Over the last few decades, scientists have discovered that breast cancer is not one disease but many. Understanding the differences between various types of breast cancer can lead to innovation, more effective treatments, and more comprehensive approaches in research overall. One breast cancer that researchers are uncovering new treatments for is invasive lobular carcinoma (ILC), also known as invasive lobular breast cancer. It’s the second most common form of breast cancer in the U.S. and accounts for 10-15 percent of diagnosed breast cancers, but it has long been misunderstood and understudied. As Dr. Adrian Lee’s research demonstrates, the unique biology of ILC requires new treatment and new ways of thinking.
The goal of Dr. Lee’s laboratory is to translate basic cell and molecular research findings to breast cancer treatment. With fellow BCRF investigators Drs. Steffi Oesterreich (Lee’s wife) and Jorge Reis-Filho, he launched a first-of-its-kind ILC biorepository, which was made possible by a legacy gift to BCRF from ILC patient advocate Leigh Pate. A BCRF investigator since 2013, he is the Pittsburgh Foundation chair and director of the Institute for Precision Medicine at the University of Pittsburgh and UPMC. He is a professor of pharmacology and chemical biology and a professor of human genetics at UPMC Hillman Cancer Center and Magee Women’s Research Institute.
Chris Riback: Dr. Lee, thank you for joining me. I appreciate your time.
Dr. Adrian Lee: Thank you for having me.
Chris Riback: I thought we should start with the context and two topics that jumped out to me in regards to you, and I’m certain they’re connected and you’ll help me understand exactly how. One, of course, is precision medicine, which you seem to have dedicated your career to. And the other is invasive lobular cancer, which we may end up calling ILC. So let’s start with the former. What is precision medicine and why did it speak to you?
Dr. Adrian Lee: Yes, so I think we’ve been very fortunate in breast cancer to be leading the charge in precision medicine. The idea of precision medicine, it’s a relatively new concept. It was only coined in 2011 so we’re 10 years into this. But it is the idea that with these great new technologies and our ability to understand the molecular features of disease, rather than calling a disease by the symptoms or the person who found it, that’s traditionally the way, why don’t we call it by the driver, the mutation, or the DNA change or the protein change, that’s causing the disease? So breast cancer has led the charge in that. For example, estrogen receptor–positive breast cancer was because estrogen receptor was identified 40 years ago. So in breast cancer, we’ve had this way to be more precise about describing the disease and a better description allows us to be better about treatment of the disease. And so I’ve been keen to use laboratory research to try and better define the disease.
Chris Riback: And it’s so interesting to hear you frame it that way because as I was researching and thinking about it, I kept coming across almost-interchangeably precision medicine and personalized medicine or personalized care. And that description, it makes sense why the growth, if you can kind of chart it in personalized care and I would imagine as well the transformation in the thinking around prevention care once somebody has cancer, even the progression of the growth of the personalized aspect of that care must be directly aligned with the development and growth of precision medicine. Am I understanding correctly?
Dr. Adrian Lee: Yes. And maybe I could just say one sentence on that because I teach this and it’s quite a confusing area. So healthcare has always been personalized. The way the physician asks you about your personal history relates to your risk and treatment in the future. So that was always personalized. The difference is now it’s precise based upon our ability to measure these features, be those features in the tumor or be those features in blood. It’s precision medicine leading to personalized healthcare, enhancing our personalization of healthcare. And in breast cancer, we have this array now of tests that allows us to really define the disease and try and give the right therapy to the right person at the right time. Tailoring better efficacy and lower toxicity, for example.
Chris Riback: That’s super helpful. I appreciate your increased precision in the explanation. And I promise I would be the student coming to you afterwards and saying, “Well, professor, can’t I get partial credit on this answer? I mean, I didn’t get it completely right, but at least half credit here, please.”
Dr. Adrian Lee: I ask that question. I ask when I teach it, I ask that on my grading exams afterwards. I ask that exact question and see what their answers are and it’s quite interesting. I think over time, people have become more comfortable with the term “precision medicine.” You might remember that President Obama, I think it was 2015, had the Precision Medicine Initiative.
Chris Riback: Oh, no. I don’t.
Dr. Adrian Lee: So in that, the government gave $100 million to start the kind of catapult of what’s happening with precision medicine. And they started something called the Precision Medicine Initiative, which is now called All of Us. And in All of Us, a million individuals are donating blood and biometrics. They already have done this on 750,000 individuals and that led to the great rise in the use of precision medicine and, I think, in the understanding of it as well.
Chris Riback: There may be a book there, professor. So let’s move to invasion lobular cancer and what is unique, if you would help explain for me, in its biology that distinguishes ILC from other ER-positive diseases.
