Dr. Bryan Schneider and Dr. Milan Radovich from the Indiana University Health Precision Genomics Program are talking to Aaron about breast cancer, and some of the cutting edge treatments that are in use, and on the horizon.
The Healthcare Triage podcast is sponsored by Indiana University School of Medicine whose mission is to advance health in the state of Indiana and beyond by promoting innovation and excellence in education, research and patient care.
IU School of Medicine is leading Indiana University's first grand challenge, the Precision Health Initiative, with bold goals to cure multiple myeloma, triple negative breast cancer and childhood sarcoma and prevent type 2 diabetes and Alzheimer's disease.
Dr. Aaron Carroll: Hi, this is Aaron Carroll. Welcome back to the Healthcare Triage Podcast. Sponsored in part by Indiana University, School of Medicine, whose mission is to advance health in the state of Indiana and beyond by promoting innovation and excellence, and education, research, and patient care. IU School of Medicine is leading Indiana University's first grand challenge, the Precision Health Initiative. With bold goals to cure multiple myeloma, triple-negative breast cancer and childhood sarcoma, and to prevent type two diabetes and Alzheimer's disease.
This week I'm very excited. We're going to be talking about breast cancer, specifically triple-negative breast cancer. We've got two experts with us, Milan Radovich and Bryan Schneider, both of whom again, work at IU School of Medicine with me. We're going to be partnering as we've talked about before with IU School of Medicine over the next year to talk about topics that are both of clinical interest to the general public, while also talking about research and things that are going on, on the cutting edge to try to improve the way we care for those illnesses. I'm going to let both Milan and Bryan introduce themselves, and then we're going to get started.
Dr. Milan Radovich: Hello, thank you, Aaron, for having us this morning. My name is Milan Radovich. I'm an assistant professor at the IU Simon Cancer Center. I'm also a co-director of the Precision Genomics program.
Dr. Bryan Schneider: I'm Bryan Schneider. I'm an associate professor of medicine and director of the IU Health Precision Genomics Program.
Dr. Aaron Carroll: Part of what we're trying to do as well as is talk about sort of the different professions and career paths that people get to these jobs. Could you tell us just a little bit about your training, what your degrees are, how you got to this point?
Dr. Milan Radovich: Yeah, absolutely. Interestingly, I'm actually a genomic scientist, so my job is really focused on understanding the underpinnings of breast cancer. What causes this cancer, what are the mutations that have caused a normal breast cell to become cancerous? And so my training actually was in classical genomics and medical genetics. I got my undergrad in biochemistry, my PhD in medical molecular genetics at IU actually with Bryan, and had then the honor to join the faculty at the IU School of Medicine.
Dr. Aaron Carroll: Great.
Dr. Bryan Schneider: I am a classically trained MD and then decided to do my specialty in medical oncology. I do fun things like chemotherapy and pills for cancer, was trained by a great breast oncologist, George Sledge, and also had a translational laboratory and subsequently partnered with Dr. Radovich in opening the Precision Genomics Program.
Dr. Aaron Carroll: Great. I want to spend a little time talking about breast cancer in general, before we get into ... I've already got tons of questions about molecular genomics, but let's back up to breast cancer first. We had an episode recently where we talked about cancer in general, but I think it's worth even revisiting some of the bigger points. What is cancer to you? When someone says cancer, what exactly does that mean?
Dr. Bryan Schneider: Cancer in my mind is a normal cell in our body that has decided to go awry. What we know today is that it's gone awry because the blueprint has been altered in some way. When I think of breast cancer, I think of a cancer that is one we've known about for a really long time. It's actually kind of fascinating as you look through art and literature, we see references to breast cancer, way, way back, and that's because breast cancer, unlike a lot of other cancers is one you can actually see and feel without a big scans or really neat techniques.
Dr. Aaron Carroll: Why does breast cancer seem to dominate our dialogue so much? Why does it seem to be the cancer that people think about all the time?
Dr. Bryan Schneider: Breast cancer is one that has an amazing history, both politically and I think socially. I think in part, because it arises in the breast, so it has implications of privacy, sexuality, cosmesis, and a variety of other things. In addition to being the most common cancer to claim lives for women. Obviously through earlier periods in social history, it became one of, "Do I want to talk about this? Do I want to tell people about this?" To one that has really become an empowered topic? One that I think women and patients, family, and friends feel very empowered to do the right things, to make things better.
Dr. Aaron Carroll: Why is it the cancer that claims the lives of most women? Just evolutionarily. It just seems ... Why does breast cancer seem to occur so often?
Dr. Milan Radovich: That's really great question, what we know first is that it's the disease of aging. As the population continues to live longer, we're seeing more incidents of cancer in general and as we do with breast cancer. Interestingly breast cancer starts in the normal ductal cells, the milk ducts where the cells go awry and become cancerous. What we know is that over time that these cells within the milk ducts can accumulate mutations, and once they do transform and become cancerous. Why exactly these particular cells are more susceptible to cancers compared to some others? Actually we don't know completely.
We believe it probably has to do with the fact that it's undergone what we call more evolution, more cell divisions. But to this point we really don't know.
Dr. Aaron Carroll: Is it something that's always been there? Have women throughout history have had sort of a very high death rate of cancer from breast cancer, or is this something that has changed socially in the last hundred years? I'm asking this question because I read an article God knows how many years ago, where people were trying to make the argument, or scientists I should say were trying to make the argument that women who had more babies, or women who spent more time nursing, or women who spent more time either in pregnancy had a lower chance of breast cancer and therefore they were making an argument. I don't know if it's right or wrong, which is why I'm asking you. That when women were having more children spending more time pregnant, that there were lower rates of breast cancer. Now that we have a different society with less time spent pregnant, that breast cancer rates have lowered.
I have no idea if that is a complete myth that has been put forward by people who think that women are not spending enough time pregnant or having babies, or if it is actually true. Do we have any idea of that? Is that been why there's been a change or has there been no change?
