From Prediction to Prevention: Rethinking Endometrial Cancer Risk

New episode alert! 🎙️

How can we move beyond BMI to better understand endometrial cancer risk? In this episode, Dr. Aline Talhouk and Dr. Andrea Neilson discuss the RESTORE study and the use of the Progesterone Challenge Test (PCT) as a functional way to assess hormonal activity in the endometrium — and identify who may truly be at higher biological risk.

We talk through the study design, as well as early findings showing strong feasibility and participant engagement. The conversation also explores how this approach could support more targeted prevention strategies moving forward.

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Transcript

00:00:02 Intro 

Thanks for listening to the GOSH Podcast, the Gynecologic Oncology Sharing Hub. We share real, evidence-based discussions on gynecologic cancers featuring stories from patients, survivors, researchers, and clinicians. Our podcast is produced and recorded on traditional unceded territories of the Musqueam, Squamish, and Tsleil-Waututh Nations. It is produced by the Gynecologic Cancer Initiative, a BC-wide effort to advance research and care for gynecologic cancers. 

00:00:35 Sabrina 

Hello, everyone, and welcome back to another episode of the GOSH Podcast. My name is Sabrina, and today I am joined by Dr. Aline Talhouk and Dr. Andrea Neilson, who are collaborating on an innovative project, rethinking how we assess risk and prevention in endometrial cancer. Dr. Talhouk is an assistant professor in the Department of Obstetrics and Gynecology at the University of British Columbia and the Director of Data Science and Informatics at OvCare, BC's ovarian and gynecologic cancer research program. With a PhD in statistics from UBC, her work focuses on predictive modeling and computational approaches to improve patient care across the cancer continuum, with particular attention to ethics, data sharing, and the impact of AI in women's health. Dr. Neilson is a gynecologic oncologist and clinical assistant professor with Vancouver Coastal Health and BC Cancer. She completed her medical training at the University of Alberta and her fellowship in gynecologic oncology at UBC. Her research focuses on translational strategies in endometrial and cervical cancer, including the development of new early detection and prevention approaches. Together, their work bridges clinical care and data science to explore new functional ways of understanding endometrial cancer risk. Welcome to the podcast, Dr. Talhouk and Dr. Neilson. 

00:02:04 Andrea 

Thank you. 

00:02:05 Aline 

Thank you. 

00:02:06 Sabrine 

To start us off, could you tell us a bit about the project that you are collaborating on and what initially brought the two of you together around this idea? 

00:02:15 Andrea 

So the project we're speaking about specifically today is the RESTORE study. And this is a study mainly about identification of patients at risk and prevention of endometrial cancer. So endometrial cancer is the most common gynecologic cancer in high-income countries. And the incidence has been steadily increasing, but also the immortality from endometrial cancer has been steadily increasing. And so many or most of the cases of endometrial cancer are hormone-driven, driven by prolonged estrogen exposure, which can stimulate the growth of the endometrium inappropriately in someone who has gone through menopause. And without opposing progesterone, which matures the endometrium and eventually allows the endometrium to shed, then mutations or cancer drivers can accumulate and then a cancer can form. And currently, the way we diagnose endometrial cancer is by a biopsy of the lining of the uterus, which is an office-based procedure, but is very uncomfortable and can feel very invasive to patients. Importantly, we are waiting for symptoms of cancer to be found before we are biopsying. There hasn't been any benefit shown to biopsy-ing patients that are not symptomatic most diagnoses occur after bleeding, which is what we're looking for. However, we have not been successful to date at finding a current useful screening or prevention strategy, which would target the asymptomatic person. So RESTORE has been geared towards looking at the feasibility of a method for further screening patients to target for potentially biopsies or other ways of detecting endometrial cancer. 

00:04:11 Aline 

And to add to that as well is that because a lot of the endometrial cancers are obesity associated, there are a lot of modifiable risk factors. And so preventions can be targeted to people that are at high risk. And we know that there are a lot of preventions that are effective, for example, you know, weight loss strategies or progestin-based hormone therapies. However, finding the people who are likely to benefit from these, doing those at the population level would not be feasible. So finding the people that are likely to benefit from these would be really important. And so even though obesity is the most important risk factor, just using obesity alone, like for example, by looking at body mass index, for example, which is one measure that we use for obesity, on its own, it's not enough because a lot of people that have obesity don't have endometrial cancer. And so we need to look at things that would be more individualized to the person and what's happening with them. So BMI is a great measure at the population level to assess risk factors, but it's not really ideal to be used at the individual level. 

