The MiDe Study’s Approach to Predict, Prevent and Detect Ovarian Cancer

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a Medical Oncologist, Director of International Programs for the Cancer Institute and Co-Director of the Sarcoma Program here at Cleveland Clinic.

Today I'm happy to be joined by Dr. Kevin Elias, the Lilli and Seth Harris Endowed Chair for Ovarian Cancer. He is a Gynecologic Oncologist and a Physician Scientist here at Cleveland Clinic and is here today to talk to us about the MiDe Study to predict ovarian cancer. Welcome.

Kevin Elias, MD: All right, well thank you very much Dr. Shepard. Happy to be here.

Dale Shepard, MD, PhD: So tell us a little bit about what you're doing here. Gave your title and things, but what is it you do on a daily basis here?

Kevin Elias, MD: Exactly. So I'm an active gynecologic oncologist as a clinician. So my practice focuses on the range of gynecologic malignancies with a focus on ovarian cancer, although I certainly see women with endometrial, and cervical cancer, and trophoblastic neoplasms as well. But ovarian cancer is certainly the heart of what I do and I direct a laboratory here at Cleveland Clinic that focuses specifically on understanding the events that lead to the development of ovarian cancer and developing new tools for prediction and prevention of ovarian cancer.

Dale Shepard, MD, PhD: So when we talk about prediction, and early detection, and prevention, kind of where are we now? This is something you're actively working on because we need to improve, where are we now?

Kevin Elias, MD: So right now there is no commercially available test for early detection of ovarian cancer. So unlike say, getting a mammogram for breast cancer or perhaps for cervical cancer, we don't have a test whether an imaging test or a blood test that a woman can go into her gynecologist's office and be screened for ovarian cancer. And that's in large part because ovarian cancer falls in this kind of middle ground of being neither a rare disease nor a particularly common disease. And so these diseases that occur at a high enough frequency in the population that there are substantial cause of cancer deaths, but the absolute numbers of patients are not as high as, say breast cancer, or cervical cancer, or colon cancer tend to not get as much attention when it comes to developing screening tools.

Dale Shepard, MD, PhD: And we think about specifically ovarian cancer, just kind of remind people what's the consequence of not being able to do that early detection and find patients that are at an early stage?

Kevin Elias, MD: Yeah, so ovarian cancer is one of the cancer types that has the largest variation in survival between patients who are diagnosed with early disease, meaning disease limited to just the ovary, where we expect long-term survival rates of greater than 90% versus advanced disease, so disease which is spread into other places in the abdominal cavity where survival rates are more in the 25% range. And unfortunately, the vast majority of women get diagnosed with advanced-stage disease. It's actually a very small percentage of women, maybe one in every 10 women, who will get diagnosed with stage one disease.

Dale Shepard, MD, PhD: And I guess something that you talked about was prediction prevention, and we've talked about detection and a lot of times we think about that early detection piece and screening. Tell us a little bit about that ability to predict who might get the cancer and even prevent development of cancer.

Kevin Elias, MD: Yeah, absolutely. So with ovarian cancer, about one in every three ovarian cancers has a genetic component to it. And so identifying women who might be at increased risk for ovarian cancer, either because of genetic predisposition or factors in their family, which suggests an elevated risk of ovarian cancer, is actually one of the most effective tools we have for reducing ovarian cancer deaths.

We know that for women who, for instance, have a genetic mutation in the genes BRCA1 or BRCA2, which we associate with both breast and ovarian cancer primarily, they are at substantially elevated risk ovarian cancer. But if we put them into a preventative program where we prophylactically remove the fallopian tubes and ovaries prior to a cancer diagnosis, you can reduce the risk of dying from ovarian cancer by more than 90%. So it is actually one of the most substantial preventative efforts that we have when it comes to gynecologic cancers.

The difficult part with that is that there are a million women in the United States who have one of those mutations and have no idea. And the reason is that the only reason that women get tested right now is because they've already developed a cancer or one of their immediate family members has already been tested and is known to have that gene. Otherwise, there's no insurance coverage for genetic testing.

Dale Shepard, MD, PhD: And I guess just that importance of the genetic testing, even women, men, who develop cancers, how effectively do we normally follow up and get that genetic testing that might be so important?

