The WISDOM Study and Breast Cancer Risk

The WISDOM Study – Women Informed to Screen Depending On Measures of risk, seeks to bring together 100,000 diverse women from across the United States to find the safest and most effective way to detect breast cancer for every woman. This study compares two approved screening approaches: annual mammograms for all women starting at age 40 or a personalized approach based on a woman’s individual risk factors for breast cancer, like her breast density, genes, and family health. Learn how your patients can participate in the Wisdom Study. This is large scale, important research you and your patients need to know about.



This transcript of their discussion has been edited for clarity and length.


Mike Sacopulos: Laura Esserman is a Professor of Surgery and Radiology at the University of California, San Francisco. She is the director of the UCSF Breast Care Clinic. Dr. Esserman led the creation of the University of California's Athena Breast Health Network.

Dr. Esserman, welcome to SoundPractice.

Dr. Laura Esserman: Thanks so much for having me.

Sacopulos: What is the WISDOM Study?

Esserman: The WISDOM Study is about a paradigm shift in the way we think about screening. Importantly, there's been so many advances in our understanding of breast cancer. Breast cancer is not one disease, and we don't treat all breast cancer as the same. And I think it's high time we rethought the paradigm for screening and prevention to acknowledge the fact that breast cancer is not one disease, and as well our understanding of breast cancer risk has changed. The opportunity here is to say, "how do we do our best effort in risk assessment? And based on that risk assessment, identify strategies for screening and prevention that are appropriate for a given person's risk and for what they might be at risk for?" The WISDOM Study is an opportunity to take our one size fits all screen, everybody, starting at 40, and compare it to a personalized risk assessment and screening and prevention strategy, and see whether it's just as safe, it's preferred by women, it's less morbid, and allows us to advance the acceptance of preventive interventions. And at the end of the day can generate healthcare value.

Sacopulos: Sounds like many laudable goals there. How do you recruit women to participate in the study?

Esserman: We do it in many ways, and I appreciate the opportunity to talk to the physician leaders who might be listening to this podcast, because one of the things that we need to do is we need to get the physician community behind these kinds of concepts and say, "Look, if we want to test new paradigms and we want to advance the field, and we want to do it in real-time, we need to participate in studies that can help us generate the evidence to enable these kinds of changes." We have several sites across the country, including our Athena Health Network, which is the five University of California campuses, plus Sanford Health in the Midwest. Plus, now we have several new sites: the University of Chicago, University of Alabama, LSU, and VitalMD in Florida, Minnesota. We have several sites that also have joined us to help us recruit and to make sure that our recruitment reflects the diversity of the country. We can invite people through our networks.

It's open to anybody in the country. Anyone who hears about it, any physician can recommend it, and any person who's in the trial or knows about it can recommend it. Anybody who has not had a diagnosis of breast cancer or in situ disease can join if they're 40 to 75. They just go to It's all electronic. You don't have to go to any particular site. It's patient-friendly. It's in Spanish and English. It is a pretty straightforward process. The one thing we ask of people, it's critical for us to get information at the beginning of every year. We need an update every year, so it's a pragmatic trial. We're trying to learn about our recommendations for screening. Were they accepted? Did they use them? Did people wind up having to be recalled for a biopsy? Do they develop cancer? These are the things that we need to know to run the trial.

Sacopulos: Excellent. You mentioned diversity and I understand that the WISDOM Study makes an effort to enroll a population of women that mirrors the diversity of women in the United States. What are the metrics for diversity? For example, is level of education considered a metric for diversity?

Esserman: That's a really good question. When we think about diversity, we can think about this in several ways. You can think about race and ethnicity. Let's address each one of these in turn. Race and ethnicities, why is this important? Well, there are two reasons why this is important. First of all, the rates of breast cancer, for example, are about the same now in African American women and Caucasian women. However, the rates of death are higher in African American women. We're trying to understand that we know that African American women have a higher rate of getting triple-negative breast cancer or this very aggressive kind of breast cancer, but again, anybody at any age, of any ethnicity can get these bad cancers. They can be more common in certain populations.

And so, we want to make sure that's represented. If everybody joins, the information we learn will help everybody. Now, another important thing is we are randomizing people to the annual arm, or this personalized arm. And if people don't want to be randomized, which will be assigned by choice, they can choose. If you feel strongly and want the personalized arm or I feel strongly that I want the annual arm, it's a pragmatic trial. We don't want to lose people from joining because there are a lot of questions we can ask for that and people have the opportunity to choose. In the personalized arm, we not only ask the standard questions that drive risk, about how old you were when you started your periods, whether you've had a breast biopsy, whether you've had kids, do you have a family history, et cetera. We get two other critical pieces of information.