00:05:28 Sabrina 

Okay, yeah. I think BMI often dominates the conversation when we talk about endometrial cancer risk. But what do you think it fails to capture about what's actually biologically happening in the endometrium? 

00:05:40 Andrea 

We do know that in patients who have gone through menopause previously, who should generally have low estrogen levels, having increased volume of fat cells can increase the conversion of steroid hormones like androgens into estrogens. But what we don't know is, you know, how to pick out the patients like Dr. Talhouk was saying that that's really happening. So we know that it happens, but we don't know who that happens in. And BMI is purely a ratio of high in weight, it doesn't tell us about the body makeup of a person and it doesn't talk about the, or it doesn't tell us any information about the hormonal environment that person has or that uterine lining is exposed to. 

00:06:32 Aline 

That for us is what raised the question, like, can we combine BMI with other biological signals that would help us to better identify who is more at risk for endometrial cancer and help direct those prevention strategies to that group? 

00:06:51 Sabrina 

Okay, and I think that leads us into our next topic. So for listeners who might not be familiar, can you explain what the progesterone challenge test actually involves and what a positive versus negative test can tell you biologically? 

00:07:05 Andrea 

Absolutely. So the progesterone challenge test has been used for decades in gynecology. It's most often As I was brought through training and in the early years of my career, it was often used as an evaluation for patients who were in their reproductive years but were not having periods. So perhaps patients that were being evaluated for PCOS or for reasons that they weren't having their cycles. And what it is, is a 10-day short course of progestin-based therapy. So there are a couple of different medications we can use and we administer it. And the idea behind it is if there is a hormonally primed or estrogen primed lining of the uterus or endometrium, the progesterone that we administer orally will then mature the lining of the uterus. And then the discontinuation of the progesterone mimics what happens in a normal cycle and the lining can then shed. So a positive progesterone challenge test is one where there is bleeding during or after that short course of progesterone, meaning that the lining was already primed by estrogen, it matured, and then it fell away when the progesterone levels dropped. And so a negative progesterone challenge test would be one where there was not bleeding, indicating that the endometrium is not able to respond to the progesterone, either because there was no estrogen around or because the lining is not functional for some reason. In this case, we're using it slightly differently. The mechanism is the same, but we are using it to detect a lining that is estrogen primed, but in this case is inappropriate for the age and reproductive stage of the patient. If a person has a hormonally primed endometrium at the age of 60, we administer a progesterone challenge test. There's maturation and then a bleed event or the positive progesterone challenge test, we would consider that to be somebody who potentially is at increased risk of endometrial cancer because they have levels of estrogen around that are causing changes in the lining of the uterus inappropriately. 

00:09:28 Aline 

I will add to that, the progesterone challenge test obviously is not new in gynecology, but it's also not new in the context of endometrial cancer. It has been explored in the 80s and 90s as a possible diagnostic signal. And so at the time, the researchers were asking the question is, if there is a bleed after a progesterone test or a progesterone withdrawal, that could potentially help identify underlying pathology. However, as transvaginal ultrasounds became more widely used, attention shifted from this hormone-based test, which still takes significant time to administer, right? The person would have to be exposed to the estrogen for some number of days and then monitor for withdrawal bleeding. So the field kind of moved, shifted towards more imaging-based evaluation, which were faster. So, you know, with ultrasounds, they offer quick, non-invasive ways to assess the endometrium, particularly in patients with symptoms. So, as a result, the PCT largely fell out of favor as a diagnostic approach, but it was never really explored as a tool for risk stratification in order to help guide prevention strategies in asymptomatic individuals. 

00:10:52 Sabrina 

Very interesting. So I think you've given us a good idea of how you are implementing the PCT test in asymptomatic post-menopausal individuals. What other data are you collecting alongside this test? 