Dr. Bryan Schneider: It's a great question. I do think there has been a definitive fluctuation and likelihood death from breast cancer. I think one of the good things is now that we are better at treating things like heart disease patients actually live longer and more likely to die of other things like cancer. The other I would say is that I think our tracking of cancer deaths was not all that good until more recently. I think in some ways hard to go back and understand that. I do think we know one of the major inflection points in likelihood of risk relates to use of hormone replacement therapy and our subsequent understanding of that. There's definitely been a downward trend more recently.
Dr. Aaron Carroll: Why does breast cancer kill? And this is something I brought up before. It seems like the cells divide, we have chemo, we have radiation, we have ... [inaudible 00:06:40] but it's still in the breasts. Why does cancer eventually kill you?
Dr. Bryan Schneider: That's a really important question. I think it becomes one of the most fundamental topics of discussion that I have with my patients when we talk about chemotherapy. Certainly it makes sense to cut the cancer out. I think most patients say, of course, I want to get this tumor out. But then when we talk about doing chemotherapy, many of them ask me, why do we do anything else? And the answer is we know that many tumors for whatever reason early on in its inception also seed its way into the bloodstream. Once a cancer cell has left the site where it started and makes its way to the bloodstream, it has the opportunity to seed up into different organs.
When this happens, it becomes very, very difficult to eradicate.
Dr. Milan Radovich: Yeah, absolutely. Metastasis is the number one killer of all cancers. There's a huge amount of research right now, trying to figure out the biology of metastasis. It's interestingly, a very inefficient process. As Bryan mentioned early on in the inception of the tumor, actually in the order of millions of cells will enter the bloodstream, but only very few will actually see it metastasize in a distant organ. That process of being able to get into the bloodstream, get out of the bloodstream, reside in a resident tissue that has nothing to do with its normal biology, where it came from, and then be able to form a tumor requires significant amounts of evolution of that cancer to be able to do that. Unfortunately, as once it begins to grow in those tumors ... I'm sorry, in those resident areas like the brain or the kidney obviously that growth impedes normal function.
Dr. Aaron Carroll: I never thought about that. I think ... Let me make sure I get this in. Because I envision metastatic cancer, like it's a fully operational robot ready to go. Like it knows how to go somewhere else, grab on, develop a blood supply. Try to ... But it doesn't, I would imagine. It's just a cell and it's a modified breast cell and if it went somewhere else, it wouldn't know how to latch on, it Wouldn't know how to command a new blood supply.
Dr. Milan Radovich: Exactly.
Dr. Aaron Carroll: So how does it?
Dr. Milan Radovich: It literally evolves. And its interesting some research that is hopefully soon to be published in IU actually discovered that the cells that metastasize in these distant organs actually begin to gain certain characteristics of the organ that it metastasized to. That the gene expression it's repertoire, it's genomic repertoire changes to be able to be hospitable to that new environment. It's a very interesting new type of biology.
Dr. Aaron Carroll: It's a podcast so people can't see me grabbing my head at this moment because this is mind blowing. It almost seems like it's becoming sentient it feels like at that point. That it's-
Dr. Milan Radovich: It literally evolves. This is what as a scientist is so fascinating about cancer for me is how amazingly smart these things are, and how quick and how adaptable cancer cells are. There's someone that one said that one dumb cancer will outsmart a hundred smart biologists. These things are programmed to survive and they will do anything they have to do to survive, and will adapt their genomes to do so. We've been thoroughly interested in really understanding what happens in this evolutionary process of a cancer going from this normal thing in the breast, becoming a pre-malignant lesion to a fully malignant lesion, to a metastatic lesion. That process of, of the biology of how that happens is obviously a hot area of investigation right now.
Dr. Aaron Carroll: It almost sounds like virus. It just sounds like-
Dr. Milan Radovich: Absolutely.
Dr. Aaron Carroll: ... it's trying to figure out how to survive in a hostile environment and make the new hosts do what it needs to do.
Dr. Milan Radovich: Very, very similar. This is actually a phenomenon we see in patients who have great responses to therapy. Where some patients will see almost near eradication of their entire tumor, but that 0.1% that's left has developed some sort of genomic evolution that allowed it to overcome that therapy and be able to continue to grow. We always explain to patients it's like weed resistance or antibiotic resistance. These things literally evolve to develop resistance to therapy.
Dr. Aaron Carroll: Okay. I'm going to ask you a question that's sort of two parts, and it might even be just the same answer. We talked last podcast about various ways to treat certain cancers and I imagine that breast cancer is going to be a bit different, but how in general do we treat cancer, or cancer best these days in your view, and then specifically what do we do most of the time for breast cancer?
Dr. Bryan Schneider: Yeah, so when we think about breast cancer, we always think of it in terms of a multidisciplinary approach. By that, I mean, for those patients where we feel that the goal is curing the cancer, we certainly think about eradicating the tumor. That usually requires surgery plus or minus some radiation therapy to that local region. But then again, as I mentioned what we really worry about in terms of the likelihood of potentially dying of the cancer is that potential for metastatic disease. In doing that, we think about some sort of therapy that covers the entire body, so systemic sort of therapy. Within that, we now have a variety of different tools.
I think those tools depend on the type of breast cancer we're looking at. I think for many years, we've thought of breast cancer as a single disease. What we recognize now with breast cancer, like many other cancers, is there's really multiple subtypes of breast cancer and we have to address them appropriately.
Dr. Aaron Carroll: What are the various subtypes and what are the different therapies you might use?
Dr. Bryan Schneider: Yeah, so the oldest subtype of breast cancer, one that we've known about for many, many years is the estrogen receptor subtypes. These are tumors and this accounts for about three quarters of all breast cancer. These are tumors that love estrogen. A very effective modality of eradicating these sort of tumors is suppressing estrogen. This can be done through removal of the ovaries or through a variety of tablets that lower the estrogen level. Another subtype that has been more recent is the, HER2 positive subtype. This accounts for about one in five tumors, and they carry a protein, simply called HER2, that acts like a gas pedal to drive this tumor.
