Breaking Down Personalized Diagnostics in Breast Cancer with Dr. Joshua LaBaer
By BCRF | November 12, 2021
By BCRF | November 12, 2021
Can breast cancer be found with a blood test? What role do genes and proteins play in developing cancer? What, exactly, are personalized diagnostics? We spoke with BCRF investigator Dr. Joshua LaBaer to answer these questions and more.
Dr. LaBaer is one of the country’s foremost investigators in personalized medicine. He serves as executive director of the Biodesign Institute, director of the Biodesign Virginia G. Piper Center for Personalized Diagnostics, and the Dalton Endowed Chair of Cancer Research at Arizona State University. Dr. LaBaer's research involves discovering and validating biomarkers to detect cancer and other diseases early.
Chris Riback: Dr. LaBaer, thank you for joining. I appreciate your time.
Dr. Joshua LaBaer: It's a pleasure to be here.
Chris Riback: So, speaking of time, in reading about you, the absolute first question that came to my mind was did you have time to sleep at all in 2020? Were you awake for 366 days straight? I mean, you didn't have enough diseases, different diseases you were working on, and then COVID came along?
Dr. Joshua LaBaer: 2020 was definitely a pretty busy year for us. Our usual research activities keep us pretty busy, but the advent of COVID-19 hit us here, in Arizona, pretty hard. At a couple points, we were leading the world in new cases. And there was not enough testing. And so, our lab was busy with that.
Chris Riback: Yes. Busy with that is just a slight understatement, of course. You were... preeminent might not be the exact word you might choose, but delivering the saliva-based testing among the many revolutions that many scientists contributed to our society, but that work of you and your team was obviously fundamental for all of us. So, thank you for that.
Dr. Joshua LaBaer: Thanks.
Chris Riback: Aside from that little piece of work, let's talk about the many other areas. And we'll have a particular focus on breast cancer. And maybe, before we get into your work specifically. Among other things, you are a scientist and a researcher, in a lot of areas, including breast cancer, but you have also received personally what you called the phone call.
Dr. Joshua LaBaer: Yes.
Chris Riback: And that changed not only your personal life, but I also believe, in some ways, the trajectory of your professional life. Tell me about it.
Dr. Joshua LaBaer: Absolutely. I mean, I'd been a medical oncologist. That was my specialty. And I was a physician at the Dana-Farber Cancer Institute when I got a phone call from my mom that they had found a mass in her breast, and that she was diagnosed with breast cancer. It's one thing to treat patients. It's another thing when it's a family member. It's a whole different feeling, right. And being a physician is a mixed blessing there. On one side, you know that, because you’re a physician, you can help in ways that maybe people who aren't couldn't, and especially because you're a cancer doctor.
But at the same time, your mind immediately does all the math and you already start thinking worst case scenarios because you've seen them all. And so, all of that was kind of going on at the same time. And yes, it was not an easy situation having to sort of think that through and try to offer her help. Of course, she was across the country. I was in Boston at the time and my mother lived in the Bay Area, so you can't immediately sort of come to her house and help her with all that. But yes, it definitely changed the way I thought about things.
Chris Riback: Yes, I would imagine so. It does for so many people, in so many different ways. The major difference, obviously, for most folks, is what you described. You're in the business. So, relatedly to that, let me ask you a question that you once posed maybe more than once, but once that I've seen, that you posted publicly. Can we find breast cancer with a blood test?
Dr. Joshua LaBaer: That's a great question, so not yet, but we are making great progress in that direction. So, we do have a screening test for breast cancer and that nominally is mammography. It's a special type of x-ray taken of the breast. And there are certain findings that indicate the presence of cancer.
It often can find cancer. It also though has its limitations. It does miss a fraction of real cancers. And a lot of the findings by mammography turn out not to be cancer. In fact, 80 percent of the time, that mark if you identify something, it's not cancer, so most of the time it's wrong. So, that puts a limit on it.
Chris Riback: Man, the false positives make for a lot of anxiety and maybe some unnecessary surgical work.
Dr. Joshua LaBaer: Oh yes, plenty of unnecessary surgery. Yes. It's not just anxiety. It is unnecessary surgeries. Women have to go for biopsies, where they have sleepless nights waiting to get the pathology results back from those studies. So, it absolutely leads to procedures that might not be necessary. And then, there are some women who their breasts, because of density or other issues, are prone to false positive results. And so, they're frequently going back to the clinic because someone saw something that they're not happy with and have to get yet another procedure. And so, this is where a blood test could be very helpful. A blood test could help us find those cancers that get missed by mammography. And importantly, those blood tests could help us identify women who may have had a finding, but is unlikely to have cancer.
