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BackTable / OBGYN / Podcast / Transcript #58
Podcast Transcript: Understanding Rising Endometrial Cancer Rates
with Dr. Amanda Fader and Dr. Matthew Powell
Gynecologic oncology experts Dr. Matthew Powell from Washington University School of Medicine and Dr. Amanda Fader from Johns Hopkins Hospital discuss the increasing rates of endometrial cancer along with future directions of treatments and screenings. You can read the full transcript below and listen to this episode here on BackTable.com.
Table of Contents
(1) Endometrial Cancer Subtypes: Endometrioid vs. Non-Endometrioid
(2) Epidemiology of Endometrial Cancer: The Role of Obesity & Aging
(3) Disparities & Risk Factors in Endometrial Cancer
(4) Signs & Symptoms of Endometrial Cancer
(5) Screening & Diagnostic Approaches for Endometrial Cancer
(6) Managing Pain & Anxiety in Endometrial Cancer Procedures
(7) Early Detection & Referral Guidelines for Endometrial Cancer
(8) Addressing Geographic & Workforce Disparities in Gynecology Oncology Care
(9) Clinical Advances & Research in Endometrial Cancer Treatment
(10) Future Directions & Challenges in Endometrial Cancer Care
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[Dr. Amy Park]
Welcome to another episode of BackTable OBGYN, and this is Amy Park, one of your hosts. Mark is not with me today, but I'll shoulder on myself. It is my great pleasure to host two esteemed gynecologic oncology colleagues, Dr. Matthew Powell and Dr. Amanda Fader. I cannot do justice to introduce yourselves, so please tell me a little bit, and our listeners, a little bit about yourselves and your interest in the topic that we're going to discuss today, which is rising endometrial cancer rates.
[Dr. Amanda Fader]
Amy, thank you so much for having us today. It's wonderful to be here on BackTable. I'm Amanda Fader. I am a GYN oncologist based out of Baltimore, Maryland, and I'm at Johns Hopkins Hospital. I've been at Johns Hopkins for more than a decade now. I'm also the current president of the Society of Gynecologic Oncology.
For as long as I can remember, since I was a fellow, I've been fascinated by endometrial cancer and particularly the rising rates of endometrial cancer and the rare endometrial histologies that may be contributing to some of this. I consider myself a rare tumor girl. I direct the rare tumor gynecologic tumor center at Hopkins and I'm a clinical trialist as well. Very interested in moving the needle in both prevention and treatment outcomes for patients with this disease.
[Dr. Matthew Powell]
I'm Dr. Matthew Powell. I'm a gynecologist at Washington University School of Medicine in St. Louis. I've been here, oh boy, almost 25 years. Main area of research interest is endometrial cancer. For the National Cancer Institute, I chair the year-end committee to our group called the NRG Oncology, and I've been doing that for about six years now and help leading a lot of the clinical trials across the country or actually across the world that touch patients with endometrial cancer. Certainly a passion for both Dr. Tatar and myself.
(1) Endometrial Cancer Subtypes: Endometrioid vs. Non-Endometrioid
[Dr. Amy Park]
Amazing. We're so lucky to have you guys on this. I've been hearing about this for the last couple of years. I'm a urogynecologist, so I don't have any content expertise in this topic. You touched on this, Amanda, a little bit earlier, but can you describe the different types of endometrial cancer and what the epidemiology has been historically?
[Dr. Amanda Fader]
Yes. There's two basic categories of endometrial cancer, endometrioid and non-endometrioid cancers. The vast majority of patients that are diagnosed with endometrial cancer have the endometrioid subtype. These tumors tend to be estrogen and progesterone receptor-positive. They tend to develop in patients with overweight or obesity, and in many cases are a low grade and early stage. Not in all cases, however. There's certainly a subset of patients with this disease that have more advanced stage or higher grade tumors, but they represent the majority of patients with this disease.
Whereas the non-endometrioid subtypes are some of those poor prognostic, rare types of cancer, like the uterine serous, the carcinosarcoma, the clear cell subtypes, and some of the mixed tumors as well. We're now looking at endometrial cancers, not just in terms of these histologies, but in terms of molecular differentiation to really help us understand the biology behind the tumors and what patients with these tumors might best respond to in terms of treatment.
(2) Epidemiology of Endometrial Cancer: The Role of Obesity & Aging
[Dr. Amy Park]
What's going on right now? It sounds like the epidemiology, has that changed or has it been rising rates in the type 2 or the non-endometrioid cancers? What's going on right now?
[Dr. Matthew Powell]
The two main things going on. One, we have an obesity epidemic in this country, and that's driving elevated risks of endometrial cancer. Most of that is through increased levels of estrogen. As people are heavier, they get more conversion of some hormones into weak estrogens, and this causes the lining of the uterus to grow and grow and grow. Over time, that accumulates enough damage to result in cancer. The obesity epidemic is certainly one.
