 Good afternoon. My name is Vence Bonham. I'm the Senior Advisor to the Director of NHGRI for Genomics and Health Disparities, and I'm pleased to welcome you here this afternoon. This is a unique lecture today because it's a collaboration between the Intramural Research Program of NHGRI and the Genomics and Health Disparities Lecture Series. And so it's an opportunity for the two groups to come together to have an opportunity for you to hear from our speaker today. The Genomics and Health Disparities Lecture Series is sponsored by NHLBI, NIDDK, NHGRI, and the National Institute of Minority Health and Health Disparities, and the Office of Minority Health for the FDA. It's an opportunity to bring different parts of the federal agencies who are interested in genomics and health disparities together to bring speakers to NIH to explore issues from the perspective of how genomics can play an important role in understanding health disparities and health equity issues. I'm pleased that this afternoon that my colleague, Dr. Nigel Crawford, is going to introduce our speaker, and we look forward to our talk this afternoon from Dr. Opalati. Good afternoon, everyone. As Vence said, my name is Nigel Crawford. I'm a tenure track investigator in the DIR side of this equation. So it's my really great honor to be able to introduce Dr. Fumi Olapati to be giving this joint seminar today. Dr. Olapati is the Walter L. Palmer Distinguished Service Professor in Medicine and Human Genetics, the Associate Dean of Global Health, and the Director of the Center for Clinical Cancer Genetics at the University of Chicago School of Medicine. Dr. Olapati went to medical school at the University of Iberdan in Nigeria. Subsequently, she came over to the U.S. to do a residency in the Cook County Hospital in Chicago, and following this, she went on to do a fellowship in the University of Chicago. Dr. Olapati is really very much an international leader in cancer genetics. She's an expert in cancer risk assessment and developing individualized treatments for both breast and ovarian cancer. Her work very much focuses on identifying patients that are at risk of the most aggressive forms of these diseases, and then implementing novel management strategies based on individual genetic assessments in these populations to perform early interventions and essentially reduce mortality in these high-risk groups. She approaches the study of aggressive cancers using a number of different approaches. She's very interested in the mechanisms of familial cancer, the mechanisms of tumor progression in high-risk individuals, and very importantly, genetic and epigenetic factors contributing to disparities in cancer outcomes in diverse populations. I really think that the power of Dr. Olapati's work and her contribution to the field is well highlighted by her work with the BRCA1 and BRCA2 genes, where she's shown distinctively that these two genes increased incidence of breast cancer and cancer outcomes in women of African descent. Overall, Olapati uses highly innovative and develops innovative approaches to studying aggressive forms of cancer. For example, she uses whole genome technologies to reduce global disparities and help in cancer outcomes. She's been the recipient of numerous awards throughout her career. I can only list a few of them here, but some of the highlights would be the MacArthur Foundation Genius Fellowship, the Doris Duke Distinguished Clinical Scientist and Exceptional Mentor Award, and she's also been elected a member of the American Academy of Arts and Sciences. So, Dr. Olapati, it's my great pleasure to be able to introduce you, and we're looking forward to hearing your talk. Thanks, Anja. Thank you. We've done. And knowing that this is a really mixed audience, I tried really hard to just give you snippets of how we're thinking about breast cancer genomics and health disparities. And, you know, the bottom line of what I really want to emphasize at the end of the conclusion of my lecture today is that we really have a unique opportunity in precision medicine to get rid of black-white differences and begin to really talk about getting care to individuals at the personal level. And to get to that, we all have to work together collaboratively. I know that this lecture has been sponsored by Office of Minority Health, but really when you talk about individual and personalized medicine, we're all in the minority because it's one genome at a time. It's one drug at a time, one person at a time that we have to take care of as physicians. So I just want to share my journey to trying to get precision medicine for all. And it's really because I came to this country to study cardiovascular medicine, and I quickly gave up on that dream to become an oncologist. I think that I was really inspired by what I was seeing in cancer at that time when we were really doing subset analysis of different chromosome changes in leukemia and lymphoma. And we were cloning one gene at a time, and General Lee and Francis Collins and all the giants in human genetics at the time said, why don't we just do the human genome project and just map every gene, clone every gene? And then once we have that, then we can really begin to think about risk assessment and best therapies. And in the 80s, that was really a broad vision, and it materialized, and now we're past that. And so the question is, how do we actually get to getting the genetic information that will allow us to do the best risk assessment and provide the best therapies so that we can in fact eliminate health disparities and improve health equity? And so I started in lymphoma leukemia, and I still think that there's just really arbitrary division of these different types of cancers, that if we really begin to think about pathways and think about how we treat individual diseases, we may find that actually more commonality among all these different types of cancers. Having said that, I think the reason why the Office of Minority Health and Center to Reduce Disparities really want me to give this lecture is because when you talk about incidence rate, and ever since people have been given, have been talking about data, it's always been that you have more breast cancer among African Americans. And even though the incidence now has approached the incidence in blacks, the mortality is really what is so disturbingly much higher among African Americans. And as we began to think about how people are diagnosed and what we've done with population screening, we now actually are having a debate in the breast cancer community about over diagnosis of breast cancer. How many of you have heard about the debate about over diagnosis and over treatment? Raise your hands. Okay, so that's been talked about a lot. But what's actually not been in the public press is the fact that there are many people who still get diagnosed with regional and distant metastasis at the time of diagnosis despite the fact that we've done large-scale population screening over the last 30 years. So the question is, who are these individuals? Well, we began to sort of break it down the minute we started talking about different types of breast