EFA’s Sixth Annual Medical Conference: Ending Endometriosis Starts at the Beginning
Thank you Dr. Seckin. What a great morning this has been and it is such an honor to be here with Deborah Bush and Robert Taylor who have always pushed me to be my best self and always teach me something every time I am with them. Thank you.
Is anyone doing anything about endometriosis? And of course the answer is yes. One of the key questions that we have already addressed a little bit that we are thinking of scientifically is what even is endometriosis? You all have seen the pictures, you all know from your own experiences that it looks different in different women. It presents with different symptoms, it has different responses to treatment. It has different long term and short term consequences. We do not understand the root of any of these differences. But we know that they must be important, particularly for considering development of diagnostics and treatments. We know that the appearance of the disease that we focus on that is basis for the staging system entirely does not correlate with pelvic pain, which is the primary, by far the primary presenting symptom.
Again, sort of being redundant from what we have already heard today we know that in the vernacular of our staging system this is mild versus severe disease with a frozen pelvis but this does not correlate with the pain experience. The woman who presents or girl who presents with mild disease has anything but a mild experience.
I want to draw some of our excitement in the current research world from really revolutionary developments in cancer research. I want to reiterate from what Dr. Taylor’s answer was that I am not invoking this example because endometriosis is a cancer but it has some similarities. Billions of dollars and hundreds of thousands of research participants have contributed particularly to breast cancer research. It is a wonderful time for endometriosis because we can capitalize on that knowledge and really, with much less time and development, learn very important elements.
The revolution in breast cancer for example has been that there are very critical sub-types of the disease. They are now very specifically defined and they are defined by molecular markers of the tumors themselves. These graphs show, on the left is the time to metastasize and on the right is survival. The different colored lines are four different sub-types of breast cancer. The faster the line goes down the worse the prognosis of the disease is the sooner there is metastasize or death. As you can see there are very significant differences.
These being fairly simplistic start with estrogen receptors status. We do testing on the breast cancer tumor itself, determine what the estrogen receptor status is, then these break down into further groups. As you can see along the bottom there is a difference by the prevalence of these different sub-types. The majority of what we focused on unknowingly in breast cancer research was originally estrogen receptor positive tumors. They are, by far, the most prevalent and we thought breast cancer was one disease and all of the discovery approached it as one disease. But in fact there are many sub-types of breast cancer and the estrogen receptor negative disease is now where a lot of the focus is. Partly, a lot of the focus is there and I think this will be very difficult to see in the back, is that the estrogen receptor negative disease behaves differently. It does not respond to our current treatments and it has several other hallmarks. So the importance for endometriosis is right now all of our research lumps endometriosis together as one entity. So, some of the difficulty in advancing discovery may be that we are lumping together several sub-types that actually have different hallmarks and respond differently.
How do we start to tackle this question? Well, we need large numbers. Breast cancer took hundreds of thousands of participants. We are getting there with endometriosis but we are really in the early stages of that development. The average study is about 100 participants. That is not large enough to tease out some of what may be important differences. Often our conclusions are that when we find something that is interesting or encouraging more and more detailed and larger study needs to be done.
What are we doing? Well, we began the World Endometriosis Research Foundation EPHect project: Endometriosis Phenome and Biobanking Harmonization Project. The goal and mission of this project is that as scientists we know that large data, a lot of information answers questions more clearly and readily. So the whole goal of EPHect is to facilitate these large, multi-center collaborative projects that can be done and initiated by groups of investigators with lots of different populations, with lots of different characteristics from across the globe and start to tease out some of these potentially very important details.
One thing that has been really exceptionally gratifying is that the contributions to this project have been international and very large. I lead this effort with Krina Zondervan from Oxford and I have just highlighted here just here presenting in this conference Lone Hummelshøj, Asgi Fazleabas and, EFA also played a major role with Dr. Seckin and Peter Gregersen who is their senior scientist. I will talk about that a little bit in a moment.
What actions are we taking? Well, to be able to combine studies and have lots and lots of participants you need to have standard data collection tools and you need to be collecting samples and information from patients in a uniform way. If Dr. Taylor wanted to do some testing of some of the alternative medicine discoveries that he is making and test with five centers across the globe as a starting study he could contact those centers and he will know exactly the information that they are collecting.
Collaboration is the key. This is true of every scientific entity and we are really seeing exceptional improvements for endometriosis in this realm.