There have been a series now of antibodies. These are antibodies literally built in mice to attack the HER2 protein in humans, which have markedly improved cure rates and markedly prolonged survival.
Dr. Aaron Carroll: I want to interrupt you only because I want to really delve into sort of the differences between what the two things you just said. One is it's a cell that needs estrogen to do well. The idea is we take the gas away. Are they that sensitive to estrogen that even if you just lowered the levels they die? I mean, is that what it is? They don't just slow down. They don't drop [inaudible 00:12:59] but they'll die?
Dr. Bryan Schneider: Yeah. Probably more women have been cured of breast cancer simply by lowering estrogen levels than any other therapy on the planet today.
Dr. Aaron Carroll: That's mind blowing. Basically you're taking out the ovaries just to lower estrogen and then that is it.
Dr. Bryan Schneider: It's not quite that simple. That is some of the older therapies, it's just removing the ovaries for premenopausal women. But fascinatingly there have been a series of tablets which really lower the estrogen levels substantially. In addition, there are some augmenting therapies that seem to help the anti-estrogen therapies too, that have evolved over the last couple of years.
Dr. Aaron Carroll: Okay. Then the second is with HER2. Are we putting anybody's in that attache to HER2 which allows the body itself to just recognize those cells as evil and clear them? Is that a reasonable description or ...?
Dr. Milan Radovich: Yeah. Exactly right. There's two functions. The one that you're mentioning is something called antibody directed cellular cytotoxicity, which essentially is simply, is allowing the immune system to recognize that cancer cell and attack it. Then the other, a function of those antibodies actually blocks the normal function of HER2. HER2's job is actually to promote cell growth and division.
Dr. Aaron Carroll: Is HER2 on all cells, and just more so on these breast cells? Or is it really only in these cancer cells?
Dr. Milan Radovich: Well, we know that HER2 does exist in some normal cells, particularly in the heart and few other organs, but in these breast cancers, they actually highly overproduces HER2. You see inordinate amounts of HER2 than you would normally see in a normal tissue.
Dr. Aaron Carroll: Is this an injection you give like in the arm or leg or somewhere else, then it just flows through the blood and it finds the breast, or does it have to be locally done?
Dr. Bryan Schneider: So again, in thinking about how we use systemic therapies, this is a infusion. One gets through the vein. The idea though is, again, this is going throughout the entire body with the hope to eradicate any microscopic disease that may be left around.
Dr. Aaron Carroll: It does that?
Dr. Bryan Schneider: It does that.
Dr. Aaron Carroll: This is where I fail to grasp ... That just seems too crazy to me. That it gets through every tissue, it finds every place. It does that?
Dr. Bryan Schneider: It does that. In the days before these anti-HER2 antibodies, the median survival for this sort of metastatic breast cancer was probably somewhere short of a year. Simply with the advent of these therapies, we're now looking at four years with many patients doing well for 10, 20 years now.
Dr. Aaron Carroll: How long does therapy take usually and how often is it?
Dr. Bryan Schneider: In the setting with which we are trying to improve cure rate, it's about a year of therapy, every few weeks. In the advanced setting where the disease has spread, we use the therapy indefinitely.
Dr. Aaron Carroll: So the people will be getting infusions forever?
Dr. Bryan Schneider: Throughout.
Dr. Aaron Carroll: Do they have lines for that, like in dwelling lines, or is it you just come in and get a shot?
Dr. Bryan Schneider: So for most of our patients they will get a port, which is a little ball that sits underneath the skin. This way it's not uncovered. They can swim shower bathe. Then we simply stick a needle into the port, which goes directly into the venous system so the drug can be administered.
Dr. Milan Radovich: Along with what Bryan said, the therapy is given indefinitely until that tumor is now evolved into ... becomes resistant to in the metastatic setting. Eventually after enough, HER2 therapy that cancer is going to get smart and figure out a way around it, just like we had chat about before.
Dr. Aaron Carroll: Right.
Dr. Bryan Schneider: But it is amazing. Unlike probably most other drugs, I have more than a handful of patients who've been on anti-HER2 therapy for over a decade and it seems to continue to work.
Dr. Aaron Carroll: I have so many questions, but I want it ... I'm going to try to come back to that before ... We'll just move on and then I'll come back to it. But so we've talked about estrogen sensitive, we've talked about HER2. Are there other subtypes of breast cancer that are significant?
Dr. Bryan Schneider: Yeah. So there's one additional major subtype that we think about. The estrogen sensitive breast cancers have an estrogen receptor and/or a progesterone receptor. The progesterone receptor is the stepchild that doesn't get talked about much. Then the third, of course, being HER2. As our targeting for HER2 got better, it left another group, and this became known as the triple-negative breast cancer, which simply meant the tumor didn't have the estrogen receptor, didn't have progesterone receptor and didn't have HER2.
Dr. Aaron Carroll: How common is that?
Dr. Milan Radovich: Makes Up about 15% of all breast cancers, is one that disproportionately affects younger women, so premenopausal women. One that also disproportionately affects women of African descent, and also women who carry the BRCA1 and BRCA2 genes will tend to develop triple-negative breast cancer. This is one that is clinically more aggressive because it hasn't benefited from the revolutionary therapies that Dr. Schneider mentioned in ER and HER2, and one that we at IU have major focus on in developing new drugs and treatments for.
Dr. Aaron Carroll: I wanted to back you up a little bit, because you said BRCA1 and BRCA2. Whenever I talk to women, they hear the words and they panic. Can you tell us what BRCA1 and BRCA2 are?
Dr. Bryan Schneider: Yeah. We know that there are certain genes that women inherit or changes, or I think of them as little typographical errors that we inherit. We know that inheriting mutations in the gene BRCA1, or the gene BRCA2 markedly increases the likelihood of getting breast cancer, and some other cancers for that matter too, like ovarian cancer and with BRCA2 pancreatic cancer.