cancer. And the fact that homoreceptor positive or too negative breast cancer is the most common type of breast cancer. And it's the one that's been studied the most. It's still also what kills most women who develop breast cancer. The reason why we've all been very excited about triple negative breast cancer is because we don't have a target for it. And as oncologists and cancer researchers, a lot of our effort has been focused on finding new treatments for diseases and less of prevention. When I came to this country, the whole mantra in our medical school was that prevention was better than cure because you have low resources. And if you have low resources, you have to really prevent diseases, keep people healthy instead of spending a lot of money to treat diseases. So it was really surprising to me that at County Hospital when I started, all we did was treat people who came into the hospital. And there was not really a lot of public health work being done in Chicago. So but now we know better. We know that when you actually collect data that you now see that African Americans are more likely to get triple negative breast cancer. It wasn't always the case that we knew that we only knew that because my good friend, Jeff Trent, when he was at NHGRI really thought he should do gene expression profiling. There was a new technology and he applied it to very few number of patients. Didn't have a lot of tumors to look at, but with, I think it was maybe seven or eight, you know, BRCA1 associated breast cancers, BRCA2 associated breast cancer and sporadic breast cancer, he actually was able to tell us that your germline genetics actually could determine the type of tumor you had. This was profound at the time and of course the Stanford group and everyone sort of really began to see that your germline genetics determines the kind of tumor you had. And when this paper was published in the New England Journal, our lab read it and, you know, as a good oncologist, what I said was, well, it really wasn't the BRCA1 signature that they were talking about. We wrote a letter to the editor that what they probably did was these were all ER negative tumors. These are all ER negative. These are all ER positive. Majority of sporadic breast tumors are ER positive. So what they are really describing is a signature of ER negative tumor and not necessarily a signature of BRCA1 because that was the level of understanding we had at the time. However, with subsequent work, with our work, a lot of work of the breast cancer linkage consortium, it became clear that, in fact, BRCA1 patients actually develop a disease that was a well-defined phenotype. They tended to have a medullary or atypical medullary very high mitotic rate. And one of the things that sort of struck me was the fact that they had high proliferation fraction. And if you are coming in as a lymphoma doctor or a leukemia doctor, you know that when patients come in with a high tumor burden and with my internship at University of Ibadan, if you had a patient with bucket lymphoma who came in with large jaw masses, big abdominal tumors, our job at that time was to make sure we treated them immediately. And with that little red drug called Adromycin, these tumors will just melt away over the weekend. We didn't even care about tumor lysis at the time because these were usually young children, but the tumors went away. And I was really fascinated why these big tumors melted away, but when we talk about breast cancer, these tumors that were growing fast, we were still really thinking about cutting them off, doing surgery and a lot of things. Anyway, cut a long story short, we then realized that these tumors, of course, had the worst outcomes and African Americans tended to have tumors that were sort of described like this and also had the worst outcomes. And that's what really got us thinking about, can we do a cheaper version of gene expression profiling? Now, this is a very good pathology and morphology of breast cancer. If you think about global health, most people would not be able to do pathology of breast cancer like this in most parts of the world. And so, most patients that are treated with breast cancer don't have a proper diagnosis of their breast cancer. And as a result of that, they will not have a proper therapy of their breast cancer. It doesn't matter where they live. If you cannot get a good diagnosis, you cannot get the best treatment. So, we know that estrogen receptor is a first drug able target. It was identified at the University of Chicago. Charlie Huggins did a very simple experiment, took the ovaries of women with metastatic disease, and if they were premenopausal and they had oophorectomy, their tumor meltaled away because you had massive apoptosis and you starved them of estrogen, and these women did well. Okay? That's a treatment that actually works. It's very effective for any woman with ER, estrogen receptor positive breast cancer. Along the way came another target for therapy in breast cancer, which is Hortune positive breast cancer. Dennis Lehmann really was also a student and resident at University of Chicago and thought if we could just target Hortune, we're going to be able to treat a lot more aggressive breast cancer. So, these two targets is really why every woman with breast cancer wants to know is an ER positive or Hortune positive because we know that if you treat women appropriately, they're going to, if they don't survive their breast cancer, they're going to live very long lives. When we were transplanting patients with Hortune positive breast cancer, they didn't respond any better than when we didn't do bone marrow transplant. However, the minute we got Hortune targeted therapy, a lot of women who would have died within two years of breast cancer became long-term survivors because of the target. So, fast forward, we then said let's go and look at the patterns of breast cancer in Nigeria. This is the last time I will show this slide because when we first did the experiment, we didn't believe that in fact the pattern in Nigeria, Senegal, and among African ancestry could be so different from what has been reported in Japanese and white women in Europe. So, anytime I talk about disparities, the thing that I always like to say is that the real gap is really the knowledge disparities. If you don't do the research, you're going to come to the wrong conclusion. And so, Office of Minority Health, whatever the NIH addresses, we've just got to just do the best science. It doesn't matter where and the best science will give us revelations of what we should be doing because we can't assume that we know everything about breast cancer. But that was what we found. And then once we did publish the paper, there was all sorts of disagreement about the fact that the way we did the analysis, the tumors were in the fridge too long and it couldn't be possible. And then subsequently, others in Africa and North and East Africa, everybody started looking to say, okay, what's the estrogen receptor status of our tumors? Because now we can do this research. And number of studies, I mean, when we did this summary prior to the aortic meeting in Morocco, I