We began this effort with a small group of planners who had already had experience with relatively moderate sized studies of endometriosis. We met in Orlando and spent two days talking about what kind of data had to be collected, what uniform methods were and what needed to be developed. We then had a larger meeting that finalized what we had months of development of drafts of what these uniform tools should be and then met again. You can see us all sitting around. There were also many participants who were included via Skype and on conference calls; it really was a fantastic meeting. That resulted, again, in a lot of collaborative work that ultimately had four publications just this past fall. These publications focused on surgical data collection, clinical, fluid samples, and I will explain what I mean by that, and tissue samples, all with standardized protocols.
For the surgical form each surgeon is asked to record very kind of agnostically defined information; so prior imaging, the procedures that were conducted during that surgery, what the pelvis looked like at the end of the surgery, if there were any operative complications, the pathology that was observed, whether there is deep infiltrating endometriosis and its locations. That currently is not information that is part of our staging system, whether there is ovarian involvement, endometriomas, endometriotic nodules, their location and sizes; and then also a lot more detail about those superficial peritoneal lesions, the lesions that you have most been seeing in the pictures today and more detail about where they are and what information we can glean. We are also collecting digital image records of all of the lesions.
On the clinical side this is where a lot of my past research has focused. We do a lot of studies where we collect questionnaire based and medical record information from large numbers of participants. We developed a standard self-administered questionnaire. We have also developed at our site and we are working on expanding to other sites a web-based self-entry so that this questionnaire, despite being fairly lengthy, takes our participants on average about 30 to 40 minutes to complete. It is a one-time baseline questionnaire. We are also prioritizing that for translation into other languages.
The questionnaire includes menstrual history and hormones, pregnancy and other obstetrical history, a lot of detail about pain, one thing that has nothing to do with our current staging system is the symptoms that the patients present with. We know that to be very important but it is actually a difficult detail to collect. There is such a variety of experience of pain. What I mean by lifecourse is did your pain start before your first period, did it start at your first period, have there been times in your life when it has worsened or improved? We are also collecting information about coping mechanisms and as Deb was explaining those pain switches to try to get at some of that information. Then general medical, demographic information and some lifestyle information like diet, smoking and exercise and those things that we believe to be important. We have some important evidence but now need more robust studies.
The fluid samples were encouraging as many centers as are able to to start to create repositories of samples that can be used again for future discovery – blood and urine and saliva. At our center we primarily collect blood during a collection that is already happening at a clinical visit. Urine and saliva are fairly easy to collect. Then during the surgery we are collecting peritoneal fluid. There are also some sites that are collecting endometrial fluid and menstrual effluent, which I will talk about in just a little bit more detail.
Then for the tissue we are collecting and storing either flash freezing or fixing endometriosis lesions. Some sites are collecting endometrium. There is a very large bank at the University of California, San Francisco that Linda Giudice’s group leads. Some groups are collecting myometrium and peritoneum. So the key is we will all have a sense of who is collecting what where and how this information can ultimately be combined.
Next steps: science is constantly developing and emerging so we have a regular schedule for feedback and modifying these protocols. We want to expand to as many languages as is feasible.
And then last, a center such as mine that already has an established research infrastructure has a fairly, I will not say easy, but a straightforward path to implementing these questionnaires and sample collection and storage. But that is not true of most places and so we are working with WERF (World Endometriosis Research Foundation) to develop tools such as the web-based questionnaire collection and software for maintaining freezer files for the samples that you have stored. Software for tracking participants over time and making those, again, freely available, downloaded from the WERF website.
I am so excited, this is really the first opportunity that we have had following these publications to really highlight the centers that are already off and running. We know that there are many more than these. I am just going to highlight the ones that I have had some involvement directly or have knowledge of. We have to start with the Rose study, Research Outsmarts Endometriosis, which I think is in the history of the world the best title for a research project. It is, of course, funded by the Endometriosis Foundation of America. It is led by Dr. Peter Gregersen. These are actually his slides. You will hear a lot more about the Rose study throughout the three days of this conference. But just briefly, the main roles are to develop early diagnostics for endometriosis, to comprehensively define the genetic components underlying the disease and to develop new assays. They are actually developing new assays that could apply to endometriosis but also can be contributions to the scientific world in general and mouse models for future testing.
