaciclib study, there were four patients with mismatch repair–deficient tumors. One had an objective response. The other had a response of more than 4 months. So, there are a fraction of mismatch repair deficient tumors that do respond to hormonal therapy with CDK4/6 blockade. I think we should keep that in mind because we know that about 70% of our patients with mismatch repair–deficient tumors can be cured with immunotherapy and chemoimmunotherapy. However, 30% of patients progress or develop resistance afterward. So, I think it's reasonable to keep in mind that some of these tumors can be very hormonally sensitive, and consideration of hormonal therapy, particularly in combination with CDK4/6 blockade, is reasonable to consider.
In terms of other biomarkers that we have to think about, and now that we send a lot of circulating tumor DNA and a lot of clinicians send that very regularly, we do see that some people do have ESR1 mutations. These are activating mutations in the ligand-binding domain of the estrogen receptor.
Where the estradiol, the ligand, binds to the estrogen receptor, that's where the mutation is, and that leads to a permanent agonist confirmation of the receptor which leads to activation, regardless of whether the ligand is present or not. So, these mutations are very rare in hormonally naive endometrial cancer and very rare in hormonally naive breast cancer. But if patients are exposed to aromatase inhibitor therapy, then we see those mutations happen. And if those mutations occur, we do know that these mutations create resistance to aromatase inhibitors, and they do create resistance also to tamoxifen. So, the drugs to use for these situations, if you do see an ESR1 mutation, are SERDS, and fulvestrant is one drug that is in the NCCN guidelines. Elacestrant is a drug that's FDA approved for breast cancer, and it's superior to fulvestrant for the treatment of ESR1 -mutated breast cancer. But again, it's important to underscore that these mutations occur after exposure to aromatase inhibitors. So, at baseline, if patients are hormonally naive, mutations are very rare.
But if we see them, then it's reasonable to use a SERD, or a SERD in combination with a CDK4/6 inhibitor, to treat those ESR1 mutations. I mentioned p53-mutated tumors. We have data that these tumors do not respond well to CDK4/6 blockade. There are a number of reasons for that. We don't have this question of whether p53-mutated tumors respond to letrozole/everolimus or megestrol acetate alternating with tamoxifen. That question has not been answered because molecular profiling was not available in those early studies, so we don't really know.
I would not say don't use it. I would say don't use a CDK4/6 blockade there because we know that it's likely not responsive. But it's reasonable to consider, if you're going to use it, letrozole/everolimus, or megestrol acetate alternating with progestin.
One final marker that I would like to mention is CDKN2A, which is P16. If there is a loss of protein, P16 — and sometimes we see it or a mutation in some settings that has been associated with response to CDK4/6 blockade — it's good to consider that. In fact, in low-grade serous ovarian cancer, two thirds of those tumors have a loss of P16 and they respond well to CDK4/6 blockade. So, if you do see in the molecular profiling CDKN2A or P16 loss, that is something to consider to use for CDK4/6 blockade. Levels of estrogen receptor and progesterone receptor have not been consistently shown to be correlated with response, so I would not use this as a reason to choose therapies. But I want to highlight again that CDK4/6 inhibitors have only been studied in ER+ tumors with a 1% cutoff. And that's why, in the NCCN guidelines, they are only included for ER+ tumors, as opposed to letrozole/everolimus and megestrol acetate alternating with progestin, which have been used regardless of estrogen receptor status.
That does not mean that CDK4/6 inhibitors may not work in ER- tumors. We just don't know because the studies have not been done there.
Matulonis: That's a great review, Panos. In our last minutes, I want to focus on your research in ER+ endometrial cancer. Maybe give an overview of the data of the different trials that have tested CDK4/6 inhibitors in ER+ endometrial cancer, and finish off by telling us what you're working on in terms of novel strategies for this particular type of endometrial cancer and also what you're most excited about.
Konstantinopoulos: That's a great question. Thank you so much. So again, I want to say that the endometrioid histology of cancer is associated with about 90% of cases having PI3K pathway alterations, beta-catenin pathway alterations with RAS mutations are also seen in 80%, and all of these pathways converge into upregulation of cyclin D1. Cyclin D1 is also a key target gene of estrogen receptor.
So all of these three pathways — estrogen receptor, PI3K, and beta-catenin pathways — converge into cyclin D1. And that's why the cyclin D1 CDK4/6 complex is a very good target for CDK4/6 blockade. The other thing is that RB1 alterations are very rare in endometrial cancer. And that's why it's a great disease as a candidate for CDK4/6 blockade.
The letrozole/abemaciclib study was published in the Journal of Clinical Oncology more than 2 years ago. That was done in recurrent ER+ endometrial cancer with a cutoff of 1%. There was no limit in prior therapies and prior hormonal therapy was allowed. The objective response was 30%. All responses were in endometrioid adenocarcinomas. The median PFS was 9.1 months. The PFS at 6 months was 56%. The median duration of response was 7.4 months. We saw responses in NSMP tumors and mismatch repair–deficient tumors. The presence of p53 mutations was associated with reduced clinical benefit from letrozole/abemaciclib, as I mentioned before.