Dr. Aaron Carroll: It's mutations in those that leave women predisposed to cancer? It is not necessarily that they get cancer. How often does cancer occur in people who have those mutations versus the general public?
Dr. Bryan Schneider: These rates very highly in part due to descent and ancestry. In general BRCA1 mutation carriers have anywhere probably from a 60 to 80% chance of getting breast cancer.
Dr. Aaron Carroll: Okay. That's high.
Dr. Bryan Schneider: So it's very high.
Dr. Aaron Carroll: That's really high.
Dr. Bryan Schneider: BRCA2 maybe a bit lower. Somewhere probably between 40 to 60%, but again, those numbers vary depending on the series one looks at.
Dr. Aaron Carroll: How many women have a BRCA1 or BRCA2 mutation, and are they all the same? Is it mutated or not, or are there many different mutations?
Dr. Bryan Schneider: Those are excellent questions. I think in the United States, it depends again based on ancestry and population and also the series we're looking at. But it probably ranges somewhere about three to 5%. For instance, Ashkenazi Jewish descent patients have a much higher likelihood of carrying a BRCA mutation. There are some other BRCA mutations in parts of Africa where the likelihood of this is markedly higher. Within the BRCA gene, there are multiple different areas that can be mutated that can lead to breast cancer.
Dr. Milan Radovich: There's probably over a thousand known mutations in BRCA1 and BRCA2.
Dr. Aaron Carroll: Do they vary in severity, or is it just ...
Dr. Milan Radovich: They can, there is some varying in what we call penetrance. what is the probability that the actual disease will manifest? But actually also and gender is another major issue in testing, is that we also know of a lot of variants that we don't actually know the function of them. There are some women who carry mutations in BRCA1 and BRCA2 and we can't tell them whether this is going to cause a disease or not. We call these variants of unknown significance. And not just in BRAC1 and BRCA2, but also other cancer susceptibility genes.
Something that we've actually personally been recently passionate about is really trying to figure out these types of mutations. What did they do? Characterize them, and be able to maybe provide some more definitive evidence for our patients.
Dr. Aaron Carroll: When you said those numbers at the beginning my mind started racing. I'm more of a health service research population level guy. When you say originally well 5% of women are going to have this mutation and somewhere let's say 60% of them could have significant disease. My mind is racing is like you've almost hit a number where its worth doing universal screening, but on the other hand, given that so many women are going to have problems and at a young age, you'd imagine we'd be able to identify most of at least a generation that has this mutation, and then just start looking at their children to see if they have it. Is there a discussion of how we best check for this? Is it, we check the descendants of people we've already found it in, since it seems the penetrance is pretty high? Or do we just try to pick everybody up period?
Dr. Bryan Schneider: No, that's a great question. There are actually a few thought leaders who do believe all women should be tested for BRCA mutations. I think as Milan alluded to, one of the major concerns are these variants of undetermined significance. Meaning if you do this population based, you're going to have a lot of patients who have these unknown variants, and this can lead to a lot of fear, a lot of excess of screening, invasive biopsies. It also can absolutely take down the healthcare system from a cost standpoint. I think there are a lot of concerns before we would want to implement this sort of thing, so that the healthcare system would be prepared to do this in the right way.
Dr. Aaron Carroll: That I'm totally in favor. Because we've done plenty of episodes and things like that on whether we have gone too far in the other direction with screening of otherwise healthy, low risk women, that we get to a point where perhaps we're now doing more harm to people who have even lesions that otherwise would not cause them harm. But clearly with a BRCA mutation population that is not the general population. We can't treat that with estrogen or trying to deprive the body of estrogen. We can't treat it with HER2 antibody, so what do we do for triple-negative breast cancer?
Dr. Milan Radovich: And it's a fantastic question. Right now a triple-negative breast cancer is treated with traditional chemotherapy. But the question is, can we be smarter with our therapies by better understanding the biology of this cancer and finding new therapies that are going to be potentially more effective? Research-
Dr. Aaron Carroll: Before I even stop you there. What is traditional chemotherapy? What does that mean and what does it do?
Dr. Bryan Schneider: Yeah, so when I think of chemotherapy, I think what me and probably most patients think about is putting in an IV and using a therapy that has a whole lot of side effects. The reason for this is most chemotherapies work very simply by killing fast-growing cells. In doing that, they kill cancer cells. But in doing that, they also kill a lot of our normal cells, which is why you see a lot of the side effects that we think about traditionally with chemotherapy.
Dr. Aaron Carroll: This is also why I think people sort of don't get it, but you intuitively know it. One fast-growing cell that you can see all the time are the cells that produce hair, which is why people in chemotherapy lose their hair. Am I right in that? Or [crosstalk 00:23:03].
Dr. Milan Radovich: Absolutely.
Dr. Aaron Carroll: What other cells in the body divide quickly though that could see side effects of chemotherapy?
Dr. Bryan Schneider: Each chemotherapy has unique side effects. I think in general, the lining of the mouth and gut divide quickly. You think about things like getting the mouth sores or mucositis, you think about nausea and vomiting. You think about things like diarrhea, hair loss, as you mentioned, damage to the fingernails and toenails. Those are uniform side effects for chemotherapy. The one I worry a lot about though, are the cells in the bone marrow. As the bone marrow turns over, this is what makes our red blood cells, so if they're low you can get anemic, but probably more importantly, your white blood cells, which fight off grow very quickly. When the white cells are suppressed, it increases the risk of serious infection.
Dr. Aaron Carroll: This works? I mean, chemotherapy goes in ... First of all, how does it attack fast growing cells? What's the mechanism by which it does that?
Dr. Milan Radovich: Each chemotherapy has its own independent what we call the mechanism of action. But one of the most common ways of these things work is by damaging DNA. Literally these molecules will enter the cell damage the DNA so these cells can't replicate anymore.
Dr. Aaron Carroll: Isn't damaging DNA how we got here in the first place with cancer though? I mean, do we worry about that?