Dr. Adrian Lee: Yes, so that’s a great kind of follow on from precision medicine is that what precision medicine says is that if we can better define the disease, the taxonomy of the disease, what makes the disease, we can then better understand it and better treat it and get better outcomes. That’s the premise. And ILC is like that.
So invasive lobular cancer, or ILC, is a histologic subtype of breast cancer. It accounts for about 10-15 percent and it has a very specific change which the others don’t have. It has a mutation in a gene called E-cadherin, its gene name is CDH1, and this is a protein that causes cells to stick together. And when you mutate that gene and you lose that protein, cells now can’t stick together. Because of that, it has very unique features, which is very different from the other [breast cancers], and those features are important clinically. So because the cells don’t stick together, they grow very differently and they’re very difficult to image the tumors.
So a fundamental understanding of the molecular basis of the disease, the E-cadherin mutation, leads to the phenotype, the different growth, which leads to a problem with imaging. So that’s the premise of precision medicine that we should probably pay attention to that. That leads to other features. Because it’s difficult to image, it tends to be detected later, which is bad. It has different types of recurrence, it tends to recur later. And then it has different sites of metastasis, very different sites of metastasis. So all of that is related to the original definition of disease, the precision medicine, if we can measure the mutation.
Now, funnily enough, we’ve known this for years. For 40 or 50 years, pathologists have looked and said, “Oh, this is a different type, 10 to 15 percent. So 40,000 cases a year of this unique type.” But there was really no research to try and understand why or what’s the importance of that. It was simply lumped together with the more common form. So I run the laboratory with my wife, Steffi, and she was really one of the pioneers in forcing this field forward and in the last 10 years have made fundamental understandings and increased awareness. You would say 20 years ago, if you look in the records, people just won’t consider it. Now I think it’s kind of come to the forefront that people should be trying to understand this.
Chris Riback: And as I understand it, you are focusing on inhibiting tumor growth. And what I found myself wondering was does that mean tumor growth from zero to the first stage, which as a lay person I would characterize as prevention or early spotting? And I’m hearkening now to what you just said a moment ago that one of the characteristics of the cells not sticking together is that they become very difficult to image, and so one sees them later. So I’m wondering is that what you are kind of focused on? Or we’ve identified the tumor finally, or I’m sure part of what you’re working on is trying to identify it obviously as early as possible, but we’ve identified it finally and now we want to prevent it from growing further. So we’re in the spectrum, or is the answer to that, “Yes, everywhere in the spectrum”?
Dr. Adrian Lee: That’s a great question. I haven’t been asked that before, but I think it’s very thoughtful, the question. It’s very hard to study the early parts of the disease. To do prevention research, it’s incredibly difficult. We don’t have many good models of it. And in humans, the disease when we detect it is already there so it’s just hard to do that. Our current goal is really a focus on, as you said, the established disease and how do we treat it? So nearly everyone dies of metastatic breast cancer. They don’t die of that early disease. If we can catch it early enough and do surgery, we can cure most of those patients with surgery, radiation therapy, and standard therapy. But it’s the patients, 40,000 dying a year from advanced or metastatic breast cancer. We really, in our lab, are focused on that.
I think it is true that most approaches to treatment in that setting might relate to preventional treatment of the early disease. So, if you take, for example, hormone therapy, tamoxifen [this is true for HER2 therapy as well] most of them act very well in the advanced setting, they work well as adjuvant once the disease has been cut out, and then they also work as tamoxifen for prevention, for example. So I do think that many of these ideas we learned from helping reduce the rate of death from metastatic breast cancer might be moved into earlier settings, but we don’t study that in our lab per se.
Chris Riback: And so let’s talk about the part that you do study and inhibiting the tumor growth. Talk to me about your studies there please.
Dr. Adrian Lee: Yes. So to try and put this in simple lay terms, when you lose this E-cadherin gene, something has to compensate for that because the cells have to adapt, because now they’re not stuck to each other. They’ve lost their natural environment and so they’ve adapted. And if we can identify those adaptions, those are probably requirements for them to grow, that maybe that’s a dependency that we can then block and then kill them off. The E-cadherin isn’t there so we can’t target that, but we can target the thing they’re now dependent upon, or this requirement. So we have ways in the laboratory where we can identify those dependencies and then target them. And the most exciting thing is what we study in the BCRF grant is that one of the things that happens is that when the cells don’t bind to each other with this E-cadherin, now it’s not sticking the cells together.