was really impressed that 30 studies in Egypt, Sudan, Libya, Morocco, Tunisia, Ghana, Mali, Nigeria, everyone trying to figure out what is the type of breast cancer that we find. And what we find is that there's really the data all over the place from in northeastern region having 63% that were ER positive to studies in West Africa showing 35% that were ER positive and South Africa showing 60% ER positive. I show this slide just to give you the impression that, in fact, if you look at African Americans, 64% in the U.S., and you look at U.S., Sierra Caucasians, 80% are ER positive, there's definitely heterogeneity in who is showing up and what type of breast cancer they have. And that's why we can't say one size fits all that we're going to have a population approach that treats breast cancer the same way no matter where they are. And this is really important because when I do my practice and I have the benefit of being a doctor, I see different types of patients and they come in different shapes and sizes and colors. And this is a 64-year-old white woman with interval triple negative breast cancer. Based on population data, this woman should get a mammogram every other year. And she went predictably March 03 and March 05. She was only two days late in terms of two years to the time. And yet her breast cancer was so aggressive, so highly proliferative, she only lived one year and didn't respond to any treatment we gave her. Okay? When you read the literature, you will think this only happens to black women who are poor and have no access to care. That's not true. So now the U.S. Supreme Court and a lot of things that really have opened up how we approach and what we do can be interpreted however we want it. So it says, you know, it takes 1,900 mammograms of women in their 40s to save one life, but only 1,300 of women in their 50s. It's more cost-effective. So just wait until you are 50 and stop calling us the death panel. Right? That's been some of the things that's been argued as we try to address the Affordable Care Act and what's covered, what's not covered, who should have access, when should we rationalize health. And I actually, you know, anytime you're thinking about any public health intervention, we always want to do cost-effectiveness analysis. And sometimes that cost-effectiveness analysis doesn't get us to the personal level where people in fact really want to have information about when should I get mammogram? How should I get mammogram? Is it going to help me survive breast cancer or not? So to move forward, I think that we're actually now post the mammograms age and I, there's a nice walk that we now do in Hyde Park with one of my African-American patients who decided that we should, you know, have mantras beyond mammography and she's trying to do a walk to let African-American women be aware of the fact that because you have had a mammogram doesn't mean that you're home free. So this is a very important 45-year-old woman who had a perfectly normal mammogram even at the time that she felt a lump in her breast. And because she was savvy and because she knew what to do in fact, because she was aware of her cancer risk because of her family history, she didn't stop there. She went, she got an ultrasound and she got an MRI and has this very tiny triple negative breast cancer. Okay, some of the stories I hear when I go on this walk with women on the south side of Chicago is the fact that they will show up to a doctor with a lump and they will say, well, you're too young to have breast cancer and so it doesn't get evaluated. Or, well, you know, maybe it's a boil when in Nigeria they will show up at the primary health center and these women have just started, you know, maybe they're lactating, maybe they've just had a child and somebody will tell them, well, you know, it's not breast cancer because you're too young to have breast cancer. Where the data are such that women of African ancestry tend to get breast cancer at a much younger age, both here and throughout the diaspora. And many of them will get breast cancer at the time that they're also lactating and having babies. And that's some of the epidemiology data that our work in Nigeria has shown. And so very often, these young women are misdiagnosed or not sent for appropriate diagnosis. However, if you are flat chested, you are not really endowed with a size D cup, it might be a lot easier for you to actually fill that lump. And a lot of women do not have the luxury of being small breasted and being able to fill a lump at the time when it's this tiny and it's picked up by both an MRI and an ultrasound. So the question is, what is the value of treating anybody to do breast exam? What is the value of telling anyone to get mammogram when it doesn't work 30% of the time? So all our public health interventions actually will fill women who develop aggressive triple negative breast cancer. So then what are we going to do about it? So my view of the world is why not just sequence everyone's genome? Right? If we knew who was going to get that type of breast cancer and we knew it by age 30, then maybe we can actually begin to personalize care. How did I come to that conclusion? Came to the conclusion because we actually know that there are some high penetrant mutations in genes like BRCA1 and BRCA2 that predictively they're very rare, but they will cause breast cancer at an early stage. And because BRCA1 is part of that gene pool, we've been really doing a lot of work trying to understand how BRCA1 and BRCA2 and some of these genes contribute to the early onset. The rare lills, the pathogenic, if you inherit them either through your father's side or your mother's side, you're predictably going to get early onset breast cancer. And then of course you have your ATM and other genes that now we have the ability to test for that have they're not that rare, but they contribute to increased breast cancer risk. And then a lot of people have done genome-wide association studies trying to look at common alleles that are going to be distributed in such a way that they may contribute to cancer risk. So this is a good model for us to think about in terms of population risk stratification, right? We started doing this work by looking for families. And families are rare if you are working in a place where people don't even have a know what a diagnosis of cancer is. People are going to show up not even knowing what their mother died for or what other diseases are in their family. If you are only focused on family-based ascertainment, people are adopted. There's so many reasons why people may not know their family history. And yet when these genes have been tested for, majority of 60 percent of women who at the time of cancer diagnosis identified to have BRC1 or BRC2 mutation do not record a family history of breast or ovarian cancer. So how do we pick those women up? So the question then is, you know, we ask that question in my clinic because we have, you know, we've had a tumor bank, African-Americans coming in, and all, you know, we've had data from European women, everyone who's really done linkage studies and who has case control studies, they've