Breaking those down a little bit – one thing that they have embraced wonderfully through their leadership in the EPHect project and decades of collaborate spirit is that collaboration is key, which really is the critical message today. Dr. Gregesen and his team are continuing to pull together and broaden research contributors. They are again working on this development of the early diagnostics looking at changes in genetic factors and utility combining diagnostics. Their primary research focus now is on menstrual effluents. They have participants using a Diva cup, collecting some of their menstrual fluid and that is where the point of testing, it is a very fantastic approach and successful for a non-invasive diagnostic. They are defining those genetic components. The key about genetics, and I will go into this in detail a little more in a moment, is that it needs large sample sizes, again, combining with known genetic repositories in research groups across the country.
And then these new, non-surgical approaches to disease prevention therapy really takes engaging scientists, you will hear a little bit from Linda Griffith at this conference as well, scientists who have expertise in some of these assay and other methods development but have not until recently been focused on endometriosis.
Then we in Boston launched through a gift from the Hatch family, in the center is Emily Hatch, who is a patient of Dr. Marc Laufer. She happens to be the granddaughter of Dick Marriott and she has very courageously been very public about her struggles with endometriosis. Through some initial funding from, very generous, from their foundation we launched the Boston Center for Endometriosis. Initially the patients primarily came from Dr. Marc Laufer but we have expanded to Brigham and Women’s Hospital as well for adult patients. I am the scientific director. We are enrolling patients as young as age seven. I had heard a comment earlier about someone menstruating at age nine, currently our youngest enrolled girl is nine years old. We are welcoming all patients who have had a surgical diagnosis.
We are also welcoming if you are going to study endometriosis you have to be able to compare them to girls and women without endometriosis. So we are also enrolling patients and staff through Craig’s List and local colleges with what we refer to as control participants. We have a plethora of information we are collecting; questionnaires, food frequency questionnaire with a method of collecting diet information the details that I explained to you. And then we are following our participants forward for years, essentially indefinitely. We have now built a large repository with lots of different sample types. We are also collecting questionnaires with questions about the different hygiene products they are using and medications trying to get at some future work potentially around environmental contaminants and exposures.
Here is just an image from one of our freezer rooms. Here is one of our team members aliquoting samples.
Today we have already in the two years since our launch enrolled 645 patients from Boston Children’s Hospital. At Boston Children’s Hospital they can be seen up until their early 20s and then at Brigham and Women’s Hospital. One important thing is we have a much smaller proportion of girls and women without endometriosis so as you are thinking of the importance of is anybody doing anything for endometriosis it is not just about those directly suffering with disease but about those who care for them and are concerned about them also participating.
Just to give you a sense of the numbers. We have hundreds now of questionnaire based data and samples that we are already sharing and collaborating with other groups. Our research assistants have attended more than 300 surgeries collecting samples there and detailed data. And we have about 200 participants now who we have a second year of follow up and samples. So those girls who had surgery in that interim, or who changed their medication or changed their diet, or began exercising we will have long term information about what is happening to them next. Our goal is to be able to follow particularly the teens that we have enrolled well into their 20s and 30s and we will have a sense of who did have a risk of fertility issues, who had interventions early on that did seem to make a difference.
We have also launched the SAGE trials, Supplementation in Adolescent Girls with Endometriosis. This is right now a very small pilot. We have now enrolled 50 participants. Jamie Nadler, who is one of our senior reproductive endocrinology fellows is leading this project. These girls who have had…capitalizing a little bit on one of Deborah’s comments earlier that the expectation is not that a diet supplement is going to be the cure for the disease or the symptoms. These are girls who have been surgically treated, most of them have had some form of hormonal therapy and are still struggling with their pain. The goal of this is to tease out if in addition to standard well-proven therapies these girls can have an extra benefit by some of these dietary changes.
I want to highlight another group leading work which is the Oxford Care and Research Centre led by Krina Zondervan and Christian Becker. One of their main focus is in genetics, I know there was a question about that earlier. Currently the large scale advanced study of genetics is the Genome-Wide Association study. Instead of targeting individual genes about which we have a strong hypothesis this is a more agnostic approach where you genotype hundreds of thousands of common genes to try to see what correlates with diseases or other outcomes. It takes a large number of people and that is one of the critical things of collaboration.
The very first study was published from a Japanese group. We then followed on in our collaboration with Dr. Zondervan at Oxford and Grant Montgomery in Australia. These findings then have been replicated in studies from Utah, Belgium and Italy. And really the result is that we have nine genetic loci that have been very consistent, which honestly the consistency is a surprise to us given how diverse we believe the disease to be.