The other thing is we have an aging population. As we get older, we're more likely to get these cancers, and there's more people at risk. The baby boomer population that's now in the retirement phase, that's where we're seeing a lot of cancers. If we look across the world, there's about 425,000 cases of endometrial cancer. In the US, we represent about 15% of all the cases worldwide. Really, with our obesity epidemic and our aging population, we see a large portion of these cases.
It is a disease somewhat of the Western world, but about 3% of all women will get endometrial cancer in their life. Thankfully, the vast majority will have disease confined to the uterus and do well. About 80% of patients do well, but unfortunately, 20% of patients will have trouble with this cancer, and where they can get metastatic disease and ultimately succumb to the cancer.
It is now our most deadly cancer. Ovarian cancer used to be the most deadly, and then this year, it looks like endometrial cancer is going to surpass that. As you mentioned, it's because of these higher-grade, higher-risk types. These are the types that not only affect our older patients, but also disproportionately affect our African-American and Black patients. We have a big effort now to try to sort out why and try to get the word out that abnormal bleeding is a big problem, and that needs to be addressed by patients.
[Dr. Amanda Fader]
If I may add to that, endometrial cancer is the fourth most common cause of cancer in women in the US. Given some of these trends that Matt is talking about, we are set in 2030 to see endometrial cancer overcome colon cancer to become the third leading cause of cancer in women. These are really, really disturbing, both incidence and mortality trends.
When you look at all cancers together, while most solid tumors in the world are decreasing in incidence or plateauing in incidence, endometrial cancer is one of the only cancers that's rising in both incidence and mortality for many of the reasons that Matt described. This is a real call to action here and a huge public health threat for women.
[Dr. Matthew Powell]
We should probably point out that you don't have to be overweight to get this cancer either. It's not solely due to that, but that's a big factor in developing the cancer. Nobody's safe, I think, is the issue with endometrial cancer with it being such a high prevalence. 3% of women get this cancer in the United States.
(3) Disparities & Risk Factors in Endometrial Cancer
[Dr. Amy Park]
It sounds like what you alluded to, Matt, is that it's really powered by a lot of-- there's a disparity in who's getting the more lethal cancers or the ones with the worst prognosis. I know you alluded to this earlier, but can you go do a deeper dive? What's going on there?
[Dr. Matthew Powell]
We don't entirely understand why there is a racial disparity. We knew patients with African ancestry tended to do worse. They didn't have this higher rate of getting the cancer, but when they got the cancer, it tended to be this non-endometrioid type and was much more associated with deaths, about twice the risk of dying when they do have endometrial cancer.
We actually have a lot of research ongoing looking at environmental factors, molecular factors. I know there was some implications of hair straightening chemicals that may be a portion of this. Then there's a declining rate of hysterectomy in this country. When we correct for hysterectomy, we see this rate really go up. People that still have their uterus are at very high risk. We're doing a lot less hysterectomies than we did in the past. I think that's another part of what's going on.
[Dr. Amy Park]
Oh, that's so fascinating. I hadn't even thought about that.
[Dr. Amanda Fader]
I think when we were all in training, there was an instance of 600,000 hysterectomies a year. I think the most recent data shows about 450,000 are being performed now with so many interventional and conservative management techniques. In addition to that, you're seeing increased tamoxifen use amongst breast cancer survivors, for example. As studies have shown that prolonged tamoxifen use may be beneficial to select breast cancer survivors, we know that tamoxifen is also a risk factor for endometrial cancer and increases that risk by fourfold.
All of these factors, coupled with the lack of community knowledge about the symptoms of the disease and when to present for care, and lack of knowledge by some providers as well, not just by persons in the community. We have just a cluster here of different factors converging to lead to these increases in rates.
[Dr. Amy Park]
Does the decrease in childbearing or less exposure to birth control pills or any of that stuff also contribute? I don't know if those are factors or not.
[Dr. Matthew Powell]
Birth control pills do help prevent endometrial cancer, but you also see in women that have not had children, they have an increased risk of endometrial cancer. Also, women who've had some infertility, typically a diagnosis of polycystic ovarian syndrome, hypertension, and diabetes also are independent risk factors for the development of endometrial cancer. We see a lot of these patients have diabetes, they get an abnormal hormonal syndrome going on that leads to this increased risk of endometrial.
(4) Signs & Symptoms of Endometrial Cancer
[Dr. Amy Park]
For our listeners, what are the signs or symptoms that we need to be looking out for? I know postmenopausal bleeding is one of the things, but what if they're premenopausal? How do you screen for it? What are the things that you guys think are getting missed when the patients present to you?
[Dr. Amanda Fader]
I think that's a really great question. Matt, if you don't mind, I'll start with this answer. The good news is that this disease is largely preventable. This is a modifiable preventable cancer in not all cases but the majority of cases. The onset of the cancer is almost always heralded by some sort of bleeding. In postmenopausal bleeding, we know that any bleeding spotting discharge is abnormal and we would recommend women immediately seek care in that situation.