all been able to use next generation sequencing to look at the estimates of patients who are in their cohorts who develop breast cancer and have mutations in one of these genes. So we collaborated with Mary Claire King and we said, okay, let's just look at 289 African-Americans from the south side of Chicago that either I or my colleagues at the University of Chicago saw. And well over 80 percent of, 22 percent of them have mutations in one of these genes that actually confer a high risk of breast cancer. Okay. So clearly, this is not the end of this story because we only picked the ones that are definitely deleterious pathogenic. And so when we take it from having breast cancer as an ascertainment, one in five have a deleterious mutation. Then we did a study in Nigeria where that study has been in the field since 2002. And we also wanted to know what is the burden of mutations in these genes in this relatively young cohort of women in Nigeria coming in to have their breast cancer diagnosed. And you can see lots more variations, lots more genes that are in the DNA repair pathways, but the predominant genes causing breast cancer is still BRCA1 and BRCA2. And these are consecutive cases. And when we look at what's it, are they found out mutations? Of course not. Each one has their own personal mutation. And the mutations are in this large gene, 1863 amino acids, all across the gene. So there was no, initially we thought, let's do a quick strategy like we can do in women of Ashkenazi Jewish ancestry where three found out mutations explained all of their cancers. And for African genomes, you can do that because they're not found out mutations and you have a whole diversity and a spectrum of mutations that are explaining breast cancer in these women. Then we asked, do these women have a strong family history where they diagnosed, you know, we wanted, we were always looking for a shortcut way to actually find the ones who have mutations. So in the literature it was described that Eleon said breast cancer. So we said, okay, let's only sequence women who had breast cancer under the age of 40. And then we got an answer. But then now that we can do next generation sequencing, we said, why limited to women under 40, just sequence everybody. And when we sequenced everybody, what we found was that, yes, whether they were young or old, we found people with mutations, right? So under 45, about 12% of the patients with mutations and over 45, you still had mutations identified in these individuals. Most people didn't report that they had a family history. However, if you had a family history, nearly 22% had a deleterious mutation versus if they didn't report any mutations. And these are, you know, cases and controls and we're continuing to actually do this work so that we can really do population estimates of this rare deleterious alleles in as a way to look at who should be screened and who should have access to genetic tests. Because if we wanted to use the rules that we used in America to tell people to go and have genetic testing, majority of individuals who didn't have a family history would not show up and will not qualify for genetic testing. So this then tells me that in fact, there are individuals among women in the African diaspora and I can go on and on about studies in Bahamas looking at women who walk through the door and clearly 25% of them have their breast cancer because they have a founder effect mutation in Bahamas, which is an island. So there's a lot more work that we have to do across the African diaspora to actually estimate the burden of disease that these young women who are getting the most aggressive breast cancers have and where we have no strategy for cancer control in these populations, whether they're living in the U.S. or they're living in their home countries. Now let's look at tumors and the cancer genome atlas. The cancer genome atlas for those of you who are not cancer genomicists, this is one of the best things that's happened where we use sequestration money money during the sequester during the financial crisis to actually develop large-scale repositories and to do big science. So initially when the call was to go and sequence all the tumors, well it turns out that the tumors that were available to be sequenced were mostly tumors from white women and they had to do an extended call to get tumors from black women to be part of TCGA. So while there's been a lot of publication about TCGA and the genomic landscape of tumor in TCGA, we're now just beginning to analyze data in women of African ancestry and so we happened to lead that analytic analysis. And what's really very important and this is actually for my good because anytime we discuss culture and race and identity the question is should you use genomic race to do your analysis or should you do self-reported race to determine you know what it is that you are. And so in TCGA there were people who reported that they were black, they were white and they were Asian, Caucasian and of course the African ancestry Yoruba. And you can see when you do principal component analysis that the African ancestry group is really nicely clustered here and the Asian ancestry nicely clustered and then you have your Caucasian. But then there are the individuals around here who you know depending on how they self-report they can either say they're black white or whatever. But one of the things we wanted to do with TCGA was to actually look at you know if you do genomic race and the patient has self-reported as black so what are they? And so if you look at this most people who say they're black whether you do it by genomic or by self-report that was actually a very good concordance. There was very few misclassification where somebody thought they were white but they actually are black based on their ancestry or but there was no one who really thought they were black that turned out to be white when you do both genomic and self-report. So the question then is what is the best approximation when you're trying to figure out whether ancestry matters in terms of the proportion of African ancestry or whether just as the patient are you black or white right and then maybe that's the best way to do the answer and I think there's still a debate in the literature about that but the thing we really wanted to do was we wanted to know within TCGA people get different types of breast cancers. The most favorable breast cancer is your Lumina A breast cancer which is estrogen receptor positive and which is treated with hormonal therapy and then you have Lumina B which is estrogen receptor positive but it tends to be a little resistant to hormonal therapy. Then you have H2N rich and then you have basal like and you can see that the reverent the most favorably treated breast cancer the more African ancestry you have the higher the proportion of aggressive breast cancer that you are going to have based on TCGA data. Okay so when we unadjusted African American women more likely to have basal like breast cancer more likely to have H2N rich breast cancer adjusting for age more likely to be basal more likely to be H2N compared to your slow growing Lumina