Another study that was done by the Memorial Sloan Kettering group looked at fulvestrant and abemaciclib. This was recently published, and that study looked at estrogen receptor and progesterone receptor expression more than 1% less than two prior lines of chemotherapy and less than one prior line of hormonal therapy. The objective response there was 44%. This was a less heavily pretreated population and included more NSMP tumors. The response in the NSMP tumors was 59%. They saw one response out of four mismatch repair–deficient tumors. There were no responses in the p53 abnormal tumors. Abemaciclib has been studied together with imlunestrant, which is another SERD. That was another study that was published recently, and the objective response of the combination was 18% there, with a median PFS of about 7 months.
There was also a randomized phase 2 study that was just published in Gynecologic Oncology, the so-called PALEO study, that randomized patients with ER+, with a cutoff of 10% endometrioid endometrial cancer, one to one between letrozole plus either oral palbociclib, another CDK4/6 inhibitor, or placebo, and only progestins were allowed in that study. It was actually capped at 50%. The study showed that the addition of palbociclib improved PFS from 3 months with letrozole/placebo to 8.3 months with the combination with palbociclib, with a hazard ratio of 0.57. All this data together support that the combinations of CDK4/6 inhibitor and hormonal therapy are actually very promising.
We looked at circulating tumor DNA to assess the mechanism of resistance to this combination at the time of progression. We did find a number of mechanisms. Most importantly, PI3K pathway alterations were identified in more than 50% of patients who progressed on letrozole and abemaciclib, and this is not unexpected. We also found ERBB2 alterations. We had patients who had ERBB2 amplification or ERBB2 mutation. This is very interesting because it means that some of these tumors that did not have ERBB2 amplification to begin with, developed this after progression through letrozole/abemaciclib, and therefore may be very good candidates for HER2-targeted therapy like deruxtecan trastuzumab, which is now obviously in the NCCN guidelines, and it's also FDA approved for HER2+ (IHC 3+) tumors. So, we obviously saw RB loss, which is cyclin E1 amplification, which are well-established mechanisms of resistance to CDK4/6 blockade.
We also saw ESR1 mutations and ESR1 amplification in some patients who progressed on letrozole/everolimus, and based on this data, I think it comes as no surprise to your question, Ursula, about what are the novel combinatorial strategies for targeting ER+ endometrial cancer. I think combinations with PI3K pathway are very interesting. We have the AKT inhibitors with capivasertib now FDA-approved in breast cancer in combination with hormonal therapy. We have the alpha PI3K isoform inhibitors, like alpelisib. We have dual PI3K mTOR inhibitors. We have a lot of other PI3K inhibitors, including covalent PI3K inhibitors. PI3K pathway activation mediates resistance to hormonal therapy. There is extensive crosstalk between these pathways. I think there is a lot of rationale for combining hormonal therapy with PI3K inhibitors. Obviously, there is a lot of rationale to do triplet combinations with CDK4/6 and PI3K inhibitors, and there are preclinical studies that have shown significant synergies with simultaneous inhibition of PI3K, CDK4/6, and estrogen receptor pathways.
This concept has been successfully applied in breast cancer with the recent FDA approval of the alpha-specific PI3K inhibitor inavolisib in combination with palbociclib and fulvestrant in breast cancer. So we are actually going to be reporting our metformin/abemaciclib/letrozole study. Metformin is also a PI3K signaling inhibitor. We have seen some very encouraging responses.
Other good combinations are combinations with new SERDs. Although we do have fulvestrant, I want to say that it's a difficult drug because it doesn't have oral bioavailability, and we need to give this drug through an intramuscular injection, which a lot of patients don't like. We do have novel oral SERDS, like elacestrant, which is FDA-approved in breast cancer, but there are also imlunestrant and camizestrant, and these are drugs that are oral. As I said, they degrade estrogen receptor alpha in a dose-dependent manner. They inhibit estrogen-directed gene transcription and tumor growth, and they have better pharmacokinetic properties compared with fulvestrant. I'm very excited about combinations with these novel SERDs.
Matulonis: Fantastic conversation, Panos. Such an incredibly rich area from a historical standpoint but obviously for future directions as well. Thank you so much, Panos, for being our guest. Today, we've talked to Dr Konstantinopoulos about hormonal therapy updates for metastatic endometrial cancer in terms of biomarkers, new therapies, what's available right now for use, and talking about genomic and genetic predictive biomarkers. We covered so much today. Thank you so much 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
Immunophenotypic Diversity of Endometrial Adenocarcinomas: Implications for Differential Diagnosis
Progesterone: The Ultimate Endometrial Tumor Suppressor
Phase II Study of Everolimus and Letrozole in Patients With Recurrent Endometrial Carcinoma
CDKN2A Cyclin Dependent Kinase Inhibitor 2A [Homo sapiens (human)]
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Cite this: Metastatic Endometrial Cancer: Hormonal Therapy Updates and Ways to Target and Treat ER+ Disease - Medscape - Feb 13, 2025.
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