We're seeing with the increased obesity and polycystic ovarian syndrome, diabetes, as Matt said, so many different metabolic syndrome diagnoses also going up. We're seeing the incidence of endometrial cancer increase in younger women. Premenopausal women can experience abnormal uterine bleeding. That can manifest in many different ways, from bleeding between periods, prolonged heavier cycles, shorter intervals between cycles.
There was actually a study done by my colleague Anna Beavis here at Hopkins that we looked at a population of women here, premenopausal women who had undergone endometrial biopsy and evaluations to determine, can we do better than our current guidelines in terms of pivoting to performing a biopsy in these patients? She interestingly found that, not surprisingly, increasing obesity and the incidence of obesity, as well as diabetes, and in certain ethnic racial groupings, especially in Black and Hispanic women, those populations had an increased incidence of pathology on endometrial biopsy when it was obtained.
I would just encourage women who have any irregular bleeding in the premenopausal setting that just doesn't seem right or just change from prior trends or any postmenopausal women with bleeding to immediately present to their physicians. Then, providers I think need to be very astute about this and not blow off these symptoms. Unfortunately, I know Matt and I see, not all the time, but not uncommonly, we'll see patients who presented for care to their physicians and they had this concern and were told, "Okay, well it's probably just perimenopause or it maybe because you missed your pill."
These women are not always evaluated diagnostically for this problem, and delays in care can occur. There's been a lot of literature about this as well. Kemi Doll, one of our two oncology colleagues from the University of Washington writes about this, how you can have these vulnerabilities and care cycles that women actually present to care but are not necessarily triaged appropriately and undergo the proper workups. That can affect the delay in diagnosis and a delay in treatment for some patients.
(5) Screening & Diagnostic Approaches for Endometrial Cancer
[Dr. Amy Park]
What are your thoughts about the pelvic ultrasound? I know for screening and if you look at the guidelines for postmenopausal women, at least, looking at the lining, I know it's not as good as catching the non-endometrioid type cancers. What are the warning signs? I see so many older patients. It's so hard to figure out if this is like a little bit of discharge, is it some pessary juice? What's going on here?
What would be your little just low threshold to biopsy? I literally have a low threshold to biopsy, endometrial biopsy or vulvar biopsy. I catch a lot of BIN and vulvar cancer actually, so I just biopsy a lot. What are your thoughts? You guys see these patients after they present for care and it's too late.
[Dr. Matthew Powell]
I do get two caveats. One is we used to say, any abdominal bleeding over age 35 should be evaluated. Now, throw that out. I think, especially with adolescent obesity, we're seeing young 20 year olds getting endometrial cancer. Really, if they've had irregular menses for a long period of time or for more than 6 to 12 months, I think they need to be assessed even if they're in their 20s. Take that caveat.
The other issue about use of ultrasound, you point out, ultrasound does a good job picking up the type 1 endometrial cancer. The garden variety endometrial cancer, you'll see either polyp or thickened lining. You're going to see an enlargement of the lining. Usually in a postmenopausal state, we use something 5 millimeters or greater to really want to proceed with a biopsy.
Now, it doesn't do a very good job picking up the non-endometrioid cancers. Especially our African-American patients and our very elderly patients, if they're bleeding, you really want to think about a biopsy because it could represent a serious cancer. The tricky part is there's obviously a lot of cervical stenosis that can happen. Sometimes it's mucus in the lining of the uterus that you're seeing.
Really, if they've had symptoms or there's thickening on the ultrasound, error on biopsy I think is the key. If you get a negative biopsy and they're still having symptoms or problems, make sure you're following up with either DNC or even moving to hysterectomy and somebody that maintains persistent symptoms.
(6) Managing Pain & Anxiety in Endometrial Cancer Procedures
[Dr. Amy Park]
Can I just ask you guys what your thoughts are because this has been coming up repeatedly? Doing these biopsies and cervical procedures, women are saying it's so painful. Do you have any tips and tricks? The IUD controversy and women not being offered analgesia, there's a lot of fear around having procedures, et cetera. What are your oncology tips and tricks that help the pain aspect and just counseling or verbal analgesia or whatever you do? I feel like these are some of the things that prevent physicians and NPs and all the people on women's health team from really having a low threshold.
[Dr. Amanda Fader]
I think that's a really excellent point, and meeting patients where they're at is really important. Obviously, on top of all of that fear, there's a stigma still associated with talking about some of these topics, talking about I'm having vaginal bleeding. We want to normalize a lot of that in terms of discussing openly and publicly, but I think it's important that patients, that we understand as providers that these are not exciting procedures. No woman likes to undergo a biopsy, let alone a pap smear.
I would say that they're incredibly important, and the literature on whether anesthesia helps in these situations is really mixed. In some of the studies, it shows that it could be just as uncomfortable to have a lidocaine injection at the cervix, while in other studies shows that significant discomfort is alleviated with analgesia. Having a conversation with a patient about this and understanding their preferences and their fears and concerns, I think is really important to help them feel comfortable about this.