I want to focus from a question earlier about heritability. This column is heritability of these diseases. Heritability is based mainly on calculations from twin studies. For example, Crohn’s disease is more inheritable than endometriosis but endometriosis falls higher than breast cancer or type II diabetes. BUT, a really important take home message is this column: this is given what we have discovered, so for Crohn’s disease there are 140 genes that have been robustly confirmed, for endometriosis there are nine. This shows you the proportion of the disease variation the proportion of sort of cause, to invoke that term, that can be explained by these genes. For complex diseases it is just very small. A maximum of 20 percent for Crohn’s disease and in endometriosis, even though we are having this great, consistent success, it is only explaining three percent-ish of the disease.
What is the importance of this genetic testing? Well, it gives us insight into etiology. It can give us insight into some of these subgroups potentially. It can give us insight into some of the findings such as…research primarily, like lean, thin women having a higher risk, what might be some of the underlying cause there. But, as a clinical diagnostic, that is not going to be the ultimate result of the study. We just explain way too little with genomic information. BUT, this might give us hints ultimately of girls and women who could be prioritized for screening and treatment.
Coming back to the general problem, this is a slide kindly shared by Linda Giudice. We know that this is an important issue. We know that the quality of life impacts, and the burdens are similar to many much better known much better funded diseases, diabetes, rheumatoid arthritis, and we know that the estimated costs are huge for endometriosis.
Now I want to come back to this slide for a moment to show in the far column this is the number of participants and the data that we have been able to combine for breast cancer research for genetics and the number that we have been able to combine for endometriosis, much, much smaller despite a much higher prevalence of the disease. One of the critical issues around this is funding and participation.
This shows the currently 215 clinical trials registered for endometriosis around the globe. As you can see, in some regions of the world there is very little clinical trial support and funding. This compared to rheumatory arthritis that is about seven times as large around the world and yet in terms of quality of life and cost impact it is very similar to endometriosis. And some of this comes from a funding issue.
This slide was kindly shared with me from Linda Guidice who received information from Lou Depaolo at the NIH. This is the extramural funding from NICHD. That is the Eunice Kennedy Shriver National Institute of Child Health and Human Development. That is the institute within the National Institutes of Health in the US that primarily fund women’s reproductive health research. As you can see it has waned a little bit but in general it is topping out at about $10,000,000 per year with an overall budget for this institute of almost $900,000,000 per year.
Also, in general, the funding for public health research has been decreasing. On the left is NIH which has decreased by 10 percent in the last four years, CDC by 15 percent and here are some other government funded agencies. This has a direct, very important, impact. And it does not only have an impact on our ability to do research this week or next week or even next year, it has a huge impact in our being able to encourage our best young scientists, our best young clinicians to enter into this field and continue in research and discovery.
Despite some of these stumbling points the good take home news is that many of us, a lot of us, are working very hard. This is a graph of the publications specific to endometriosis, we are at about almost 30,000 publications to date. It has done nothing but increase over the past years. There is really a dedicated core who are very focused despite difficulties in this field, and also who are working very hard to encourage the next generation of scientists into this discovery. These publications really span the globe. The US is at the top but also the United Kingdom, Japan, Brazil, Italy, Australia, New Zealand and there are a lot of international contributions to this effort. There is a lot going on for endometriosis.
What can you do? You can reinforce that killer cramps are not normal and you can reinforce that discussing female reproductive health is normal. That girls should not have to feel like they have to say they have a migraine instead of discussing with their family, with their friends, what is really happening in their lives. You need to demand from government representatives increase in medical research funding. Citizens contacting their governmental representatives does make a difference and that is internationally a huge issue for science in general. It is true for every area of medical discovery, especially reproductive health. Keep in mind that science is not a straight path. When there is more funding in general there are discoveries made in other fields that then can apply to our own specific focus on endometriosis.
We also have to be continuing to prioritize S.T.E.M. education, Science, Technology, Engineering and Mathematics. We are dreaming out the brilliant potential new scientists and clinicians and those discovering what we need for the next generation. That is absolutely critical. You and your loved ones and your families and your friends can contribute to medical research in many ways; with your money, with your time and as participants. Each one of you has a unique characteristic, unique samples, unique information to contribute whether you have endometriosis or not. I very much encourage you that if given the opportunity to participate in research studies to please take advantage of it.
This is the end of National Public Health Week. There is a lot of great information at the nphw.org website about national funding and the importance of health research.
Then I just close with thanking the WERF EPHect community, the Rose study, the Oxford team and our team in Boston. And I truly have – it has been an exceptional last two to three years and this is just the start of huge advancements for our field.