There's only one piece of information we get from people's medical records and that's their mammogram report. We need the breast density. It's been really hard to get that, so we have a way that people can get it themselves and upload it for themselves. And again, we're going to get back to literacy and technology in a minute. But the second piece of information we get is information about their genetic makeup. And so why is this important? This is important because, in 1996, and 1997, the genetic sequences for BRCA1 and two were down, and we were able to test people for this. At that time, it was a brand new test, kind of a big deal. And you had to go through the IRBs. It's been 25 years. There are nine genes associated with a significantly increased risk for breast cancer.

But we do not routinely test for those. And if you have one of those, when's your biggest risk? In your 30s. Turns out that 60% of the people who have mutation carriers, we have 45,000 women in the trial now. Of the people in the personalized arm who have, the number of people with mutations is not a lot, right? It's one to 2% of the population. But if you have those, when are you at risk? 60% of those people do not have a first-degree family relative with breast cancer. Why? Because you may have come from a small family. You may have mostly men in the family. It's an old notion that is family history-driven. The new notion is it's about your genetic makeup. And COVID may reduce people's knowledge about their families because a lot of people in families have died.

Why can't we use the test that we have? It's now because of several advances, and probably the most important advances that the Supreme Court ruled that Myriad could not own the patent, could not patent the genome. That was the Supreme Court ruling that said, can't do it. Took the patent away from Myriad, opened up the door to NextGen sequencing, bringing the cost of the test from the many thousands of dollars to something that's in the 250 range, the price of a mammogram. For one price of a mammogram, you can understand not only your risk, not only can we get the genetic testing of these rare mutations, but there's another thing we can get. We can look at the genetic profile looking at single-nucleotide polymorphisms or SNPs. And what are these? These are the small variations in risk that by themselves don't mean much, but together many, poly, genic, genes, polygenic risk can identify by a group of people that are much more at risk, maybe 10 or 15%, or much less at risk.

And that bell-shaped curve, again, helps us understand who's at that lower risk and who's at that higher risk. How do we start down the path of making the first improvement, but using the platform to continuously learn and improve? Isn't that what we should be doing? And it also turns out that the polygenic risk varies based on your ethnicity and race. There's a different polygenic risk algorithm if you're Asian if you're a Latina if you're African American, and the Caucasian SNPs, which we know the most about because so much research has been done on European ancestry, that it's not that applicable to these other populations. Now, we can do that. And even in the trial today, based on people's race or ethnicity, which basically can also ascertain from the genetic tests, you can give people a much more appropriate risk assessment.

It's really important to have the diversity of the population in the trial so that we can make these kinds of changes. And the United States is unique because we are a melting pot and have so many people, and increasingly people of mixed race, so you want to be able to use these tools to make that. This is important. This is about personalized medicine coming of age in this screening era. These tools and techniques can be applied across diseases. That's the diversity of the population. Now you can also look at the diversity in terms of who has access to technology? Well, it turns out that we also want to be looking at populations who are insured and not insured and we are partnered with Medi-Cal Partners to make sure that we're trying to reach out to populations who have less risk.

We're hoping to start a partnership with DHR, which is a group in Texas who are at the border town where insurance might be more of an issue, and we have a more diverse population there. But it's not true that technology is always a barrier based on your education level. A lot of times people have access to smartphones or phones and technology. And we've found in some of our work that iPads are the low literacy option. We're looking for people to partner with that have access to clinics where we can put iPads either in a mammo van or in centers, that's one of the experiments that we're doing. We're also partnering with the VA. And one of the important opportunities is that in the VA, there's a much more diverse population there. And so that allows us to change.

And we're constantly trying to think about ways in which we can address the gaps in care in this country and so we are trying to adjust to it. All of these, we have an RO1 from the National Cancer Institute to help us think about these strategies and improve the way we accrue. But one of the things that we need is we need partnerships with primary care physicians and obstetricians, gynecologists, and physician leaders everywhere who say, “why are we not asking these questions?” You have to say, when I started this trial, when I first pitched this, I initially pitched it to the Robert Wood Johnson Foundation for Pioneer Pitch Day. And we won this bill, so that gave us the resources to create the pilot. One of the things I had said, this was back in 2014 or 2015, I said, we have to aspire to better. We need to aspire to the iPhone eight. I would like to point out that we are on the iPhone 13, and we still haven't solved this problem.

Sacopulos: Some of us are, Doctor. Not all of us.

Esserman: Us. Okay. But I'm just saying that we need to be demanding that we generate the information to improve the lives of the people we serve.