I think talking to patients about whether they'd prefer doing something under sedation or in the office is important as well, but I don't have a magic bullet for this. I don't know, Matt, how you handle this in your practice. Some of my patients do end up using some local anesthesia, others do not. In some cases in postmenopausal women, I find that in 30% to 40% of cases, we may not be able to do a successful biopsy in the office because of discomfort or stenosis or atrophy, or there's a pathology there that prevents us from doing that. I think defaulting quickly to offering a procedure either in the office with some sedation or within an operating suite or an ASC, I think is reasonable.
[Dr. Matthew Powell]
I think it's a quick way to make enemies if you don't have them well prepared. It's really often the uterine cramping that really gets them. The cervical dilation is usually not the part that hurts. The paracervical block, I wish it would do better than it does. The patients that get a severe cramp and maybe even a vagal type reaction, their uterine usually because the endometrial biopsies cause some severe cramping up in the uterus.
Usually, as you just said, good counseling. A lot of patients, they're not excited about having to go to the operating room to get an anesthesia either. It's a delicate balance and every patient has to be individualized.
(7) Early Detection & Referral Guidelines for Endometrial Cancer
[Dr. Amy Park]
I know one of my colleagues, Linda Bradley, she is such a proponent of doing office hysteroscopy. She gives meso at a drop of a hat, like some PO Ativan, all the things like magnesium, I guess. I was just doing a co-case with her the other day and she gives IV magnesium to help with the cramping postoperatively. I hadn't heard of that trick, but I haven't dilated somebody in a long time.
In any case, I think when you get into the day-to-day of your clinic and you're looking at your template, you're like, oh my God, I have to-- especially for a generalist, I have a little bit more time on my template, but it's like, how are you going to-- they're like, "Oh, by the way, I have some bleeding." Then you got to get them to that point.
I know for me, oftentimes I'm like, "Let's just take care of this while you're here," because I'm never sure when they're going to come back. You want to catch them when you can. I think having the right kind of counseling mechanisms where you can just have your spiel to be like, "Okay, I would really want to diagnose this. We just want to make sure it's nothing bad. Let's just make sure." Then if you have a pretty high suspicion for this, we usually wait for the tissue diagnosis before sending to GYN onc. Where do you guys stand on-- there's all these terminology now but I know it's called EIN. Is that something usually is referred to GYN onc or generalists or how does that work?
[Dr. Amanda Fader]
I think this is a variable practice at our center and within our system because EIN or pre-invasive disease is associated with upwards of a 40 to 45% risk of cancer on final hysterectomy specimen, especially if there's complex atypical cells seen under the microscope, which is by definition EIN, we manage this, the GYN oncologists manage this at our institution.
I think it's important that whoever is managing this is a very high volume provider, can counsel patients about the risks of underlying malignancy, can appropriately and surgically stage the patients in those cases if needed. At our institution, we generally will perform sentinel lymph node biopsies because there's such a high risk of concurrent invasive cancer in this population.
I think what's most important is understanding that the patient is getting the care from the right provider, so right provider, right time, right procedure. In most cases, the GYN oncologist is going to have the most experience and have the highest volume approach to managing those patients. I don't know, Matt, if you did the same thing at your institution.
[Dr. Matthew Powell]
Yes, I completely agree. Sometimes we'd use the amount of thickness on the ultrasound to help us gauge whether there's higher risk of cancer than 40%. In reality, it's just not accurate. We do tend to err on performing sentinel lymph nodes. That's certainly not uniform. Across our practice and across the country, if I have a cancer or pre-cancer, I want to have as much information to help guide the patient as we can.
There's nothing worse than your post-op having had the uterus out, you have a deeply invasive cancer, then you're not so sure about how to follow that patient because the lymph nodes certainly are repressed and how best to follow that patient is a big controversy. If we can take the sentinel lymph nodes out with really low morbidity, more information, the better to help us in this situation.
(8) Addressing Geographic & Workforce Disparities in Gynecology Oncology Care
[Dr. Amy Park]
There must be GYN onc [unintelligible 00:23:06]. I've seen Jason Wright's info, his data looking at these oncology centers. How does that work when you're not in close proximity? A lot of people have to travel quite a far distance, right?
[Dr. Amanda Fader]
We actually did a study on this at Hopkins. One of our fellows, Nerlyne Desravines, actually presented this work last year, and it was about the geographic disparities in gynecologic cancer provider, the workforce. We have so many at-risk women for gynecologic cancers and especially for endometrial cancer. It was staggering how many thousands of counties and surrounding areas had no GYN oncologists for more than a hundred miles or more away. I think the geographic disparities in care contributes to some to the overall.