Dr. Milan Radovich: Absolutely. Obviously there is this concern for secondary cancers down the road with certain chemotherapies, that we also know for pediatric patients who are treated when they're young that they can develop cancers later in life from these types of therapies, both chemo and radiation.
Dr. Bryan Schneider: Yeah. I mean, there's no pretending. No one likes the idea of chemotherapy and there's a reason for that. But what we do know is that for some people it works really well. Traditionally, if we have a patient with triple-negative breast cancer, we will often give them chemotherapy, then go to surgery. One in three patients, regardless of the size of the tumor will have no disease at the time of surgery. The surgeon is literally cutting out dead scar tissue. What we know about that one third of the population is the cure rate is probably somewhere around 90%. Fascinatingly, the other two thirds who have residual disease at the time of surgery, the curate drops from 90% to 50%. From this, we know that chemotherapy can make a substantial difference.
Dr. Aaron Carroll: Why are there cure rates of surgery so much less if the chemotherapy didn't work in the first place? Is it because the cells are different?
Dr. Bryan Schneider: Yeah. I mean, I think the hypothesis is if you can't eradicate what's in the breast, what is also not happening is eradication of the microscopic disease outside the breast.
Dr. Aaron Carroll: Why do the surgery at all if chemotherapy's ... Is it because we don't know until we do the surgery that it works entirely?
Dr. Bryan Schneider: Yeah. There's a lot of research right now looking at non-surgical intervention. Do we have imaging modality to tell us who doesn't need? Can we freeze what's left behind?
Dr. Aaron Carroll: Besides chemotherapy and surgery, are there other treatments for triple-negative breast cancer I mean?
Dr. Bryan Schneider: As Milan alluded to earlier, one of the causes or one of the frequent types of triple-negative breast cancer from those patients who carry a BRCA1 mutation. If you think a BRCA1 is a spellchecker when BRCA1's mutated, the cell has a lot of typos and this is what causes it to be cancer. There is a backup spellchecker called PARP. There is a medication called a PARP inhibitor that literally destroys the backup spellchecker so that there is complete chaos in the tumor and the cells spontaneously die.
Dr. Aaron Carroll: It's almost as if you're leaning into the mutation. Almost saying that it's functioning okay with the mutation, but we're going to make it even worse so it dies.
Dr. Milan Radovich: You're inducing catastrophe.
Dr. Aaron Carroll: Really? How does that work?
Dr. Milan Radovich: It's a concept known as synthetic lethality. What we know is if we get rid of one spellchecker the cancer can still survive by having the other spellchecker.
Dr. Aaron Carroll: But getting rid of the first spellchecker is what allows it to cancer to start?
Dr. Milan Radovich: Exactly. But if we get rid of the second spellchecker, now, the cells become dependent on the second spellchecker. If we get rid of it, we can actually induce this sort of catastrophe where so many DNA mutations have accumulated that the cell just cannot survive.
Dr. Bryan Schneider: But this is actually amazing. We had talked earlier about evolution of the cell. What we've also learned as while PARP inhibitors are a fantastic medication, the tumor can actually revert BRCA from mutated back to a normal BRCA. It resumes having a good spellchecker and becomes resistant to the PARP inhibitors. It's a game of chess.
Dr. Aaron Carroll: But if you remove the PARP, the second spellchecker, does that happen on every cell in the body?
Dr. Bryan Schneider: It does, but because the BRCA is mutated with two copies in the tumor, it becomes catastrophic.
Dr. Aaron Carroll: No I'm just wondering, does this wind up ... If one spellchecker going can cause cancer in the breast does removing the PARP spellchecker in other cells throughout the body allow cancer to start somewhere else?
Dr. Bryan Schneider: I would look at PARP as a less dominant spellchecker. I think the data to date would not suggest a marked increase risk of malignancy, but of course, one that we'll keep looking for.
Dr. Aaron Carroll: Okay. That's amazing. Okay. I assume, is this like an approved therapy or is this like something we're doing research on?
Dr. Bryan Schneider: This is actually an FDA approved therapy for BRCA1 mutation carriers ... BRCA1 and BRCA2 mutation carriers.
Dr. Aaron Carroll: What kind of results are you seeing with that?
Dr. Bryan Schneider: Again I think when thinking about triple-negative breast cancer, this is a disease subtype where we've not had any targeted therapies, so it's very exciting and that by simply using a tablet now that has a really reasonable toxicity profile, it has markedly improved the duration of response, and one that has definitely made its way very early into the cadre of treatments for patients with metastatic disease. I think equally important though, this is a drug that is now being tested in the curative setting, where hopefully the payoff is increasing cure rates.
Dr. Aaron Carroll: And it's just a pill you take? That would also seem to be much better, and certainly with a lifestyle perspective.
Dr. Bryan Schneider: Absolutely. I think people in this setting are certainly thinking about quality of life, but also not just side effects, but not having to come and sit in a chair for a couple hours every few weeks.
Dr. Aaron Carroll: Okay, so there are other therapies we're using right now? Or before we get into sort of research, this is sort of ... We discussed everything that's going on. All right, so where are we looking in the future? What are the areas of research we're [crosstalk 00:29:13]?
Dr. Milan Radovich: That's absolutely a fantastic question. One thing that we're lucky at IU is that we're home to the Susan G. Komen Normal Tissue Bank. This is actually the largest repository of normal breast tissue in the world. Over 5,000 breast biopsies donated for research. Prior to that tissue bank, we as researchers actually you'd be shocked, we would compare breast cancers to other breast cancers to figure out what's gone awry in a triple-negative, or we would compare it to benign tumors or compare it to adipose tissue from a reduction mammoplasty or whatnot. Having this resource has really revolutionized our ability to figure out what's really gone haywire in triple-negative breast cancer compared to normal tissue.
Dr. Aaron Carroll: Let me back up. Where did you get all the normal tissue?
Dr. Milan Radovich: It's amazing. These are volunteers. These are women who are from our communities, actually from a variety of different cities now that there have been collections who actually volunteered to come give a biopsy of their normal breasts. And you think, "Oh, that must be hard to get those volunteers." Interestingly, when they open up a slots for volunteers, they actually fills in a single day. The demand for people to want to donate tissue is unbelievably high.