00:11:05 Aline 

So yeah, so that's kind of the PCT is definitely the premise of the RESTORE study. So the RESTORE study is a prospective feasibility study around risk-stratified prevention. So it begins with identifying a high-risk group. So we are defining that high-risk group using BMI. And then participants will then undergo the PCT, and then everyone at the end who is positive on PCT receives the lifestyle intervention. And then PCT positive participants also underwent further clinical evaluation via biopsy, which that would be standard of care for anyone who experiences that type of post-PCT bleeding. And so, in addition to, we wanted to capture additional biological signals along, you know, along this process just to make sure to find correlates to the PCT or maybe other features that could help us further stratify risk. And so we looked at collecting vaginal swabs and looking at genetic signals and other markers that might help us understand what is really happening in the endometrium. So, this would help us begin to build a more complete biological picture rather than relying on a single measurement. And I will say that the way we designed the study, we focused particularly on equity, recruitment, and optimizing clinical flow. Maybe Andrea could talk a little bit about that. 

00:12:56 Andrea 

Certainly. Yeah, so we really did try to reach as many patients from as many backgrounds in BC as we could. And to do that, we decentralized our recruitment and formed community partnerships with primary care to allow the most diverse groups of patients to access our study. And this was because importance of equity and accessibility to the study was really important to us. And this allowed us to really operationalize our study in a real clinical environment, meaning that we, the patients, once they, or the participants, pardon me, expressed interest in our study and consented, we did reach out to their primary care providers. And in the instances where patients didn't have primary care providers, we actually connected them with a gynecologist in their community. And we had to get buy-in from our gynecology colleagues and our primary care colleagues to provide this progestin prescription for the patients and evaluate them, help us evaluate these patients for any reasons that they may not be able to take the progestin. So this allowed us to really have conversations with gynecologists, patients, and primary care providers across BC both during and after the study about how they felt about the need for this study, how they felt about the progestin and administration, and really the feasibility and acceptability measures were gathered throughout the study and then after more formally in studies as well. 

00:14:44 Sabrina 

Very interesting. So it sounds like a super fruitful study. What have you guys found so far? And was there anything surprising that you've found in your findings? 

00:14:56 Andrea 

So we should be clear from the outside that RESTORE was really a proof-of-concept study, meaning we wanted to make sure that this was something that we could implement on a larger scale to see if it was actually a meaningful signal within this. So we combined recruitment testing, intervention, and biological sampling to do this. What we have observed is that the RESTORE protocol is feasible, meaning that it can be implemented and it is acceptable, meaning both primary care providers, gynecologists, and of course, most importantly, the participants themselves found our intervention reasonable to undergo and the side effects associated with any medications and the swabbing and everything else that was required were acceptable to patients. We did collect a lot of qualitative information on the patient experience of the protocol as well. But ultimately, we had wide acceptance of the lifestyle intervention component and adherence as well. Key findings of RESTORE are that greater than 95% of patients completed the progestin course once they had started it and a high proportion of them found the medication both acceptable in terms of side effects and they found the study itself very valuable in terms of the information it provides or is intended to provide. 

00:16:29 Aline 

And I'll add to that, with the lifestyle intervention that we proposed, so this was a six-week program with sessions, one-on-one sessions with a health coach. They had to come in and have a session where the coach would explain to them a certain topic and would assign certain tasks for them to do. And that would help them to, again, reduce body weight and get them into a more active lifestyle. And there was a lot of acceptance and adherence as well to the lifestyle intervention and all the participants were very willing to engage with it. We are currently preparing a separate paper focused on that component. In addition to, we've also started looking at some of the additional biological data. As I mentioned, we've collected vaginal swabs and other biological samples that we've started analyzing. And again, a lot of these additional analyses are ongoing. And we're looking at, for example, the microbiome signal, which we found some interesting finding associated with PCT positive participants. And we're currently preparing a separate manuscript about that as well. The one thing I would say, though, is that despite our efforts to try to be as inclusive as possible and to make the study available to everyone throughout British Columbia, we still did not meet the inclusivity criteria that we had set out for ourselves. We did a lot better than most studies out there because we've included rural participants and participants from different ethnic backgrounds. However, we still don't have the right level of representation, which really signals that we still have a lot of work to do in order to engage and make sure that everybody is included in research studies to make sure that all of the findings that are coming out of the research studies are generalizable more broadly. 