Kevin Elias, MD: That's a big point. So with ovarian cancer, only about 50% of women who get diagnosed with ovarian cancer actually get the genetic testing, even though it's recommended for any woman who's been diagnosed with ovarian cancer to get genetic testing. Either because they get lost to follow-up, or unfortunately, a lot of these women at diagnosis have a relatively short survival time they may just have never made it for genetic testing, and then that message doesn't necessarily get to their other immediate family members.

One of the things that's often overlooked with ovarian cancer is that these gene mutations occur in both men and women. And so sometimes you have a woman who gets diagnosed with ovarian cancer, she has brothers and sons, and so nobody thinks that they should be getting tested as well. But these same genes can put men at increased risk for pancreatic cancer, prostate cancer, male breast cancer, or certainly if the men in the family go on to have daughters themselves can be at risk for ovarian cancer and breast cancer.

Dale Shepard, MD, PhD: So from a development of a way to approach this issue, how have you tackled it? What is the approach that you're taking?

Kevin Elias, MD: Yeah, so for about the last 40 years, most of the efforts for early detection of ovarian cancer have focused on ultrasounds to look at the ovaries and blood tests primarily using a protein marker called CA 125. And CA 125 is a very useful blood test for monitoring women who already have cancer and particularly for gauging their response to chemotherapy. But it's not a very good blood test for early detection of ovarian cancer and the reason is that about half of early ovarian cancer, so cancers that are limited to just the ovary, will not have an abnormal CA 125 level, and it's a marker which tends to be elevated in a lot of non-cancerous conditions. So, it goes up and down during the menstrual cycle, during pregnancy, with benign gynecologic conditions like fibroids and endometriosis. Anything which causes inflammation inside the abdomen, whether that's a diarrheal illness, any kind of other colitis can elevate a CA 125.

So unfortunately, the vast majority of elevations in CA 125 are false positives. And even among the people who actually have cancer, half of the people who actually have early stage cancer that we're hoping to pick up don't have a change in level, so we don't use it as a screening test. There's lots of interest in using ultrasounds to detect early ovarian cancer. The problem is that we've learned in the last 15 years that most ovarian cancers don't actually come from the ovary, so we have the naming problem now. It turns out that about three quarters of ovarian cancers actually come from the fallopian tube, and we only diagnose them as an ovarian mass as a secondary process, that actually already represents the metastatic stage of the disease. And so if you're only screening women using an ultrasound and you're waiting for some sort of abnormal cyst or mass to form in the ovary, you've already dealing with a metastatic condition.

And there have been a couple large clinical trials both here in the United States and also in the UK looking at hundreds of thousands of women seeing if CA 125 and ultrasound could detect ovarian cancer early. And what they both found was that even though you might detect cancers a little bit earlier, it was not early enough to improve survival from the disease.

Dale Shepard, MD, PhD: So tell me a little bit about something you've been very involved with something called the MiDe Study.

Kevin Elias, MD: Yes. So as I was saying, most people have focused on ultrasounds and CA 125 or other protein markers. One of the things we learned about from the Human Genome Project is that most of our DNA doesn't actually code for proteins. So whenever we think about a gene or getting gene testing, we're talking about what's done as the coding part of the genome, the part of DNA that actually turns into a protein. And that turns out that's less than 3% of all of our DNA. The vast majority of our DNA is what we call non-coding RNA, and those are sequences that don't make a protein, but do regulate how our genes get expressed.

My laboratory has focused on a specific category of these called microRNAs, which as the name implies are very short sequences of genetic information, usually about 18 to 25 base pairs or letters in sequence. And what we know about these microRNAs is that they get out into the bloodstream and we showed in a study a few years ago that the pattern of microRNAs that we see in the bloodstream of women with cancer is markedly different from the pattern of microRNAs for women who don't have cancer. And that was true for both very early stage cancers as well as more advanced stage cancers, and also true for some of the less common subtypes of ovarian cancer, not just the more common ones that we see.

So the MiDe Study is focused specifically on women for whom we've identified they have an elevated risk of ovarian cancer. So those would be women who have a known genetic predisposition to ovarian cancer, meaning a mutation in either the BRCA1 or BRCA2 genes, genes that are associated with a condition called Lynch syndrome, which makes women at risk for both ovarian, uterine, and colon cancer. Or some of the other less common genes which we associate with ovarian cancer, which might come up on a genetic testing panel. Even if someone hasn't had genetic testing, if they have a family history, which would suggest that one of those conditions might run in the family, they're also eligible for the study. Or if there's a known genetic alteration in the family but a woman hasn't been tested yet, she's also still eligible for the study so it's a pretty broad inclusion criteria.