A breast cancer. No wonder population screening for mammography actually doesn't work especially if what you do is to have mobile mammographies go to churches and then this we may have to then wait to see who will take the breast tumor out or who will do the biopsy. So this is really hard data. Then we asked there are some you know a single nucleotide polymorphisms that have actually come out from GWAS of breast cancer and we wanted to know if those SNPs were genotyped in TCGA is it possible that there would be a little differences between the individuals who are genomically characterized as African American and those who are Caucasian or other races and clearly 46 of the 55 SNPs had different allele frequencies by race. So at the population level we know that the allele frequencies of every gene that is important is going to differ based on your ancestry and the diversity across the African diaspora makes it even more challenging. So then we wanted to know are there some alleles that actually are going to determine subtype and some of these have now been verified that there are actually some you know like the Babam1 SNP that predominantly depending on the allele that you inherit you might have ER negative breast cancer versus ER positive breast cancer. Okay so looking at allele frequencies then we ask the question is it possible that subtype so the different types of breast cancer that you get that it might actually be heritable. Now the challenge for this analysis is that the number of samples that we have in TCGA to actually do this complex analysis is only about 110. You need a larger data set to be able to really nail down the results but whether we when we look at it what we found is that at least when you compare Bezel versus Lumina A or Lumina B versus Lumina A Houttu versus Lumina A there's a very high likelihood that the differences in the different subtypes of breast cancer actually is determined by differences in the kinds of alleles that you have right. So again showing that your personal germline genome determines the type of breast cancer that you have and I bet it's also going to be the same for all types of cancers. So these are really and then we ask you know how about for estrogen receptor is it a heritable factor and you can see that in fact based on TCGA data you are more likely to have less expression of estrogen receptor if you have African ancestry genome versus not and it's not so compelling for Houttu positive breast cancer but these are really sort of big data science that is allowing us to get some insight about the biology of breast cancer and how it's distributed across different race ethnicity. So let me transition to what we have done trying to actually replicate data that we get from you know European ancestry women into African ancestry patient and so this is we've now formed a consortium trying to look at you know everyone who has samples just give us your samples and so samples from Barbados, African Americans, Baltimore, Philadelphia, Pennsylvania and I'm showing this just to tell you how challenging it is to actually do research that would be meaningful among women of African ancestry or populations of African ancestry just because the data sets are not there and because it's easier to get European ancestry data sets we're going to have a lot more knowledge about the diseases that impact those populations before we get any knowledge of minority populations that's just the way science is you have an idea you have a resource to do it you do the experiment you publish your data end of story but the story is actually just beginning because if we're going to get to precision medicine we need to do a lot of things so this is a very busy slide but I surely because every time we try to replicate what others have done in European ancestry because of the linkage you know the short LD blocks in African ancestry we can't do it until we repeat the experiment we do our own analysis and then we can trust the data that we have just because these are the top index markers in European populations and when we look for it in a polygenic risk score for African ancestry it just didn't do anything however when we mapped our own best markers in African ancestry population then we're beginning to see odds ratios that are actually meaningful and so that really has informed the kind of work we do because what we want to do is to now pull all the samples so this is the African-American breast cancer consortium we called our own African consortium the root because Africa is really the root of all of genetics and so in our discovery phase we had more than 1500 cases and controls from Nigeria and then we use the AMBA consortium which is the breast cancer in a black women's study to replicate some of our findings so clearly we're looking for SNPs that predict ER positive versus ER negative and by doing that we're beginning to actually identify SNPs that have genome-wise significance that are able to distinguish women in the population with ER positive breast cancer and ER negative breast cancer and we are really hoping that by doing this work we're going to be able to develop a polygenic risk model for individuals of African ancestry so let me end by then thinking about the big science that we're all doing which is really the signatures of mutational processes in human cancer the most important thing that's happening in oncology now is immunotherapy the fact that there are all these new antigens that are created and that you can use this new antigens to develop novel therapies immunotherapy vaccines that it's just unbelievable the how we can in fact advance the field I'm excited about it because the genetic the epidemiologists have always said that some of the risk factors or some of the genes that actually make you get cancer should also be target able right and so when we're looking at the mutation signature so everybody's looking at the significantly mutated genes in breast cancer and some of them just like ER, PR, they're drug-able and there's a lot of new drug discovery based on this mutational signature but what I think is actually really exciting is that we're able to do that experiment in a Nigerian cohort as well right because the genome technology is there and we can ask if you have ER, PR and HOTU positive breast cancer and you walk through the door in Nigeria do you have p53 mutation of course you do do you have HOTU amplification of course you do gutter one all of the genes that we can test for right is it important in your breast cancer of course it is so the question is if it is how do we get drugs how do we get treatment how do we actually make sure that this patients have their the tumor personalized so in the US the same thing the women who have been diagnosed in Alabama in Louisville wherever they are what is the mutation as signature of their tumors if we really are serious about reducing health disparities and improving health equity right what tools would they have to be able to do this they I love the way that the AIDS activists actually taught us what we needed to do in cancer you know with funding everybody went out and we had point-of-care diagnosis and