And so, that was an important direction that our laboratory sort of took off on, was could we help identify what we call biomarkers? These are things that are circulating in the bloodstream that indicate the presence of cancer. And the hope of course is to find those cancers early, because the earlier we find the cancer, the better chance we have of stopping the disease. In my mother's case, for example, by the time it was positive in the mammogram, it was already pretty advanced. And so, who knows? If there had been a blood test for the earlier mammography, maybe it would've tipped people. When we went back and looked at the old mammogram, you could see something that was at the spot. It wasn't enough to call it, but it was there. Maybe a blood test at that time might've helped.
Chris Riback: I saw, at one point, a statistic you'd noted that the blood tests, or at least in a trial, and you'll correct me if I'm getting this slightly wrong, reduced the biopsy rate by 63 percent, which kind of knocked me off my chair. I mean, that's a... What a massive percentage. So, where are you on the trials? And what do you see ahead on this part of your work?
Dr. Joshua LaBaer: Right? So, the markers that we identified were licensed out to a company called Provista [Diagnostics]. And they ran a number of prospective clinical trials. What they found in those trials was that the test that included these markers was... had what we in the business call a strong negative, predictive value. That is to say that, in women who don't have cancer, the test said they didn't have cancer most of the time, 90-something percent of the time. So, that was looking very positive.
Unfortunately, Provista ran into some business challenges. And so, right now, they don't exist anymore. And so, the test has now been transferred to a new company. They plan to offer the test at the end of this year. So, the test is right now not on the market, it's kind of waiting. This is where science meets business.
Chris Riback: I was going to say, I mean, you're solving all the scientific problems. Perhaps, for your next trick, you can solve all of our business problems as well.
Dr. Joshua LaBaer: Right, right. Diagnostics is always a funny space in medicine because if you offer a drug, people are willing to pay for a course of therapy. But that’s not always the case if you order a diagnostic test. And sometimes the diagnostic tests are critical because they can save you all that therapeutic stuff. And the clinical trials you have to run for diagnostics are not that different from the clinical trials you have to run for a therapeutic.
So, it's often very expensive to get a diagnostic to market. So, this is a battle that we in the diagnostic space are always fighting. We're always trying to remind people how important it is to be able to find something, because you can make such a difference if you can find it early.
Chris Riback: Yes. Well, boy, this surely could be a whole separate conversation, but it feels to me like you may have just described a metaphor for the US healthcare system overall, and some of the challenges. This could really change the way we treat cancer in the future, couldn't it?
Dr. Joshua LaBaer: A lot of us agree that a key element of cancer management in the future is the ability to find it as early as possible. Cancer typically takes many years to develop. Many studies that have been done here suggest that it may take well over a decade for cancers to develop in our bodies. So, the key is, can we find them when they're still small and before they've spread?
Because most of the time is where the damage occurs, is when the cancers breakout and spread around our bodies, something that we call metastasis. And oftentimes, cancers may form initially in the breast, for example, or if it's a lung cancer in the lung. But where they cause their damage is when they spread to the brain, as it did in my mother's case, or when it gets to other parts of the body, critical organs, and such.
Chris Riback: Yes. And I've had the privilege of having conversations with other researchers like yourself, some of whom are focused really specifically on the metastasis issues, and how to recognize when it's starting to travel and if it's arrived someplace else. And yes, particularly with breast cancer, metastasis is just among the massive challenges, which actually may help describe some of what I want to ask you about next, which is, what are personalized diagnostics?
Dr. Joshua LaBaer: Right. So, personalized diagnostics is an interesting term. On one hand, those of us who are physicians always know that, from the day we became doctors, we always personalized our care. In the very early days of medicine, people described symptoms. People would say that the patient has a fever or the patient has diarrhea. And that was the diagnosis at the time. In the 17th and 18th centuries, people recognized that there were different causes of those things, and that, by recognizing the cause, you could be more precise in the treatment of that thing.
And then, I would say, in the 19th and the 20th century, the dominant tool to look at that stuff was the microscope. Doctors would get specimens from patients. They would look under the microscope and they would make a diagnosis. And when I went to medical school, a diagnosis might be something like ductal adenocarcinoma of the breast, and it looked like something under a microscope. And that was the diagnosis. What emerged in the last bit of the 20th century, and it's certainly dominant in our 21st century, is the addition of molecules to that process. So we now know that ductal carcinoma of the breast can actually take many different molecular forms, something called luminal A, or luminal B, or HER2-dominant, or triple-negative. These are all terms that you'll hear doctors use now.