00:18:33 Sabrina 

Absolutely. Well, it sounds like you guys tried very hard and we can always learn from all of the findings of the study, including who you are able to reach as participants. So based on your findings, how could integrating the progesterone challenge test into risk stratification change the way that we think about prevention? 

00:18:54 Andrea 

With the caveat that we have to say that all that we have shown so far is that the progesterone challenge test is feasible and acceptable to participants. If this bears out as something that we really can use to risk stratify people, this would be something that can really change the face of prevention. So as we mentioned at the beginning of the podcast, A majority of endometrial cancers can be prevented because they're hormonally driven, and we have the means to prevent them with progestins, either oral or by use of an IUD that has progesterone in it. Also, weight loss strategies can also be helpful, and this has all been demonstrated and borne out in studies. The challenge is that we don't know who is going to benefit the most by this, and There is both a cost to patients in terms of their time and any negative side effects or outcomes they might have from these interventions. And there's a cost to the system and society to apply them. And so if we can further risk stratify people reliably, we can apply prevention measures. And of course, the goal would be a healthier, happier population, but also lower upfront health costs to system and to our country as a whole, because any prevention strategy is always something that's less expensive to treat, both in terms of out-of-pocket costs for patients and also system costs than it ever cost to treat a cancer. 

00:20:36 Andrea 

And just to kind of go back and reiterate that this was really a proof of concept study, and it still requires some validation. So we've shown that with Restore, the PCT is feasible and acceptable, as well as participants who are willing to provide additional vaginal swabs and specimen. But all of this does not prove predictive value just yet. So we still need larger studies to see if the signal that we saw in Restore will really correlate with future risk. And as you could imagine, prevention studies will take years before, you have to wait, do something now, and then you have to wait 10, 15 years before you see the impact on cancer incidence, which is what we're trying. We ultimately were trying to reduce incidence, but also reduce mortality and adverse outcomes from this disease. And so it may take years before we're able to find that. And with this, you know, our endpoint occurring so much longer after our initial intervention, you know, we need to come up with creative ways to basically try to monitor how effective the study is. So designing these types of prevention studies effectiveness is very interesting because it would require us to develop surrogate biomarkers that would tell us whether or not, you know, we are on track or in order to prevent incidence and reduce mortality from this cancer. And that's what we're focusing on in the next phase. 

00:22:18 Sabrina 

Okay. So you've mentioned a couple of things you're working on next there, but do you have any immediate next steps that you want to share to move this from a proof of concept study towards something that could realistically be used in clinical practice? 

00:22:34 Aline 

Definitely. So we've started already planning the next phase validation study, which is going to be a larger, definitely a larger study. We are applying the PCT more broadly, so we are collaborating with other provinces as well. So we don't want to focus only on BC. And we are trying to integrate the molecular correlates to ensure that we're really able to define certain endpoints that are more reasonably evaluated within the study time period. 

00:23:07 Andrea 

Yeah, and we should highlight that collaborating with other provinces is imperative because the larger data set is what's going to really help us to drive the numbers that we need to prove validation and not to ignore the equity and inclusivity aspect, which is that there are different populations across Canada. And so if we focus only on one geographic area, then we won't meet our own targets of being able to provide a solution that will work for Canadian women broadly. 

00:23:42 Aline 

And I think having this larger study, we could demonstrate not only the effectiveness of the intervention, but also potentially get enough data for cost-effectiveness calculations, which then would allow us to start, well, to begin to... make recommendations for clinical processes. But it's very important until this is evaluated and long-term study monitoring, it's very important that we keep track of everyone that's received the intervention as part of our studies that has been directed by the PCT. So we really think like this could be a great opportunity for a registry-based trial that would link with administrative data for long-term outcomes monitoring and follow-up. 

00:24:31 Sabrina 

Fantastic. Well, it sounds like you guys already have lots of things in the pipeline, and I'm sure our listeners will want to check in a couple of years to see what your eventual findings are. Thank you so much for joining us on the podcast today. 

00:24:45 Aline 

Thank you very much for having us. 

00:24:47 Andrea 

Thank you so much. 

00:24:50 Outro 

Thanks for joining us on the GOSH Podcast. To learn more about the Gynecologic Cancer Initiative and our podcast, make sure to check out our website at gynaecancerinitiative.ca.