What happens is this frees up growth factor receptors that drive growth and they become hyperactive. And this has been shown by us, been shown by a number of groups now, and that gives you a potential therapeutic target because we target these pathways all the time in breast cancer. So we first showed that the loss of E-cadherin upregulates a classic growth factor pathway called IGF1 receptor, and there are drugs targeting that in clinical trials. And most recently, we showed that it also upregulates HER2, which is one of the major drivers of breast cancer and there are lots of drugs available for that. So this is this kind of translational relevance. We’re trying to identify these therapeutic vulnerabilities. Hopefully, we have drugs already available or FDA approved, and we can then use those in our models and hopefully move those into clinical trials.
Chris Riback: And so the part that folks always become interested in, which is rubber actually hitting the road, where are you in the stages of those studies? Are you re-finding patients or people to join? And what’s your hypothesis?
Dr. Adrian Lee: Yes, so I think the pre-clinical laboratory and pre-clinical data is very solid. I mean, you have different levels of confidence. I’d say probably it’s the highest level that this, we’ve done as much as we can relatively do. And so now, as you said, the rubber has to hit the road. Does it work in the clinic? And sometimes it does and sometimes it doesn’t. Maybe our models are wrong, for example. So we have been discussing the idea of testing these growth factor receptor inhibitors, specifically in lobular cancer. And I think there’s a number of clinical trials in development that are floating around to do that. I think there’s quite a lot of interest from pharmaceutical companies to do that.
So, there’s a number of concepts at the moment where we will do trials, specifically in lobular cancer, to try and understand better imaging, for example. Such that we can better understand response and then tailor the therapy, make sure that maybe we will increase, put in this growth factor receptor inhibitor, or maybe we’ll decrease some form of chemotherapy. So we have quite a few of those trials now in development.
Chris Riback: Excellent. And when you do work like that, does it involve, so there are so many clinical trials going on obviously. There are so many, let’s call them, banks where various samples are being collected. Do you do this type of work by connecting with those types of groups or other partners, or do you need to create a unique cohort and that one very hard part of the job is getting that cohort together? How do you attack the problem?
Dr. Adrian Lee: Yes, so I think that’s generally been the problem with lobular cancer. Because it’s only 10-15 percent of the whole of breast cancer, any one study doesn’t have enough to have the power because the study is powered on the total. And then if you take 10 percent of it, it’s never going to have the statistical power of the whole thing. And so you need the community to come together. And actually, that’s what happened in the last five to 10 years. It’s like studying a rare disease, yes? It’s not rare, 40,000 women a year, but it’s rare compared to the total. So basically what we’ve seen is this real coming together of those groups to say, “Hey, there should be a focus on lobular.” We’ve now had lobular cancer as educational sessions at the San Antonio Breast Cancer Symposium. BCRF was very helpful in that they were one of the main sponsors of our recent ILC Symposium. So we held a meeting here in Pittsburgh in September 2023. That was the biggest yearly meeting. We had over 220 people come.
Chris Riback: Wow.
Dr. Adrian Lee: The audience of that meeting was a third physicians, a third scientists, and a third lay patients and advocates. That’s pretty unique. Normally, that would never be that. And that was a great opportunity to share these ideas and concepts, like you said, to share knowledge, share models, talk about tissue banks, all of those things. All those things you said came together. And particularly for something that’s challenging, like a rare subtype of this, you need to have community to get those things done. No one is going to be able to do it alone.
Chris Riback: That’s super interesting. So the fact that this was at Pittsburgh, obviously I’m assuming that means that you generated and ran or led the conference. I mean, that would seem extremely rare for researchers, scientists, heads of major departments and medical efforts, such as what you represent, to include patients, or advocates as you say, at a symposium on the topic. And please, you’ll correct me if I’m wrong, I would think that frequently the incentive is for scientists to talk to scientists or maybe scientists to talk with pharmaceutical companies or potential funders. One, am I right? And two, regardless of whether I’m right or not, what’s the inspiration and the thesis behind including people who maybe, let’s say, have the most stake in the game?
Dr. Adrian Lee: Yes, so I think that last statement is you summed it up, is the patient has the most stake in the game. I think they had somewhat been excluded for a number of years. Stephanie and I were lucky to be trained at Baylor College of Medicine, where they were one of the earliest to incorporate [patient] advocates into their specialized program of research excellence in breast cancer. So we had a training in needing to do it. And when we came to Pittsburgh, we formed an advocacy group immediately called the Breast Cancer Research Advocacy Network. This is a Pittsburgh local group that meets every month, about 15 women meet every month to discuss research and help researchers. And then when we held the very first ILC symposium that was held in Pittsburgh in 2016, I think 35 advocates came to that because it’s kind of natural to us that advocates should have a say and be involved.