And what they're referring to is molecules that they see in the cancer. And the pattern of molecules in those different cancers tells us that they behave differently, that they respond to different drugs, and that they may have a different prognosis. And so, by recognizing those different molecular forms, we can be more precise in what we know the patient has, and we can be more precise in treating the patient. And so that's what we're referring to as personalized. Some people now use the term precision diagnosis to kind of more referred to that molecular form. And the better we get at understanding those molecular forms, the better we can get at treating those patients by knowing how to tailor our therapies to the specific molecular form that that patient has.
Chris Riback: And what is the p53 protein? And why does it demand so much of your attention?
Dr. Joshua LaBaer: Well, p53 is a protein that was identified well back in the 20th century. And it's the most commonly mutated gene in cancer in human cancer. It is mutated in many, many cancers. It was controversial when it first was identified because initially it was thought to be what we call an oncogene, a gene that drives cancers. And then, later was found to be the opposite. It was a gene that prevents cancer called a tumor suppressor gene. And then now it's come around full circle. And there are elements of it that act both as a tumor suppressor gene and as an oncogene, which may explain why it's so commonly mutated in cancer. People have referred to it as the guardian of the genome. It's a gene that somehow prevents mutation in its activities. But when it gets mutated, it can definitely cause trouble and lead to cancer.
It is commonly found in breast cancer. It's especially commonly found in a type of breast cancer called triple-negative breast cancer.
Chris Riback: The triple-negative, yes.
Dr. Joshua LaBaer: And triple-negative refers to the lack of the estrogen receptor and the progesterone receptor and the HER2 receptor. And so, women with that type of breast cancer often have mutations in their p53 gene. And we and many, many other scientists are trying to better understand how mutations in that gene lead to cancer, and perhaps a little bit understand this sort of dual role that this protein plays, both as a protector against cancer, but also, when mutated, as something that helps drive cancers.
Chris Riback: And if I'm understanding correctly, some of your work is to try to determine how to reactivate that protector part, how to reactivate the tumor-suppressing powers. And so, where are you on that? Is a challenge how do you activate the good without also stimulating the bad part of that protein?
Dr. Joshua LaBaer: One of the funny elements of p53, and one of the reasons we believe that it has these sort of dual roles, is that, classically, when a gene prevents cancer, then anything that messes it up, any kind of mutation that messes it up like a deletion or a truncation, meaning they cut it out completely or break it into pieces, that's typically the kind of mutation pattern you see with genes that prevent cancer, but p53 doesn't follow that pattern. Most of the mutations found in cancer have very specific point mutations. They have very subtle changes in one or two what are called bases, these little letters that are in our DNA alphabet. One has changed, just one subtle change. And that changes everything. It causes the cancer.
And so, that's the pattern you see in p53, which would be more typical for the genes we call oncogenes, genes that drive cancer. So, what our group has done is we've identified the 10 most commonly mutated changes that occur in breast cancer. And we've introduced them into a cell line that doesn't normally have a mutant p53. And we've asked, what does it do there? How is it changing the behavior of those cells in a way that leads to cancer? And do the different mutations behave differently? Which they do. And what other genes are they collaborating with to cause the cancer? And that latter question is an important one because it turns out that cancer is not commonly caused by single gene changes. Most cancers arise because multiple genes have changed over time.
Recall that I mentioned earlier that cancer takes well over a decade often to occur. And during that time period, multiple genes are getting altered. And so, what we're trying to understand is how do we under... What other genes are participating with the cancer? We're doing that because, as you mentioned, what we really want to do is replace the good function of p53. Well, it's hard to give back a function. So, what we're looking at is, well, maybe these collaborator genes, these other genes that are also helping cancer, maybe we can block those.
Maybe, if we identify what those other genes are that are working together with p53 to cause the cancer, that will be a target that we could inhibit, we could block, and at least prevent part of that cancer causing pathway. So, we've actually gathered up a huge amount of information, on these different mutant forms of p53. And the goal, of course, is now to get all that information out there so people can use it to help identify where to target those cancers.
Chris Riback: In listening to you right now, also in reading about you, it was evident. You just talked about we. And reading about you, a word that I came across a lot is “team.”
Dr. Joshua LaBaer: Yes.
Chris Riback: Talk to me about that. Because many of us outside of science, we've got this image. There's a crazy mad scientist, maybe someone who looks a little bit like you, in a white lab coat, working all night in bad lighting. How do you describe a team approach to science research? And why does it matter?