now we're talking about the end of HIV AIDS in oncology we're just not serious about it yet because we're still only now at escalating how we treat cancer patients by finding more and more drug-able targets that extend life for a few months where women who actually have diseases that can be cured with targeted therapy are not being treated so we're looking at mutation as signature when you have a triple negative breast cancer versus not and you have p53 mutation what actually causes that mutation to occur it's we knew in studies looking at aflatoxin in hepatocellular carcinoma that there's actually a particular mutation that occurs in p53 because people were exposed to aflatoxin so for a Nigerian breast cancer study we're looking at cartridges and looking at the hyper mutation that occurs in particular regions of the genome to give us insight into what exposure might actually cause these cancers in this place where the exposure of a woman with breast cancer in Nigeria is going to be very different from the exposure of the women with breast cancer in Chicago what is common among those two and what is different and would that allow us to begin to understand population genetics and then gene environment interactions so we're really quite excited because when we then put everybody together and we look at if you have triple negative breast cancer and here's the west african breast cancer study and we've only done 40 exomes by the time I put this together we have TCGA black or african-american 22 we had twice as many Nigerians that we've been able to do and then TCGA 78 because there's just more triple negative breast cancer in Nigeria and that's where we went to try and get it it doesn't matter you can see their p53 they mutate p53 at about the same rate right there's no difference why is that the case however if you look at all that genes so take this in TCGA you're going to find that this gene is more highly mutated and you can see that the the spectrum of mutations among white women okay is different from the spectrum of mutations among black and african-american women whether they're in TCGA or not these are small numbers but they're telling us something about how genes interact with the environment so let me end by saying that there's a lot of things that we need to do to do population stratification who has breast cancer that just needs to have routine mammography who has heredity breast cancer who and who needs genetic risk assessment and needs to have more modern modalities or new modalities to screen them and so this is what where we are now where we're just telling every woman when you're 50 or 40 go and get a mammogram it doesn't work we have to do better now we're doing genetic risk assessment and we need to spend money where the money is to get people the care that they need and I think that at the end of the day when we don't have just one version of what women should do we're going to actually be able to get to precision healthcare and get better outcomes there's very exciting work now being done in radio genomics where you can actually classify from the first image that you get whether you know the prognosis of a tumor so all of these things really give me hope that we will get to the point where we can have precision management of individuals at the highest risk and then people who have low risk maybe they don't have to do much so a lot of people have heard about Angelina Jolie I've been doing BRCA1 mutation analysis now since 1997 and she's actually not the typical woman who has BRCA1 mutation most women all over the world are not dying to have their breasts removed in fact it's a barrier to having testing done if you tell them the only option is to go and have bilateral mastectomy yet in the US the only way people know about things is when celebrities talk about them okay and then they can't really relate to that celebrity because they're not going to have their breasts removed no matter what so what we know now from is that not all women need risk reducing mastectomies we know that because we don't have a way to screen ovarian cancer that we can actually reduce ovarian cancer death rate by having people tested this is why OB-Gynes are now all through their practices asking women to get genetic testing and we have a debate about that now we know that women with BRCA mutation actually need to be treated with PARP inhibition and now a lot of oncologists are doing testing positive trials in ovarian cancer prostate cancer and even head and neck cancer so the challenge we're going to have in oncology now are all these people who get tested because they were dying of cancer and then their at risk relatives have inherited the same genes what are we going to do how we're going to treat them so precision medicine i'm all for it but i think we need to really think about how this individual characteristics can actually be learned so this is the ad from my hospital they want you to come in and have you know specialized care genomics and personalized medicine but you're only going to come in if you have insurance right and then you're only going to come in if you can get into cutting-edge research so how do we do cutting-edge research in the places where people actually need it right how do we develop innovative clinical trials how do we use genomics for preventative care and treatment because certainly what we're doing now isn't working okay every oncology clinical trial if you do subset analysis will tell you that there's black white differences that the drugs don't work is it doesn't work or is it that it's the wrong medicine for the wrong treatment so let me end by saying that i've had the privilege of being a physician and a scientist and it's really allowed me to really have a different perspective of what it is that we're going to i think we need to really begin to engage in community based research and network so that we can get to where patients are we can deliver care where people can actually access them and we need all sorts of research in terms of implementation science and and we need to really think about how we do this global cancer research so that we all benefit because America is an immigrant country and people's ancestry does matter so my lab is very large but we have a lot of collaborators the GWAS data we had to put a consortium together a lot of people contributed to it and then of course the TCGA data is work of a lot of people so for team science we need diverse individuals who are engaged and then we need access to funding and the populations and NHI NHGRI can lead the way and thank you all so lovely to any questions any questions thank you for the talk interesting um so i have a question when you mentioned african ancestry um how much of that applies to entirety of Africa given that there's a huge so much diversity there and even in the United States you know as we grow to become a more diverse nation people's genetics you know people from different ethnic groups intermarry how do you think that will change the landscape yeah so so the the question is so the analysis we did we had to sort of say how much african ancestry are we going to really say is sort