But we are looking for women who have not been diagnosed with ovarian cancer themselves, but for one of these reasons, either family history, genetic predisposition, or family genetic history we think might be at risk for ovarian cancer and they have to have at least one ovary. Those are the inclusion criteria. And what happens in the study is that we ask for a health questionnaire and then the study is a blood draw. So we ask for a blood sample once every six months for up to five years.

Now, we're primarily interested in women who are considering having preventative surgery, so at some point having removal of their fallopian tubes and/or ovaries so that we can be definitive about who develops cancer and who doesn't. But a lot of what the study is based on is this idea that if we're monitoring high-risk women, are we accurately able to predict who is likely to develop ovarian cancer within the next five years and who isn't? So in the short term. Because one of the problems we have right now, even for high-risk women, so even for women who, for instance, have a mutation in BRCA1, those women have a 40% risk of getting ovarian cancer in their lifetime, but we have no idea when that cancer will occur.

So right now, we advise all of those women to start thinking about having their ovaries and fallopian tubes removed, starting at age 35. So that's advancing menopause for these women by up to 20 years, and certainly can be a major issue when it comes to completing their families as well as all of the medical consequences of premature menopause for heart disease, bone density, neurologic health. So without a test that can even for those women tell them are they at risk for cancer at 36 or are we not worried about them getting cancer until 56, having a blood test which we can accurately tell them, you're at very low risk for cancer this year, next year, or the following year, we can put off having preventative surgery is really the first step for getting an early detection test to the general population, which is what the follow-on will be.

Dale Shepard, MD, PhD: Are there differences in this microRNA sort of sequencing patterns? Is it different based on age? Is it younger? When we think about people getting younger onset ovarian cancer, is that different? Are there racial differences?

So the answer to all the above is yes. So there are some microRNAs which change naturally with age. There are some very subtle microRNA differences between different racial and ethnic groups. We've actually tackled both of those questions. What we have found is that the microRNA pattern that we see that we associate with ovarian cancer is not affected by those factors. So we've actually looked at more than 70 different clinical and demographic factors that might affect microRNA patterns, everything from race, ethnicity, age, socioeconomic status, geography, to common potential comorbid medical conditions like hypertension, cholesterol, obesity, diabetes, to see how those might influence microRNAs.

And so we've done, I would say, a lot of stress testing of this microRNA diagnostic to see is it likely to have a lot of false positives associated with it, or are there common factors which might make the test less useful in different populations? Because we're very emphatic, we want an ovarian cancer test that works well in Cleveland to also work well in El Paso and also work well in Northern Maine. So regardless of where people are, we want to test which is going to be generalizable.

And you mentioned focusing on high risk at this point, but then hopefully looking at more normal risk populations as well. Do we have data so far that suggests that those patterns are similar in those patients that aren't at high risk?

Kevin Elias, MD: Yes. So we've looked at the microRNA patterns that we associate with ovarian cancer for women with known genetic predisposition to disease, and those with no known genetic predisposition and the cancer pattern is the same, so we don't see a difference there. What is different though is that if we look at women who don't have cancer, and we look at the microRNAs of women who have no genetic risk factors for ovarian cancer, and those who do have genetic risk factors, those microRNAs are different. So they're slightly different sets of microRNAs we're talking about. But we can, based on a blood test alone, accurately predict who's going to have a genetic mutation and who doesn't.

And so when we talk about the general population, so women who have no reason to think they might be at risk for ovarian cancer, we're foreseeing what's going to be a two-step triage. The first question is, is there some underlying condition we didn't know about which suggests that you actually are a high-risk person because this genetic pattern isn't specific for BRCA1 or BRCA2, it suggests a general sort of predisposition to developing cancer. We can use that to then select women who should actually be in an active screening protocol.

And we think that's an important approach for a couple of reasons. One, we want to reassure women who are at exceptionally low risk of ovarian cancer that we don't really need to be having them coming in, getting excessive amounts of blood tests or imaging studies. But also from a practicality point of view, looking at the cost of screening the entire population, there's 180 million women in the United States over age 40 that you might plausibly be thinking could be at risk for ovarian cancer. Well, even if you had a test that only cost, let's say a hundred dollars a test, well, you're talking about almost $20 billion for healthcare costs in the United States every year. And so if we can narrow that down to really only the maybe 1% to 5% of women that we really think are at risk for ovarian cancer, we can develop a test which is much more likely to make it into clinical practice because it'll be feasible to implement it across the population.