Sacopulos: I wholeheartedly agree with you. Now, participants in the WISDOM Study are in the study for five years. How was that period selected? Why not three or six or eight years?

Esserman: The first big grant we had to start this trial was from PCORI, the Patient-Centered Research Outcomes group. One of the things they wanted was something that you could answer in five years. And so, we had to come up with a framework that wouldn't be a 20-year or a 10-year study. And I applaud them for pushing us to say, “how could we answer this question more quickly?” And the reason why people are afraid not to do annual screening is they're worried that you're going to find cancers, that you're going to miss the cancers that kill you. Well, what are those? Those are the stage 2B cancers, people whose tumor has spread to the lymph nodes. But I can tell you if you look to see where screening has missed the mark... I'm not for or against screening.

I am all about trying to figure out how to make it better. And I think that what we need to do is be thoughtful about what we're trying to accomplish. I think about, well, where are the problems with screening? Well, the problem with screening is that we haven't addressed the issue of these stage 2B cancers. And in fact, I run a big trial called the I-SPY trial, where we specifically focus on women with locally advanced breast cancer or the more aggressive cancers, molecularly high-risk cancers, and where we're trying to change the treatments to figure out how to get people cured so that they don't die of their disease. But what I'm struck by is the majority of these cancers are not screen-detected cancers. They are fast-growing cancers. We need to do a better job of identifying who those people are, figuring out what we can do and screen them more frequently, and also get to the issue of prevention because that is a place where we're not so good and screening every year hasn't solved the problem because there are still 40,000 women a year dying of breast cancer.

We can and we must do better. Another issue for screening is that any test and any of the audience members know this, doesn't matter what you're screening for. If you screen the whole population, you are going to identify a reservoir of more indolent disease, that every disease varies from low risk to high risk. And of the low-risk things, the more where you look, you're going to surface more of those low-risk events, prostate cancer, and pre-diabetes. It doesn't matter what it is. This is just so. It's not a ding against breast cancer. You just have to recognize it so that you can fix it. But we do have tools to be able to say, okay, when is this over-diagnosis and when is this overtreatment. So, some of it is, if you really have a low risk, look less frequently in that group. We do that in colon cancer and no one's screaming about it because we say, oh, well, if you don't have a family history, you start at 50, or you screen every 10 years if you don't have a poly.

We're doing the risk-based screening. We do risk-based screening if you happen to have a mutation that predisposes you, you get screened every six months. These are all notions that we are applying. The question is how we systematically do this so that we can learn and continue to improve. Looking to see a difference in the rates of stage 2B cancers, that would answer our primary question of safety. And if it's just as safe, there's no reason for us to just rapidly iterate and keep improving our models. Where now we think we can probably explain 70% of breast cancer, but if we keep working on it, maybe we can get to 90%. And we've just submitted a program project grant because once you've built up a lot of infrastructures, you don't want to tear it down and waste it.

Now, how can we do better? If it turns out that it's just as safe to proceed at the end of these five years, why wouldn't we then say, well, at least for the mutation carriers, why shouldn't we be doing that first genetic test at age 30? Because then you know who doesn't need to be screened in their 50s and who should be screened probably in their 30s. For the small group of people that need more, you can easily adjust that by not overdoing it and the people at the very lowest risk. I think this is a really important notion in healthcare and medicine, and it's such an exciting area. We want to take our science, the best of what we know, and not just do it, but put it to the test and study it. And I think this is another really important notion in the WISDOM Study is to partner with organizations, whether you're a pair, whether you're an employer and you're self-insured to say, these are all within the range of many of the guidance’s that are out there.

Partner with us and do coverage with the evidence development. This genetic test has been on the market for 20 years. Why aren't we using it in novel and important ways and helping make the care that people are receiving part of our learning engine? I'm a big fan of coverage with evidence development. When you have something that can really drive healthcare value, improve the outcomes for people, and also reduce the burden and the cost by using your resources in a better way, more for the people that need it, less for the people that don't. I invite all the listeners who are interested in participating to join us and be an ambassador for the study, be an ambassador for this concept. I say that we should hold our payer partners accountable for helping us improve care. It should not just be about doing stuff and waiting 10 years for stuff before we disseminate, but say, why can't we be generating the evidence as we go and learning.

Sacopulos: Unfortunately, some of our fellow Americans are distrustful of medicine and research at the moment. If you were talking to the ambassadors that you just mentioned, what's the message to help them convince their patients to participate in the WISDOM Study?