There's multiple A's to disparities, access being one of them. That's something that we're grappling within our field right now is how do you get subspecialty, especially preventive care and some treatment to these rural areas where it might not be feasible. Having rural urban partnerships with hospital systems and clinics, I think is happening, and increasingly, telehealth has really helped revolutionize the approach to rural medicine and cancer care, and I think is really beneficial in that regard.
The solutions aren't perfect and some patients can't travel to the bigger community hospitals or academic centers to see the highest volume providers. We need to make sure that we're training our GYN surgeons in a standardized way and educating them about endometrial cancer symptoms and other cancer symptoms that women are going to be at risk for so that they can really be wonderful multipliers in the community and in the rural settings to help women get the care they need, whether locally or at a regional center.
[Dr. Matthew Powell]
One of the things I might add is, sometimes these patients might have a BMI of 30, 40, 50, 60. It's not just me as the gynecologist, it's our anesthesia team, it's the whole crew that's helping take care of this patient, get them through surgery safely. Rural hospitals often may have a limit on the BMI, but they might be willing to put somebody to sleep to do a hysterectomy. Most all these can be done minimally invasive, either laparoscopic or robotic.
The tips and tricks that we use to get patients through safely I think does warrant referral for patients. I think obviously the position around the community doesn't want to hurt the patient, especially with large obesity, that's never an easy case. If you have to think about opening the patient for open hysterectomy, that's even going to be harder for a general practitioner out in the community.
[Dr. Amanda Fader]
The other thing that I know has come up is, the surgery is one thing, but you diagnose the cancer and then the access to the chemoradiation. Chemo, I don't know the schedule, but I assume it's pretty taxing if you're coming from out of town. Then also the brachy, if you're doing brachy, I know one of my friends was the only radiation oncologist in her system to do brachy. When she was on vacation, brachy stopped. On a conference, there was no brachy happening.
When I talked to my radiation oncology colleagues, they were like, "Well, there was a movement for a couple of years and we're doing more--" They thought that they could get away from brachy. They were doing whole beam or something more targeted, but then it wasn't the case. Then going back to brachy, there was this whole generation of residents who didn't train up in it.
Then now, it's one of those more rare things. It's actually a differentiator for radiation oncology residencies. I just wanted to hear what your take is on that because it sounds like that is actually also a really rough component of this, or not rough, but--
[Dr. Matthew Powell]
It's one of those things we even made a quality metric out of. For brachytherapy, for cervical cancer, it became a quality metric through KCS because we saw it falling off, especially in rural communities or low volume providers not using it very much. The survival's so much better when you can deliver good brachytherapy in cervical cancer.
Brachytherapy in endometrial cancer is typically also not so much technically challenging, it's just equipment challenging. It's expensive to have the equipment to do it. It's not offered in a lot of the rural radiation centers. They usually do need to travel somewhere where there's a high volume provider allowing them to purchase equipment to do vaginal brachytherapy.
[Dr. Amy Park]
Do you see a disparity in care? I assume there is, but I'm not sure what the data is on it.
[Dr. Matthew Powell]
The good news is, typically, only three or four treatments are needed for the vaginal brachytherapy. Often, patients are willing to travel for that short course of vaginal radiation, but if they need to get combined external, they can usually get that locally. Yes, there's a disparity because obviously, patients aren't sometimes able or can afford travel, but at least it's not so onerous where they're having to come for six weeks worth of treatment. They often can just come three or four times to have their radiation treatments delivered to the high volume center. There certainly is a disparity there. I think we've tried to narrow it when we can.
[Dr. Amy Park]
This conversation is just making me think, I saw radiation oncology match was like, they go unfilled sometimes. I just wonder about the workforce there. We're in an anesthesia crunch right now. I just wonder, are we going to encounter radiation oncology workforce crunch? Are you guys seeing that? You're at big centers, but is this the topic of discussion?
[Dr. Amanda Fader]
I think that there's a workforce crunch across so many disciplines in medicine now, especially post pandemic. As we look at the number of patients that will be alive in 2030 and 2040 over the age of 65, as Matt mentioned earlier, we're going to see potentially a rise in several cancers, including a continued rise in endometrial cancer, unless we flip script.
ASCO, the American Society of Clinical Oncology performed a workforce analysis. I think it was over a decade ago now, to look at workforce challenges and geographic disparities across multiple oncology provider types and predicted a workforce shortage in the 2020s and 2030s based on the demographics of the aging cancer population. This is an issue for GYN oncologists, radiation oncologists, and multiple sub-specialists.
[Dr. Amy Park]
It seems like it's coming to the floor. We're already seeing that across multiple specialties. Urology has been tight for a long, long time, anesthesia. It's like COVID times, not enough people to staff the rooms.
[Dr. Amanda Fader]
If we really get back to the heart of this conversation, we're dealing with a preventable cancer here. If we can, again, educate more women and individuals in the community about the signs and symptoms of endometrial cancer and ensure that more providers, as Matt mentioned earlier, have just a quicker response time to assessing the endometrium and patients who may be at high risk for endometrial cancer, as well as addressing the overall obesity epidemic. It is really something we need to, I think, from a population health level, really commit resources to.