of driving the disease and we came to well if you have 50% ancestry then we're going to categorize you as african ancestry whereas with european ancestry it was clear so i think those are the kinds of challenges that we all have to solve as as scientists you know when you do your analysis are you going to do analysis based on what right is it one percent ancestry that's driving it or is it just a rare allele so i think the challenge is really that there's a lot of work for you you know i see that there you know good statistical geneticists here and population geneticists they need to help us because their little frequencies are different just talking about the us then if you go to africa every tribe has a different allele frequency right there's so much different so to do black and white it doesn't quite get it so i hear you and america is a melting pot there's going to be much more and more intermarriages so that the the the distinction by color will get sort of morphed and then the question is it doesn't matter or you know brca one is brca one if you have that disease or if you have that mutation if you get the drug that targets brca one doesn't matter whether you're black or white or asian it works right so that's why i'm thinking that precision medicine will actually get us to know what we're talking about and then march disease with the right treatment thank you for me for such an interesting talk so you mentioned in your somatic profiling analysis and so you mentioned that you found the patterns of the driver mutations and varied by race and so that might be related to the different exposures and so i just wonder like you know whether you could give us some idea about you know what kind of those exposures and how in your analysis how you can link uh these somatic alterations with the exposures okay that's your job i'm a doctor but that's the thing is that when you look at this and you see the pattern that actually varies then the next question is what's the exposure is it common and that i think is the beauty of global health the applebeck signature was first discovered and a lot of the the um shanghai breast cancer study and the alleles and the different types of breast cancer in asia may be different from what we're talking about but i think now we know that we should go and find the exposure because now we have this big big data showing us that something is smashing the chromosome and causing this mutagenesis what it is we haven't had the opportunity to do it before because we always ask people about their reproductive health history there this and there that maybe that's the wrong question that we've been asking so we have only 110 patients in tcga we're not going to be able to use tcga to answer that question but boy i hope we'll get money to go and ask the question in other cohort right and in the epidemiology study i guess you know now this is a direction right and so we would like to actually combine so integrate the the exposures and the somatic profiles but then like you know to begin with and of course you know you can only do a certain number of the the patients like you know for the this genomic analysis because they are very costly to do but then like you know to what kind of the exposure is like in your mind and so we because we have to we will collect the the epi data right the risk factor data but what what kind of the exposure yeah so i mean so the the important thing is that so so one of the things we learned from our nigerian breast cancer study was every time we asked the questions about what we know about reproductive health risk it was always in the opposite direction right the women had lots of children and the breastfeed for you know 120 months versus african-americans where the average number of months of breastfeeding was two months so they're not obese they're really very lean and they haven't eaten a lot of hamburgers so many of the risk factors that we associated with african-american here doesn't apply in nigeria and that's why every day we're looking at our data and putting different hypotheses and so what we want to do is an ecological study what are these women eating what are they doing and why the breast cancer in a low resource setting so there's a lot of questions really that i i think i just now ready to be answered because we have the tools to do it thank you thank you for a great talk i really liked your points about um health care disparities and the fact or the the challenge of delivering health care to those who need it most and i noticed um in your data a lot of your um samples come from nigeria but there's a lot of countries in sub-saharan africa with um very unsophisticated health care systems and lots of barriers to care so i was wondering like moving forward what do you see um as kind of a vision for addressing cancer diagnostic in those areas is it collaborations with genetic information from those countries that or is it developing point of care testing that may be applicable in places yeah actually my point is about local global they are parts of this country that don't have any sophisticated way to diagnose breast cancer and we still have to think about how we equitably distribute you know uh cancer care even in this country so i'm throwing it you know i met with the um fellows at lunch and i'm throwing it at everybody we all have to think innovatively even for those of us who have big hospitals and all that it's too expensive for us and we can't afford it our patients are going into financial toxicity because they can't afford the drugs that we have worked so hard to deliver to them so i think that we all have to work on this together and think about the low resource setting and how we can accelerate progress by getting the the studies done quickly and getting point of care diagnosis so that no matter where you are you have a chance to survive i mean that's it's that's just how i see it and when we started this you know delivering her to targeted therapy even in chicago northwest indiana there will be still people who managed to come to a clinic and had been seen by their local oncologist there's a 20% disparities gap between where you are treated and your outcomes just because there are not enough resources so equity health equity is a question that we all have to answer we have to think outside the box about how we all do it together whether it's in nigeria or it's here but we're in this global community and we have to work together across africa across latin america asia i mean there's just a lot of places that need help including my neighborhood thank you for a great talk and it's actually got my mind exploding about in trying to make a message to the public based on the data you showed today if 30 of the time a mammography isn't going to show the cancer yet in such a high percentage of women you're testing who already have breast cancer they're showing that they have mutations in your control group it wasn't very high i mean women who don't have breast cancer don't tend to have these mutations especially the age variation so what's the message um if because i think in our attempts the public health service to send a message