Dale Shepard, MD, PhD: If we get a blood-based test, I mean, I guess one problem we always face is underserved populations and how do you address delivering care in those groups. Do you think a blood test like this might be sort of easily transferable to helping screen those populations?

Kevin Elias, MD: So the advantage of a blood test is that as long as someone can get to a place they can have phlebotomy, we can offer it. So it has some advantages over say imaging tests or pap smears because it doesn't necessarily require going to a center of some specialized capacity.

I will say for the MiDe Study, in fact, in order to encourage enrollment, we actually have mobile phlebotomy as part of the study, so they will come to your house and draw the blood. So it's been open nationwide, we've had women enroll from 46 states so far, including Alaska and Hawaii. So I do think that blood-based tests to some extent are potentially easier. Now that said, microRNAs do get into all body fluids, and so we've been looking at ways of potentially offering home-based testing beyond a blood draw. Whether that's microRNAs in saliva, microRNAs in urine, we've even tested a skin patch absorbed microRNAs transdermally. So these are, I would say, technologies that are a little earlier in development, but certainly there's the possibility that down the line we might be able to offer home-based screening just like is happening now for colon cancer, it's actually starting to develop for cervical cancer a home-based screening. Ovarian cancer may be that way in the future as well.

Dale Shepard, MD, PhD: Based on your enrollment, what's the projection of when you might be able to have some data?

Kevin Elias, MD: So the study is planned to enroll a thousand women, we're at a little over 700 so far so it's actually been occurring quite well. We're hoping to have an initial set of data within the next year, actually, because we do have baseline blood samples and subsequent blood draws for several hundred women at this point.

The initial question that we have is that we've known for a while that this microRNA pattern for women with known genetic predisposition is abnormal at baseline. We're really interested in women who have very strong family histories of ovarian cancer, but they've had genetic testing and no gene has been found in the family because that's a very difficult group of women to counsel. Let's say you have a sister with ovarian cancer, your mother had breast cancer, your maternal aunt also had breast cancer all at early on, so there's this striking history where you think there must be a gene running here in the family, but the genetic testing is normal. How do you counsel that individual about what her risk of cancer is?

We think that the microRNAs can tell us that because it's essentially a functional test. We know that it's kind of an end result for pathways that could be resulting from a number of different genes. And so if we can tell somebody, yes, you're an increased risk, or no, you're not, then we can put them into a risk prevention program, whether that's surgical intervention, enhanced surveillance, either way. So we'll know that already from the patients that are enrolled in the study so I'm hoping we get that data this year.

Dale Shepard, MD, PhD: Good. So somebody's listening in, a healthcare provider that has patients that they'd be interested in having enroll, patient might be somebody, a woman that might wonder about a risk and want to enroll. How do we make that happen?

Kevin Elias, MD: So as far as enrollment in the MiDe Study, there's a website that women can go to it's mide, for microRNA detection, midestudy.org. Patients can self-enroll in the study, there's a very quick enrollment questionnaire they fill out online. The study coordinators will reach out to them and they will set up for a mobile phlebotomy to arrange the blood draw or for them to get their blood drawn locally. This is a collaboration between Cleveland Clinic and the Dana-Farber Cancer Institute. So women should know that if they get a phone call from someone at Dana-Farber, that's why, they're the data coordinating center for this. But they can be anywhere in the United States, we've been experimenting a little bit to see if maybe we can expand to Canada as well, but at least within the 50 US states, women can go online, fill out the questionnaire themselves and enroll, and then a study coordinator will reach out to them.

Dale Shepard, MD, PhD: That's fantastic. So really serious cancer, and you're doing important work to try to make things better.

Kevin Elias, MD: Well, I do hope that we can reduce deaths from ovarian cancer mostly by preventing the disease. We've seen that for the last half century we've been focused on trying to reduce deaths from ovarian cancer only through early detection. I think really the best way to prevent ovarian cancer deaths and what's been the most effective is identifying women who might develop the disease and then taking actions to prevent them from getting it in the first place.

Dale Shepard, MD, PhD: Fantastic insights, thanks for being with us.

Kevin Elias, MD: Oh, happy to be here today. Thanks for having me.

Dale Shepard, MD, PhD: To make a direct online referral to our Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You will receive confirmation once the appointment is scheduled.

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