Right now, one of the issues is that endometrial cancer research is underfunded federally. When you look at the funding to lethality score for endometrial cancer compared to some other cancers, we're almost at the bottom of the list. My hope is that as we bring more attention to this issue on a policy level and advocacy level, that we'll see a greater number of efforts, both at the federal and foundational level to fund science and to fund initiative, public health initiatives that will help us address these issues so we can prevent more cases.
(9) Clinical Advances & Research in Endometrial Cancer Treatment
[Dr. Amy Park]
I'm just going to break it down. If patient has abnormal bleeding, post-menopausal for sure-- I know what I'm thinking, which is pap if you haven't had a recent pap, and then endometrial sampling and ultrasound are the top three things that I'm thinking of. Especially in the case of women with risk factors that you mentioned. Obesity, if they're African-American, have the hypertension, diabetes, and the pre-menopausal patient also with the risk factors and haven't responded, it's a little bit harder to rely in pelvic ultrasound because obviously the lining can be variable but have a low threshold to biopsy, and then increase in funding for research on this.
Matt, can you tell us a little bit more about your work with the clinical trials and what's on the horizon, what's currently available and what's on the horizon for endometrial cancer?
[Dr. Matthew Powell]
Yes. The last year has been quite exciting. We've had major steps forward. A lot of this came out of Hopkins with the use of immune checkpoint inhibition. Immunotherapy has really become a standard for patients with metastatic endometrial cancer. There's different types. There's four big molecular types of endometrial cancer. One of the larger one has a defective mismatch repair. These cancers are uniquely sensitive to immunotherapy, either by themselves or combined with chemotherapy.
Last March, we had two studies that came out using different checkpoint inhibitors, when combined with chemotherapy, dramatically improved the progression-free and overall survival for patients with really bad disease. They had recurrent disease that you could see on a scan or they had advanced stage disease. These are the worst of the worst and the fairly dramatic improvements with the use of immunotherapy.
It's not just the mismatch repair, but also the group that had P53 mutations seemed to be a benefit, and perhaps all of them had some benefit. The FDA is looking at the data currently and has approved the mismatch repair indication or MSII indication, but still looking at all the rest of that intervention. That's a big one. We also have learned to target the HER2 molecule. Just like in breast cancer, HER2 really was led by Dr. Fader, and I'll probably turn that over to her to let her talk to you about some of the excitement in that area.
[Dr. Amanda Fader]
Oh, thank you, Matt. Matt is incredibly humble and didn't mention that he was a leader in both of those international randomized control trials that he just spoke about that have revolutionized the approach to treatment of advanced and recurrent disease. We've identified that uterine cancer may be one of the last bastions of HER2 positive tumors and that HER2 positivity is more likely to occur in some of those poor prognostic non-endometrioid subtypes that we really want to help the patients in terms of improving their survival outcomes when diagnosed with these cancers.
This uterine serous and the uterine carcinoma sarcomas are among those that have up to a 20% to 30% to 40% rate of HER2 positivity. Several of us have been studying this question for some time and found in a randomized control trial that when added to conventional carbo-Taxol chemotherapy and patients especially with advanced stage disease treated in the upfront setting after hysterectomy, that the addition of an anti-HER2 monoclonal antibody, trastuzumab, otherwise known as Herceptin, to many, improved both progression-free or remission-based survival, as well as overall survival in that population.
That spawned, there's just been a revolution right now in novel drug development and now a novel class of drug called antibody drug conjugates that are more selective at targeting, delivering drug within the cells and to the cancer cells. There's a number of HER2, anti-HER2 antibody drug conjugates being developed that show great promise for treating this disease, including an antibody drug conjugate called Enhertu among others, known as trastuzumab deruxtecan that have shown really impressive response rates in patients with recurrent heavily pretreated HER2 positive uterine cancers, as well as other types of gynecologic cancers as well.
Molecular medicine is helping us realize the promise of cancer care for patients who previously had very few treatment options available to them. It is an exciting time. I will say, however, that these clinical innovations in care won't matter if access to treatment is undermined or if we don't understand the disparate incidents and types of cancer and responses to treatments in different populations.
It's really important in our clinical trials, a big focus at the National Cancer Institute and within our cooperative groups like the NRG Oncology and GOG Foundation are really ensuring that we're enrolling enough patients of ethnic racial diversity so we can best understand how different populations respond to these novel treatments and to conventional cancer treatments as well. That's going to hopefully allow us to further improve outcomes for all patients with these diseases.
[Dr. Amy Park]
That just sounds like such sophisticated molecular genetic profiles need to be performed on these pathology specimens, so another reason to go to a high volume center that can perform them. I don't know what an immune checkpoint inhibitor is. Can you just explain to me in layman's terms what this means?