Dr. Aaron Carroll: How do you do it? How do you get the tissue? Is it a needle? Is it you cut and take a piece? Or how does it work?
Dr. Bryan Schneider: Yeah. Very simple, it's a little bit of numbing medication on the breast and then it's a needle biopsy. The needle is pushed up against the skin and then it literally pops in and pulls out a little piece of tissue.
Dr. Aaron Carroll: Do you need a stitch or anything afterwards, or just that's it and you're out?
Dr. Bryan Schneider: That's it.
Dr. Aaron Carroll: I can imagine people would be interested. I'm not surprised that people line up to do this. How do people donate tissue if they were interested?
Dr. Bryan Schneider: Yeah. As Milan mentioned, there have been a variety of different focused collections where we're really trying to represent the diversity of women in America. The Komen Tissue Bank has a website for which they'll have information regarding upcoming events.
Dr. Aaron Carroll: Okay.
Dr. Milan Radovich: One of the things early on in our research endeavors was really trying to figure out, "Okay, what's really different between triple-negative breast cancer and normal breast tissues?" We embarked on a study where we applied some cutting edge genomic technologies to figure that out. What's interesting, there's about 3000 genes that are different between triple-negative breast cancer and normal breast tissue. To give you a little context, there's about 22,000 genes in the genome, 12,000 of those are at any time active in a cell, so about 25% of the active genome is different. That's a huge amount of variation. What we've come to find out over quite a bit of research is that many of these genes actually operate in what we call pathways.
If you think of the inside of a cell is a complex electrical wiring diagram, some of these nodes actually act in concert to elicit a certain biological effect, whether that is growth, metastasis and so on and so forth. What we've been able to discover is that triple-negative has some key pathways that we can hit with experimental drugs that may actually be effective. We at IU have really been passionate on this concept of drug combinations. How do we hit multiple nodes at the same time that have gone awry in these triple-negative breast cancers, and be able to elicit a effect? We actually just opened a phase one clinical trial of a new drug combination at IU looking at that.
Also moving on, we are really excited about this concept of how we harness new modalities in immunotherapy to target triple-negative breast cancer.
Dr. Aaron Carroll: I want to go back to the first thing you said, which is we hit the gene? What does that mean? What does that mean? Hit it?
Dr. Milan Radovich: Yeah, absolutely. What we do is we begin to identify these certain nodes that are highly active okay, so these are proteins that have gone aberrant in this cancer that are basically stuck in the on position. They're constantly telling the cell to grow, to divide, to metastasize. What we do is we partner with pharma and actually identify experimental compounds that will hit these new targets. What, I mean, by hitting them, actually turn them off, shut them down, elicit a new break. What happens is when we shut these down the cells lose their ability to survive.
Dr. Aaron Carroll: When we say shut it down even, are we talking about sort of like destroying that part of the gene or is it we just want to get in the way of building the proteins, or what exactly are you trying to do?
Dr. Bryan Schneider: I mean, I think kind of stepping back and thinking about this in a little more simple fashion. When you think of genes being accurately turned on, I think of this as the accelerator of a car being stuck on essentially. In what we really try to do is figure out where that accelerator is stuck. Then if we can find a specific drug to wedge off that gas pedal, this is what we think about in terms of hitting a gene or knocking that gene down.
Dr. Aaron Carroll: I guess I'm even getting into the molecular in my head, how ... Are you attaching a protein to the DNA? Are you attaching a protein to the RN? What is actually happening?
Dr. Milan Radovich: Getting a little bit more techie these molecules actually inhibit the catalytic action okay?
Dr. Aaron Carroll: Okay.
Dr. Milan Radovich: These proteins actually have what we call active pockets, whose job is to, elicit a certain catalytic reaction. These molecules will literally go in there and put a wrench in it, actually stop that catalytic action from actually functioning.
Dr. Aaron Carroll: Okay. Is it sort of like doing what HER2 does, but just for something else, or is it something different?
Dr. Milan Radovich: Sort of. Most of these targets are in the cell where HER2's on the top of the ... on the surface of the cell. Most of these targets are intracellular, so these drugs will actually go through the cell membrane, travel to the protein and we call actually bind it. It binds that catalytic pocket, puts a wrench into it and keeps that protein from functioning normally.
Dr. Aaron Carroll: Given that there are so many genes that could be going awry, in what you're describing, and therefore there are so many different proteins [crosstalk 00:34:41].
Dr. Milan Radovich: Correct.
Dr. Aaron Carroll: Do you have to make a different drug for each of these different things?
Dr. Milan Radovich: That's a fantastic question. The reality is we just can't make a ... We can't make a drug to every single protein, and not every protein is druggable. But we know that there are certain proteins that are probably the key mediators. And so what we're trying to do is really identify those key mediators, and by doing so hopefully elicit a more downstream effect that gets rid of all the other proteins it works with.
Dr. Aaron Carroll: Okay. How many of these do you think ... Is it just, you're making one, or are you working on a different number of these? How many key actors are there?
Dr. Milan Radovich: Oh my goodness. That's a very tough question. To the best of our knowledge if you're going to really press me to it, we're probably looking around a hundred.
Dr. Aaron Carroll: Okay. How many do you think we have, or do we have any? Where are we in the research?
Dr. Milan Radovich: We're really early on in the days of trying to figure out what are all the main mediators of what's driving cancer growth. This has been really made possible by advances in cutting edge technologies and genomics that were just made available in the last five to six years on a large-scale basis.
Dr. Aaron Carroll: That was my next question. How in God's name do you even do this? What do you do?
Dr. Milan Radovich: Yeah. What's been so fascinating is that you think about it 18 years ago it took $3 billion in 11 years to sequence a human genome. Right now, if you were to go to my lab era and I can sequence your genome for a few hundred bucks and a couple of days. Like cell phone technology has gotten cheaper, faster and smaller. Our ability to sequence genomes on a population scale is absolutely unbelievable.