And there was a patient there, Leigh Pate, who drove a lot of what’s happened in lobular advocacy. She was a tour de force. She had an incredible ability to communicate. She was an incredible writer. She unfortunately passed away recently, and she does have a legacy. She donated money to BCRF to develop this legacy, which is a biobank we’re developing of models of ILC that we characterize and then we’ll make publicly available to everyone. So I think it’s kind of all come full circle. I think her spearheading advocacy in 2016 really drove a lot of these groups to form, and now you have this huge international advocacy. I mean, she really was the pioneer for this. And there were many others involved, but she really kind of drove the subject.
And I think patients, particularly when it’s been understudied, have really raised awareness through social media, through advocating, and I think that’s been good. And it’s driven a lot of scientists to think, “Yes, I should be studying lobular.” It’s easy to do that easy science. Science is never easy, but you kind of drift to the thing that’s a bit easier. And it’s hard to study a disease where you’ve got to collaborate. That’s not easy so I think that’s been a good thing.
Chris Riback: What a remarkable legacy. Isn’t that a wonderful thing? Tell me about you. How did you get into this? Was it always science for you growing up or did you just marry into the business?
Dr. Adrian Lee: I married my wife into the business, yes. No, I got my Ph.D. in London and came to San Antonio. San Antonio, at that point, was the mecca for breast cancer in the US. That’s where the San Antonio Breast Cancer Symposium formed. Nearly all the top leaders were in San Antonio. And Steffi, my wife, got her PhD in Berlin and was recruited around the same time when we met and married, had our kids there. Breast cancer has always been a passion. I think both of us feel we are lucky to have a job where we’re doing our passion. It’s one of those kind of rare instances where our job is part of our life. Obviously, we have a work-life integration, not a work-life balance like many scientists, and our kids would tell you the same. They didn’t become scientists.
But I think we get great joy particularly, like you just said, with the advocates of seeing patients and explaining. We do a lot of lay presentations. I run the Correlative Science Working Group for the [BCRF-supported] Translational Breast Cancer Research Consortium, and I gave a lay talk about biomarkers to advocates last week. I think you said this, you were the one that stated this, they have probably the biggest stake in the game and we should be listening to them around toxicities, all of these things. They’re the ones facing that. And so I think we take their comments seriously, and we appreciate hearing from them.
Chris Riback: And growing up, was it always science for you? Was there a chance that you might become a great musician or that literature was a passion? Or from day one, you were busy experimenting with chemicals or something in your parents’ kitchen?
Dr. Adrian Lee: That’s interesting you say that. There’s no science in my family. I have four brothers. They all do something incredibly different. None of them do the same thing. One’s an engineer. One’s in big banking. One’s in computer science. My dad was a painter and my mom worked, but there was zero science. I think like many, I got the opportunity to work in a lab when I was 16, and it was very transformative. I have this passion to learn. I do. Like most scientists, I am continually wanting to learn. I’m not very satisfied to stop at the status quo. Every day is a different day in the lab. There’s never a day that we are just doing the same thing. Every day is, most days, “This didn’t work and we have to figure out what to do next.”
Chris Riback: Now what?
Dr. Adrian Lee: When it does work and you get a grant and you get a great clinical trial or a great translational result, it can be super fulfilling. And as an example of how it’s changing, one of the biggest things that’s changing is computational biology.
Chris Riback: Yes.
Dr. Adrian Lee: In your life, you’ve already used AI 15 times this morning, yes? It’s integrated into everything you do. Some people don’t want to believe that, but it is. It’s driving everything you do now, from your use of the internet to everything. And that’s true in our research as well. We’ve really had to adapt to learn computational biology. That’s one of my newest things is I’m doing a lot of high-performance computing, supercomputing. I wasn’t trained in any of this.
Chris Riback: Yes, wow.
Dr. Adrian Lee: I’ve learned it on the fly and it’s not an easy data sharing and handling and wrangling. Data is not trivial, but it is exciting to have another kind of stage and another kind of thing to learn.
Chris Riback: Yes, what a terrific opportunity. And I couldn’t agree more. The field for someone who is, let’s say, genetically inclined to be a continual learner, where that is instinctively a passion, you’re obliged to do that. In fact, people like you are partially perhaps to blame for it because you keep discovering something new and that necessarily requires continual learning and learning something new. I can understand why that’s inspiring, and I thank you and your wife and others like you for that continual work, that inspiration for the rest of us. And thank you for taking the time with me today.
Dr. Adrian Lee: Thanks for having me. Those were great questions. It was a very nice conversation.
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