[Dr. Matthew Powell]
Yes. You probably see them advertised on TV. You see Keytruda advertised. I often tell patients, well, do you remember when President Carter had his brain tumor? He received an immunotherapy for his malignant melanoma, and that took care of his brain tumor. That was one of the early success stories we had with these new class of drugs.
Basically, cancers can hide from our immune system by using certain molecules. Basically, the checkpoint inhibitors unmask the cancer so it's seen by the immune system and really has led to dramatic, not just a little bit of prolongation, but we are starting to use the cure word where we see patients that really were never cured before being cured with immunotherapies.
[Dr. Amy Park]
That's amazing. I cannot believe you said that some of these uterine cancers have a worse prognosis than ovarian. Ovarian has, for so long, been just this fatal killer. The fact that this is taking over just speaks to need for more study in this area. That is really fascinating. I find that very interesting. Then you give those adjunct immunotherapy and monoclonal antibodies, and then give the Taxol carbo and radiation or whatever else. Then it sounds like the progression-free survival and recurrence rates have decreased.
[Dr. Matthew Powell]
That's right. Even for one of the drugs we have mature overall survival data. It's making a big difference for these patients. We're actually using less radiation than we were in the past as well. Back when you're OB-GYN resident, you remember all the radiation complications that we dealt with on our service. A lot of that's disappearing as we're using much less radiation.
(10) Future Directions & Challenges in Endometrial Cancer Care
[Dr. Amy Park]
That's amazing. That's really cool. Where do you see us going in the future? Obviously, call for more research, more funding. What are some other things on the horizon that you foresee may be coming?
[Dr. Matthew Powell]
I think you really hit it. We're trying to personalize care, and that's through molecular-based medicine. The minimally invasive surgery I think has really been fairly standard now for most patients with endometrial cancer. We're able to get small incision surgery. It seems to be equally efficacious as far as how it treats the cancer. Patients are often able to go home the same day from their surgery. The minimally invasive surgery feels is quite standard of care now for patients with uterine cancers.
As far as what type of therapy to get, that's still this evolving factor. Whether you should have radiation, chemotherapy, or just watch carefully or undergo targeted therapy with immune therapy. All of those things are still in development and trying to decide what the best therapy is, is still being developed.
As Dr. Fader mentioned, utilizing HER2-directed therapies. We have some really active antibody drug conjugates now, which should really revolutionizing the way we treat these cancers. It's not just HER2, there's other targets that are being developed, and I think the future is bright. It's a really exciting time to be an oncologist because we're actually making a difference and we're going to turn the tide on this deadly cancer.
[Dr. Amanda Fader]
I love that answer, and I don't have anything further to add to the therapeutic approach and the diagnostic approach. I think that a lot of interest remains in the possibility of screening for endometrial cancer. We currently do not have an FDA-approved screening test. We have an organ that we could potentially sample for screening, unlike with some of the intra-abdominal, other intra-abdominal cancers.
However, as you mentioned, Amy, earlier, it's very invasive and uncomfortable to think about undergoing endometrial biopsies routinely, and then in whom would you do that? There's a lot of interest in research happening in that area about, is there a high-risk population? We know, for example, that patients with Lynch syndrome or those patients who have a genetic or inheritable risk for endometrial cancer and colon cancer are right now the only populations approved by national guidelines for screening after the age of 35 because of their higher overall population-based risk of cancer.
However, there are studies happening at centers like WashU, Hopkins, Mayo Clinic, where we're looking at novel approaches to potential screening that won't be as invasive. Using vaginal tampons to detect some of these molecular [Dr. Mark Hoffman]ers that we know are associated, these tumor driver mutations that may be associated or that are genetic signatures specifically for endometrial cancers. Using the PAP test and repurposing that, which is something colleagues of mine at Hopkins have looked at intensely. Then looking at things like cell-free tumor DNA in the bloodstream as another mechanism as well.
There's really exciting diagnostic research happening right now and potential screening research. It's too early to say if that's going to become prime time or not, but I think it's an important focus right now for us as well in terms of preventing and diagnosing early.
[Dr. Amy Park]
That's such a good point. If we can look at cell-free DNA to diagnose fetal or in utero conditions, genetic conditions, if we can-- I hear there's an endometriosis blood test in the pipeline. There's an ovarian cancer one that I heard about 10 years ago. Are we any closer on that or not really? Maybe a little closer?
[Dr. Matthew Powell]
Maybe a little closer and still not ready for prime time.
[Dr. Amy Park]
Not ready. Okay. Then I would be remiss if I didn't ask about AI. What's AI going to be doing for endometrial cancer or GYN onc? I know here at the clinic, we have this big push on targets and using this supercomputer, this IBM supercomputer to do a quantitative analysis and sort through all the targets. Is that something that's happening in GYN onc? I just don't know.
[Dr. Amanda Fader]
I think AI certainly has a lot of potential here and is being currently studied in diagnosis and staging through analysis of histological slides. We do use AI-based programs with robotic surgery, and there's a lot of research here being done in this arena. Matt, I don't know if you have anything you want to add to that.