Dr. Bryan Schneider: I look at this, like the days of the old, I remember growing up having an Apple IIe computer. Back then you could play a few video games and some simple programming. I think the same is true of genomic sequencing and its impact in medicine right now. I think we'll look back and think how naive and how simplistic we looked at a thing. Right now we're approaching this like go fish where you have a mutation, you try to find a drug, match it up. But the reality is we're probably looking at very sophisticated patterns, very sophisticated combinations, and also these very rare drivers, that account for a very small fraction of the population, but that ultimately as we learn more about it may start to cover a greater proportion of the population.
Dr. Aaron Carroll: But even if you can sequence the thing you think you need, how do you get it to fold correctly? I mean, how do you get it to become the molecule, the protein that you need to go in there and gum it up?
Dr. Milan Radovich: Oh my goodness. Yeah, that's a great question. This is an area of computational biology and drug development that is a really neat. What we know is we can actually now use really powerful supercomputers that will literally test millions of compounds computationally against these proteins to try to identify the right protein. I'm sorry, to develop the right drug to target that protein. Actually this is a lot of work now being done by our new chemical biology pillar at IU as part of our precision health initiative, using the best in cutting edge technologies to discover drugs that target all these various targets.
Dr. Aaron Carroll: Yeah. I'm just like literally my mind is blown. I'm thinking about my experience and this is incredibly minimal, but I did a little bit of ... My thesis in college was on organic chemistry and so I did a little bit of synthesis trying to make these tiny little molecules to [inaudible 00:37:52] and we failed every single time. The idea that you could build proteins or whatever these are, just maybe they're not proteins, but to go in there and sort of [inaudible 00:38:00] how?
Dr. Bryan Schneider: Yeah, but this is big teamwork, right? I mean, once we start to understand where the problems are, now you have industry pharmaceutical companies spending an entire pipeline on a given gene. You have academic institutions collaborating. This becomes a community-based teamwork that is certainly a daunting task, but at least now we know where the problem is, and this is a really good start I think.
Dr. Aaron Carroll: What are you guys working on now? Is this exactly what you're working on now?
Dr. Bryan Schneider: Yeah, and as Dr Radovich mentioned, I think there's a lot of work at the bench top and understanding what's gone wrong. But I think one of the areas of focus that has been passionate for us is moving this quickly to patient care.
Dr. Aaron Carroll: Sure.
Dr. Bryan Schneider: We also have a really neat ongoing clinical trial funded by The Vera Bradley Foundation, where we literally look at that population of patients with triple-negative breast cancer, who had chemotherapy upfront and did not get a substantial response to therapy. As I mentioned, the cure rate there drops from about 90% to 50%. In this trial we do cutting edge genomic technology on that patient's tumor, we identify a genetic problem. We match it to a drug that's in existence, and the trial actually randomizes patients to a tailored therapy versus a standard approach. Really the idea here is to embrace the question, does a personalized approach beat a non-specific approach?
Dr. Aaron Carroll: There was an article in the New York times that I was reading it was like this week or in the last week, and you must've seen it. Because it was [inaudible 00:39:32] talking about how the promise of personalized medicine versus what's actually going on. But it seems like this is one of the areas where the focus is. Where if there is actual progress being made at the patient level, it's here because we've identified a problem, we have a number of different options. It's a small concentrated population where we know where the genes are and we know we can look at. So is this the cutting edge of personalized medicine? Is this where progress is going to be made?
Dr. Bryan Schneider: Yeah, I think so. Again, I think it's always important to step back and take a good perspective of this. I think there was probably over-hype and overexcitement with this new technology for good reason. But I do think we're really in that logarithmic phase of the curve where the advances aren't going to be seen today, but the major advances are going to be seen down the road in a few years.
Dr. Aaron Carroll: This is an area where you actually are testing individual patients and then trying to ... Like this is where it is. I mean I hear it all the time and drugs where I'm like we don't even have three options, let alone to try to figure this out. But this is an area where we have a bunch of different options to try that we believe work better on people with different gene variants?
Dr. Bryan Schneider: It's a fantastic question. The answer is we do have a variety of markers. We have a variety of drugs, but if your question is, are we going to be a whole lot better at this 10 years from now when we have more ...?
Dr. Aaron Carroll: Yes. That's my question.
Dr. Bryan Schneider: Of course we will. We'll have more drugs, we'll understand a little bit more about what's functioning, we'll understand which combinations synergize best. Again, these are the very early days, and I think as we get better in all ways this is going to ...
Dr. Milan Radovich: It's also an extremely fast paced field. New biomarkers and new drugs are coming out literally on a weekly basis. Our armamentarium continues to grow substantially.
Dr. Aaron Carroll: This also seems like that each drug might treat a pretty small population. Is it super expensive to make each drug, or is it like now that the technology's there cranking out each individual drug is not as bad as it otherwise would be?
Dr. Bryan Schneider: There have been two recent reports of very rare fusions where two parts of different genes come together, where small molecules were developed. I'm talking this affects probably less than 1% of the cancer population, but in both cases, the response rates to these drugs were in the 80% range. While again, these are probably expensive while this accounts for a small population, this is where you see massive, good effects. I think down the road, these will be the way we approach all cancer.
Dr. Milan Radovich: I remember going to a plenary lecture at a major conference several years ago, where a prominent scientist came up on the stage and said, "We have discovered all the druggable targets. We have discovered everything in cancer that we're going to hit." The reality, that's just not the case. I mean, seemingly now at every major conference, we have a new discovery of some rare type of driver that Dr. Schneider mentioned, where we're seeing some major responses. I think we still have some more out there.
Dr. Aaron Carroll: When you find the new target, is this something that in your lab, you could create a drug? How big a deal is it to say, "Oh my gosh, we've now found this new target, we need to make a drug that [crosstalk 00:42:35]"?
Dr. Milan Radovich: Well developing drugs from scratch is a huge ordeal. Dr. Aaron Carroll: Sure, of course. Right.