out that for most women most whatever that means not stratified under a certain age you don't worry over a certain age you go more often and what you're saying is the most aggressive cancers are in the young women that may have mutations so what's the sound bite that we give to the public if there is one well you know the the the prevention task force actually already gave you the sound bite but we rejected that as a as a community there's no data that mammography helps anybody right and when we looked at the data and we looked at it and we massaged it politically we couldn't say don't get mammograms we said talk to your doctor and have your doctor recommend when and how you get mammograms and so now the affordable care art and and a lot of cancer prevention guidelines says for every woman do risk assessment the obi gynae have been very aggressive about it they pushed out information to all obi gynees and said test everybody but the geneticists were not ready we say oh there are too many variants of unknown significance it's too expensive this is the and we can't do it and we have to do the experiments first and so i don't think we have a public health message other than what the task force has said which is talk to your doctor and most doctors don't even understand the the nuances and most people are so afraid of genetics and yet you know you know your cholesterol level you know you know if you're obese you know your risk factors and so in cancer it's the genetics that we know now and until we know all the other things that we can measure it's a hard sell but i tell i mean i my clinic is a cancer risk assessment clinic and there are many people are embracing that and are trying to help families to know when to go for screening i made a click king and i have actually come out openly to say every woman at 30 should just have a genetic test done and everybody's oh it's too expensive well if the test is 200 dollars i'm sure everybody wants to do it but if it's 3600 dollars then we can't do it so the cost is coming down and i think at some point people are going to have the data to know the genotype phenotype correlation and people will be able to have access to it the question is will they come down enough for everybody and will generate i mean you know point of care diagnosis just like cell phones that we all use cell phones now in the most remote country place in Africa they have cell phones so hopefully the technology will really drive and the innovation will drive how we move this forward but the time is ripe to actually do it i don't know if i answered your question good that's the whole point that's why i'm here filming that lovely talk and and there's such diversity from each tribe within africa you wonder if you're better off to go to a place which has much less diversity i go back to think about the japanese migrants when japanese women had very low rates of uh breast cancer when they come to the united states their risk goes up over time with generation probably not because their genes are changing so is that an epigenetic phenomenon are their special genes that change or mutate what's happening there yeah thank you that's actually the part of my talk that i didn't get to because i've only really laid the framework for genetics i'm coming back for another talk in october and then we will talk about the epigenetics because in fact it's only even if i tell you about you know 20 you know one in five or 22 positive for brca one we're finding that in fact the regulatory region and the epigenetic changes in these tumors might actually just be related to exposure and to other things that are not based on your that you were born with a mutation so the field is exploding but you don't get epigenetics without your genetics right and that's why we really need to do a better job with measuring exposure measuring population differences and and then figuring out what exactly should we be measuring so i think you know the genomic revolution is giving us new biomarkers it may be that there will be blood-borne biomarkers that we can look at that would be better predictors than doing DNA analysis but i think this is what we have now this is where we are and the field would advance the more we are able to do these kinds of studies hi fantastic talk um so i like the direction we're going because we're opening a discussion about risk and knowing the differences between risk and people from african descent in america but we also need to look at more drug-able target so how can we have that conversation where we are looking at other targets and getting targets that potentially already FDA approved and seeing if we can use some of those already to to look at the triple negative like uh efgr for example and maybe i know some of the triple negative have a claudin's are involved so are you looking at some other targets and how can we get that conversation because at the end of the day you want to treat the cancer yeah thank you so so what we actually found where my first experiment at the university of chicago was to look at a database and to look at women that our surgeons had treated a long time ago because chemotherapy was sort of you know after the manhattan project sort of folded leon goldberg was an oncologist that was really treating uh leukemia patients and cancer patients with chemotherapy and if you didn't even get any new drug to the market but you treated everyone with triple negative breast cancer with chemotherapy and you treated them that woman i showed you with a small triple negative breast cancer she got new adjuvant chemotherapy had two more disappeared and when you have a pathologic complete remission with triple negative breast cancer it never occurs it's just if you know 50 percent of them don't recall so the issue is their drugs are work even for triple negative breast cancer the problem is most of it occurs when it's already too advanced for us to actually use effective therapies if that woman had been on the south side of chicago and she felt a lump the time he would take her to get to me or to get to anybody to treat her will probably be another six months to a year and the thing is these tumors have a high proliferation rate and they double right they're not slow growing so what happens is the mutation burden then increases the tumors are beginning to mutate and have different changes and then they become resistant to therapy so i think that implementation science means what we know works now let's do it right and let's not wait for a perfect situation to start implementing what we know works so if we can use chemotherapy use it well support women in their communities a lot of women with triple negative breast cancer will be cured of their breast cancer and those that are not cured they should be part of the research to find new therapies and there's certainly new therapies immunotherapy vaccines there's just a lot we can do but we need to organize ourselves where women wherever they live can have access because not every woman can come to the University of Chicago or come to the NIH so how do we equitably distribute resources in communities so people can get care on that note