[Dr. Matthew Powell]
I would say it's gotten complicated enough that we need the help of AI to help guide us with all the inputs. Dr. Fader and I do this for a living all day long, but the average practicing oncologist may not have that many patients with this problem. Allowing all that good information to get to the patient and really allow personalized care everywhere to narrow that world gap and things, I think that's where AI could really help us.
[Dr. Amy Park]
I just talked to one of my urologic oncology colleagues. We're at the Surgeon's Lounge. I love the Surgeon's Lounge because it's where all the things happen. Essentially, we were just talking about AI. We're raving about ChatGPT. Definitely use it for letters of rec, med student evals, all the things. People were raving about it at the boards in April. So many conversations about it. People are using it for residency application or fellow applications, high level stuff.
[Dr. Amanda Fader]
That's a great point. We're using it some at Hopkins for denial and insurance approval letters for novel therapies and other imaging denials and that sort of thing, which is a huge administrative burden for all physicians right now as you know. It particularly impacts patients or cancer care providers because of all of the tests that we order and the treatments that we utilize in our armamentarium. I think that's an excellent point. How can we ease the administrative burden, and more importantly, get care to patients that need it at the right time?
[Dr. Amy Park]
He was telling me that they used this LLaMA LLaMA, which is I guess the meta version to look at renal cancer specimens. It was really good at reading the past reports and looking at the size, so analyzing all this. It performed just as well as a human or predictive models or whatever. I'm just really curious how it's going to transform because it's real.
The other thing to know about these inputs, this is a side note, but I just have to mention it, is if you are nice and say please and thank you in the input, because it's made of all these other inputs, it's really sensitive to tone. You'll get better results if you're polite to your AI input. I'm just telling you this because I didn't know, but when you ask it, just put please in a nice way.
[Dr. Matthew Powell]
Great point. I would have not have known.
[laughter]
[Dr. Amy Park]
I know. Instead of do this, if you just say it in a nicer way, I guess AI will work for you better. Just like with a person. [laughs]
[Dr. Amanda Fader]
Kindness matters.
[Dr. Amy Park]
Even with your AI machine. Anyway, I just wanted to see if there's any other parting thoughts or wisdom that you want to pass on to our listeners because I just find this so fascinating. This is mind blowing how much things have changed over the course of my career. I love it. It's amazing, but it's also bad because it's getting better for ovarian cancer, getting worse for endometrials. I have hope because you guys are on the case. It sounds like there's a lot of things in the pipeline. What are your thoughts?
[Dr. Matthew Powell]
Yes, I think you're right on target that there is reason for hope. I think we're actually looking at some of the GLP-1 medications to see if we can counteract hyperplasia with that. You're already seeing these headlines, oh, baby's born because of Ozempic. We were reversing some of the abnormal hormone milieu that these patients will have with these new drug. If we can attack the obesity epidemic, if we can attack the hormonal imbalance, I think we can make a difference in women's lives and with endometrial cancer. Screening, patient awareness, physician awareness, all are very key.
[Dr. Amanda Fader]
I agree wholeheartedly. I don't know that I have anything to add to that. I think that weight is the fifth vital sign and paying attention to that. If we don't have time in our practices or the expertise to make sure patients are getting referrals for nutritional and obesity, weight counseling, we know bariatric surgery and these newer class of drugs are helping patients significantly. Consider progestin-containing IUDs in high-risk women or patients with symptoms that don't-- and we use that in some cases to treat endometrial cancer in patients when they're appropriate and desire fertility.
We all have to do this together. This has to be a collective action here to reverse these public health trends and just very privileged to be part of this movement.
[Dr. Amy Park]
Thank you so much for sharing your expertise and insight on this topic. I think it's really timely and I know our listeners are going to get a lot out of it. Thank you so much for coming today. We really appreciate it.
Podcast Contributors
Dr. Amanda Fader
Dr. Amanda Fader is a professor of gynecology, obstetrics and oncology and a gynecologic oncologist with Johns Hopkins Medicine in Baltimore, Maryland.
Dr. Matthew Powell
Dr. Matthew Powell is a professor of obstetrics and gynecology and a gynecologic oncologist with Washington University in St. Louis, Missouri.
Dr. Amy Park
Dr. Amy Park is the Section Head of Female Pelvic Medicine & Reconstructive Surgery at the Cleveland Clinic, and a co-host of the BackTable OBGYN Podcast.
Cite This Podcast
BackTable, LLC (Producer). (2024, June 25). Ep. 58 – Understanding Rising Endometrial Cancer Rates [Audio podcast]. Retrieved from https://www.backtable.com
Disclaimer: The Materials available on BackTable.com are for informational and educational purposes only and are not a substitute for the professional judgment of a healthcare professional in diagnosing and treating patients. The opinions expressed by participants of the BackTable Podcast belong solely to the participants, and do not necessarily reflect the views of BackTable.
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