Dr. Milan Radovich: Pharma will tell you it takes 10 years-
Dr. Aaron Carroll: I know right.
Dr. Milan Radovich: ... and a billion dollars plus.
Dr. Aaron Carroll: That's why I'm asking you.
Dr. Milan Radovich: Yeah, so as Dr. Schneider mentioned you could. You could start developing drugs from scratch, or you can actually start a little bit later in the process where you have drugs that are in trials or drugs that have been FDA approved, and then trying to find the right patient to match the drug. That allows us to really move the translation quicker to patients.
Dr. Aaron Carroll: Are we going to get to a point where it's like, okay, now we figured out the target, now I can just pop on this machine and just crank out the exact drug to get them ... because that seems to be the Holy Grail [crosstalk 00:43:12]?
Dr. Milan Radovich: Actually I do, but I don't think it's going to be with small molecules. I think where we're going to see this is in the concept of a vaccine based therapies and cell based therapies, where we actually design immune cells for specific personalized aberrations of a person's cancer and allow that immune cell to hone and destroy the cancer.
Dr. Aaron Carroll: That seems to be a more broadly applicable idea, that if we could ... yeah.
Dr. Milan Radovich: I personally think so. I do. I do. And so we're actually really beginning to see this. Actually the first example of this ever in breast cancer was just published a few weeks ago by the National Cancer Institute where scientists at the NCI took a woman with a heavily pretreated estrogen receptor positive breast cancer. Took out her tumor and actually isolated immune cells that were reactive for the tumor.
Dr. Aaron Carroll: Okay.
Dr. Milan Radovich: Okay? They took those immune cells, made huge numbers of them and then reinfused it and got a phenomenal response, actually a complete response to therapy.
Dr. Aaron Carroll: Yeah, so you hear about this, and I'm always skeptical when you have your out of one.
Dr. Milan Radovich: Yeah of course.
Dr. Aaron Carroll: But that at least I can wrap my head around that. Like I get it. It seems like if we could do that, that it would be something that could be more broadly applicable.
Dr. Bryan Schneider: Immuno oncology has become a huge excitement. Clearly all my patients are asking me, is this something for me? I would say in the world of breast cancer, we've not been great at it so far. What I would also suggest is with the drugs and approaches we have today, probably not all patients benefit from it. But as Dr Radovich mentioned, I do think for that subpopulation who gained benefit, it can be pretty substantial. What I think we have to do is get better at identifying the patients who are going to be those that respond to this sort of therapy.
Dr. Aaron Carroll: I mean, chemotherapy obviously has a lot of toxicity and a lot of side effects that are associated as well. Is there work or things going on to try to look into that or how we can make that better?
Dr. Bryan Schneider: Yeah. Interestingly for anyone who's had a family or friend with cancer, you'll know that many of them fear the word chemotherapy as much as they fear the word cancer. I think that's a reflection of the side effects that we see with chemotherapy. We've talked a little bit about those earlier today, but clearly also serious side effects like heart failure, things like neuropathy, where you get numbness, pain and tingling in the fingertips and toes that can be irreversible and life altering. Our laboratory with the help of funding from Susan G. Komen have really worked to understand which patients might be ultra susceptible to those sort of side effects so that we can better tailor our therapies, better counsel our patients and try to avoid them when possible.
As we mentioned before, whereas the DNA that each of us share is 99.9% identical, that 0.1% difference can impact drastically how we metabolize drugs and how our body accepts it. We've worked very hard to try to decode which patients carry those different changes that make them more prone to these side effects.
Dr. Aaron Carroll: I want to ask one other question just sort of broadly. You mentioned before how women are donating tissue and we'll make sure to put a link under the description of this podcast for how people could donate breast tissue if [inaudible 00:46:19]. What are other things other people can do to get involved in research and trying to make things better for everyone?
Dr. Milan Radovich: That's an absolutely fantastic question. We at IU have launched the All In campaign. This is a campaign that allows volunteers to be able to donate their tissue for research. We are actually right now collecting tissue on 500 triple-negative breast cancer volunteers, where we'd like women to donate their tissue and also fill out some history and telling us a little bit about their disease and their background. Where we will actually do a full comprehensive genomic characterization of that tumor, of which that data will then be used for research. And primarily for our work in drug development, in toxicity, in understanding better immunotherapies.
What we'd really like to do is get a lot of diversity from a variety of racial and ethnic groups. We really like to encourage these women to donate their tissue. If you go to our Precision Health website, there's more information there on how to donate.
Dr. Aaron Carroll: We'll make sure to put that link below in our description.
Dr. Bryan Schneider: I think what we're looking at is, as we fight cancer, we look at this as a team effort. Certainly I think there are lots of things that our constituents and people in the community can really do to help out. Not only do we hope to educate the population about breast cancer, we want to be educated about what patients feel the gaps are in terms of our learning.
Dr. Milan Radovich: Yeah, we really want patients to feel empowered that not only are they fighting their cancer, but they can help other people fight their cancer. One of the easiest ways to do this is to participate in research.
Dr. Aaron Carroll: Yeah, you know it's [inaudible 00:47:44]. We talk about research all the time. I think maybe ... probably we don't do a good enough job to encourage people to participate in that kind of research, but that's how we move the ball forward.
Dr. Milan Radovich: Absolutely. There's something empowering about them being able to be altruistic through giving their tissue. And what we are also tasking ourselves is making sure that they also know what we're doing with that tissue and the research and impact that it's having. We're very, very excited through this campaign to really have a, I think what is a great back and forth relationship with these donors.
Dr. Aaron Carroll: Well, that's great and certainly we'll have to have you back here to talk about how all of that is going in the future. Well, I can't thank you both enough for being here. Thank you again. Dr. Milan Radovich and Dr. Bryan Schneider. Thank you so much. We'd love to have you back in the future and talk about what progress is being made.
Dr. Bryan Schneider: Thank you for having us on.
Dr. Milan Radovich: Thank you.