Dr. Joshua LaBaer: The team is everything in science. And I think that's only becoming more and more the case as science advances further and further. Years ago, when I was a graduate student, it was not uncommon to find what I would call boutique scientific labs. They were small labs, five or 10 people working on a very focused question, using a kind of technology that their lab had developed, and using that approach to solve their problems. But as science has advanced more and more, and we've gotten much more technological, now, the kind of science that my lab does involves whole teams of individuals, because we're using very high technology. So, part of what, frankly, BCRF has been critical for, for us, is enabling us to build a library of genes for humans. So, we've built the largest collection of full link genes anywhere on earth.
We now have nearly every human gene assembled, because we want to look at how those genes might participate in causing cancer. Well, to do that, you need a team. You need people who are good at computers to identify those genes and gene sequences and assemble them in a format that allows you to produce the clones. You need people who are good at robots to be able to run the actual devices that can actually run thousands of genes at a time. Because doing something five or 10 times, you can do by hand, but doing something a thousand times, you need help with. And then, of course, we need people who are good at chemistry to set up the assays that those robots will activate. So, you need people with lots of different scientific expertise, people from different disciplines, to come together in a group, in a team, to make this sort of thing happen.
That became critical, for example, when we set up our COVID testing as well. We had to have people from eight or 10 different disciplines come together as a team, working in parallel to make big things happen. And so, the modern science, modern biology, really occurs in a coordinated team approach. And part of the fun of it, frankly, is learning how to speak all those different scientific languages, and sitting at the table when all those different people are talking in their different languages, and bringing them all together so they can all understand each other and work as a group. It’s really a lot of fun.
Chris Riback: Yes. It sounds like it. And it sounds like people like you are part scientist, part conductor, part maybe multi-lingual translator. And it's a wide range of skills. As we close out the conversation, how did you get into this? I mean, was it always science for you? Were you ever thinking you were going to maybe be an orchestra conductor instead, or did you know from the start you were a science guy?
Dr. Joshua LaBaer: So, it's interesting. When I went to college, I had in those days, the classic middle-class notion that I was either going to be a lawyer or a doctor and very quickly decided that I didn't want to be a lawyer. So, I knew I wanted to be a doctor. But then, I took this course in organic chemistry from a very famous organic chemist at Berkeley [named] Henry Rapoport. And that organic chemistry course, it was an honors course. The difference between the honors course and the regular course was rather than doing cookbook experiments, where you basically do the experiment because you know it's going to work, we did a multi-step long-term synthesis of a molecule that we learned early in the course had never been made before.
Chris Riback: Wow.
Dr. Joshua LaBaer: And when I heard that, something tripped in me. I thought, "That's pretty cool. We're doing something that no one's ever done before?" And the more I looked into research, I realized that's what research is. It's about doing things that people have never done before. And it's about standing on the edge of human knowledge, and looking into the dark, and saying, "I'm going to go out there and I'm going to discover something new." And when that bug bit me, it bit me hard. I thought, "I got to do that. Whatever I do in my future, it has to be about discovering new things."
And so, then I decided that if I was going to do... I still like medicine, but I had to do the PhD part, I had to do the research part. And since that time, I've always been a physician-scientist. I love medicine, and I love caring for patients, but what I love the most is discovering new things. And so, that sort of set me on that road. And then, as I got further and further into science, I think my passion for learning different disciplines of science and learning how to integrate them only grew. And that's kind of how I ended up in the role I'm in now.
Chris Riback: Well, we are grateful that you're in the role that you are in now. How would you describe your role at BCRF?
Dr. Joshua LaBaer: It's hard to overstate the role that BCRF plays. With our role as scientists, we always have to justify what we do by writing what are called research grants and these applications to get funding for what we do. The funding mechanisms in this country are fantastic, but they are complex. And they are often challenging. These days, it's gotten so competitive to get some of those grants that you have to have already done the work, to get the funding, to do the work that you're trying to apply for. And sometimes, when you have a creative idea, like the type of protein microwaves that my lab does, or cloning a large library of human genes, it's just not something that the government is set up for funding. And they're just not going to even look at it.
And that's where BCRF comes in, because BCRF helps fund the investigator, and they say, "Look, you're a creative person. You've done very good work on these other things. Let's give you funds to do something new, to do something creative, to do something that you might not get funded from an NIH grant, or it might take you years to get funded, and we don't want to wait that long for you to get that funding. We want you doing that right now."
And so, it has enabled me to do projects that I just could not easily get funding from NIH. And I've been pretty successful at getting funding from NIH, but there are some things I just can't get from them. And BCRF is sort of willing to fund us to do those things just because of what BCRF does. It's been phenomenal.
Chris Riback: Well, that's terrific, and glad that it has been, but more importantly, thank you. Thank you for your time. Thank you for the work that you have done and, in your words, kind of standing on the edge and staring into the darkness, trying to find the light for the rest of us.
Dr. Joshua LaBaer: Thanks very much.
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