Esserman: Well, I think that we should be clear. Breast cancer is the most common cancer in women. 40,000 women a year still die of breast cancer. We have made a lot of strides by understanding more about breast cancer. We can take what we've learned and improve the way we offer opportunities for early detection and prevention. Everybody doesn't need it, but some people probably do. We want to take what we believe are going to be tomorrow's best strategies and bring them to you today. And these are things that you're going to screen.

The recommendation is for people to screen anyway. Why not do it in a way that we're doing more for you? And as we learn, those learnings pass on. You're going to want to do it because every woman has friends, has mothers, has daughters, nieces, and cousins. This is something that you can do that is good for yourself and good for your community and good for your family. And unless we work together, we aren't going to solve the problem. And we don't want to be in the same place in 10 years having the same song that we haven't made the right progress. And I'd say that you could maybe be distrustful of medicine, but if you look over the last 20 years, we now have medicines that mean if you have HER2 positive breast cancer, you're not going to die of it. Highly likely you won't die of it. We have treatments for it. And increasingly those treatments are getting to be less toxic.

The same thing for triple-negative breast cancer. And we know now from our I-SPY trial, that it works for African Americans and white women, the same. These are amazing things. There are drugs like Gleevec that have changed the outcome for people with CML. These are the kinds of improvements that science and trials and medicine have brought to people. We don't want to turn our back on that. And we want to find a way to take those lessons and bring them to every woman who might be at risk. Some people might be at such low risk they don't have to worry about it. And maybe they're anxious and worried about it. One of the great things is we can set their mind at ease, but maybe we'll find somebody. Here are two examples of people in the trial.

I had someone who came from a family where everyone died of breast cancer. She just couldn't bring herself to get tested, but she was willing to join the trial. And she turned out to be a BRCA1 carrier, and she decided to have surgery and she had a tiny little cancer found incidentally. And that very well may have saved her life. We had another person who found out she was a carrier and had a tiny little ovarian cancer, which probably saved her life. Several people can do strategies that will make a difference. Someone I saw just yesterday, whom I had encouraged to join the trial, had had multiple biopsies and she'd come to talk to me about having a prophylactic mastectomy. And I ran her risk. I said, you just don't have that higher risk. And so, when she had already been signed up to have a prophylactic mastectomy, she joined the trial.

She's actually at very low risk. And instead of being in tears and wanting to have something she didn't need; she feels very different. These are the tangible things that make a difference where we're frightening people because she'd had two biopsies and misunderstood. Both sides of the story are really important. They're both important. We do too much. Sometimes we don't do enough. How do we right-size what we are doing? This is the opportunity to make a real, tangible difference individually. And collectively as women, we should come together and say, we don't accept this rate of death from this cancer. We must come together and find a way to make a change.

Sacopulos: Dr. Esserman, we're almost out of time, but you are conducting a very important study. And I would like you to tell our audience one more time how they can involve their patients in the WISDOM Study.

Esserman: Yeah. And I just wanted to also say one thing we have a lot of patient advocates and a lot of women involved in designing the trial. And we have a community board. We have people who are engaged with helping us reach out to the community who are either in the study or have helped us design the study because they have breast cancer, and they want to see a change. Anyone can recommend that their patients join the study. It's a very simple thing. You can do that. If you are interested in being an ambassador, we are excited to hear from you. You can go to the website, I believe, and there's a button you can say I'm interested in getting more information and we can send information.

It's pretty straightforward. I believe, especially for people who are interested in women's health, this is a really important opportunity to show that we can make a difference and that we can continue to work to not only improve how we screen based on risk but that we can focus on prevention. We have an embedded set of breast health specialists and genetic counselors who, if you have a mutation, do the counseling and then we help you find the right resources in your community to reach out to. We have a tool called the breast health decisions tool, where we take people through the things that put them more at risk. We talk to them about lifestyle changes and things they can do to improve their health.

There's a series of articles in Time Magazine and a series of videos about the trial that I think is very informative, which we also have on the website. But one of the people who were in the trial told us that every year she had to fill out that health questionnaire and she noticed that every year she was checking off one more health problem. And she said that just made her realize that she needed to get serious about her health. She lost 40 pounds and started exercising. In some ways, it's a women's health study. That there are a lot of secondary benefits that we want people to pay attention to in their health. And I think it's a great opportunity for physicians to join with us and the larger community and our payer community and our employer community to say, look, come join with us, help us solve this problem. It's something we can all do together.

Sacopulos: We will let that be the last word. Dr. Laura Esserman, thank you so much for your time today.


For more information on the WISDOM study.

For physician leaders to enroll patients in the WISDOM study:

If you’d like to be an ambassador for the study, or to learn more,



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