Triple-negative breast cancer (TNBC) is an aggressive subtype of the disease, and treatment remains a major clinical challenge because it lacks the three major receptors (estrogen, progesterone, HER2) that targeted therapies can successfully home in on. Immunotherapy, which harnesses the body’s own immune system, is a major focus in TNBC research but questions and puzzles remain; namely, how TNBC cells can avoid attack by the immune system. Solving that could lead to new and better immunotherapies.
That’s just one of the many research challenges Dr. Hope Rugo has taken on. Another: Determining whether or how circulating tumor DNA in blood samples can be used to predict metastatic breast cancer or treatment resistance in patients with aggressive breast cancers.
A BCRF investigator since 2007, Dr. Rugo is the director of breast oncology and clinical trials education at the UCSF Helen Diller Family Comprehensive Cancer Center. She is a medical oncologist and hematologist specializing in breast cancer research and treatment, as well as a professor of medicine and an active clinician.
Chris Riback: Dr. Rugo, thanks for joining. I appreciate your time.
Dr. Hope Rugo: Thanks so much for having me.
Chris Riback: Obviously, I want to talk with you about your extraordinary work and career, but in researching you, the most pertinent question quickly became obvious. Is it true that at eight years old you saved up your S&H Green Stamps to buy a children’s chemistry set from a Sears catalog because you knew even then that you wanted to be a scientist?
Dr. Hope Rugo: It is in fact true. I thought that science was the coolest thing at the age of seven and eight. Of course, I started saving those green stamps at seven.
Dr. Hope Rugo: Then, you could go to the counter at Sears and buy that chemistry set. That’s something I had wanted and worked towards for quite some time, and indeed, it was all it lived up to be.
Chris Riback: Yes. You’ve certainly graduated from that Sears chemistry set and done just a couple things.
Dr. Hope Rugo: It was amazing what they would let little kids have at that time. I don’t think they would now. You could make all sorts of fizzy things and things that went poof and that was very exciting.
Chris Riback: It sounds like it. I also read where you’ve described working in medical oncology as a tapestry of experiences. The word, of course, tapestry, brings such kind of harmonious visions to mind. What did you mean by that?
Dr. Hope Rugo: Working in medicine is already a tapestry of experiences and practices, but in oncology, in particular, there is a necessary melding of many different aspects of biology, science, personal aspects of care, compassion, communication, dealing with the early aspects of life all the way to the end of life by bringing in all of the different elements of medicine, science, biology, human interaction, and also by collaborating among professionals in many different specialties within medicine and the extended fields of medicine. I’m not working in other fields, but I think oncology, more than any other field, manages the whole person and you’re not organ-focused. You really are looking at the whole person, the whole biology of the interaction of that person with their environment and their family and their goals, as well as trying to understand what the cancer is doing to driving to both develop into dysregulated cells, and then what promotes that growth and changes that biology over time.
Chris Riback: Can I tell you in these conversations that I have had, perhaps the most surprising, but really, in a sense, the most uplifting and motivating comment that I have heard is the way in which so many different disciplines, the ways in which it brings almost literally everything together, psychology, emotion, biology, so many different aspects.
Dr. Hope Rugo: Yes, I think so. I think that one of the really tremendous opportunities and gifts that is part of clinical and translational medicine. Being a clinician is an incredible skill, but being a clinician where you can also interact with your laboratory colleagues and do clinical research, I think brings together the different aspects of medicine in oncology in a very unique and special way. It’s interesting, if you’re in the lab, you have to see the perspective from the laboratory into the clinic, and if you’re in the clinic, you have to be able to draw the aspects from the lab that aren’t yet applied to the clinic and think about novel ways that you can move forward, so there are those aspects on both sides.
When you’re a clinician, you have that additional aspect, which is just communication and understanding, which I think is a quite unique aspect of clinical oncology, where we really are talking about a scary disease and how to manage it and what the optimal treatment options are at each step of the way, and then interacting again with our psychologists, our social workers, our geneticists, et cetera, to try and provide that optimal care, so you have all those different aspects brought together in one area.
Chris Riback: Let’s talk about the disease, the treatment, and the care. Why don’t we start at the most basic level, because I think that understanding the risks your patients face will provide context as to the challenges around improving the response to immunotherapy and understanding the mechanisms of resistance in aggressive breast cancer. What is triple-negative breast cancer and how is it identified?
Dr. Hope Rugo: When I was training, we had something called Non-A, non-B hepatitis, meaning that it didn’t fit into any of the markers that we could identify, and it turned out to be hepatitis C and a number of other liver inflammatory conditions, but that’s how I first thought about triple-negative breast cancer, and indeed, we’ve evolved far from there, so we, in the 1800’s, understood that most breast cancers seem to be hormonally motivated, I think driven by hormonal mechanisms because if you had a woman who was premenopausal went into menopause, the tumor could shrink. That was the first understanding that the majority of breast cancers seemed to be driven by receptors for estrogen and progesterone and can be their growth, in many situations, can be driven by those hormones. Then, we identified that a subset of breast cancers, regardless of whether they had receptors, were driven by this amplification of a gene called HER2, and that story is a huge story of targeting HER2 and really completely changing the outcome of that subset of breast cancer that continues until this day. Then, what about all the other breast cancers? We identified those breast cancers initially as not having receptors for estrogen and progesterone, and then subsequently as not having HER2 gene amplification, and so once we had HER2, of course, that became triple-negative, where patients’ tumors do not express estrogen and progesterone receptors and don’t have amplification of the HER2-neu gene on chromosome 17.
That triple-negative breast cancer then underwent further characterization, and indeed, just like all subsets of breast cancer, triple-negative breast cancer is quite heterogeneous, so you don’t just have one triple-negative breast cancer. In the United States and in Caucasian patients, there seems to be a sort of a particular subset that predominates in triple-negative breast cancer, where most triple-negative breast cancers seem to be very rapid in the tumor growth. When I say rapid, it’s important to keep it into perspective. This isn’t leukemia, where it’s growing every day, but compared to the more indolent or slow-growing hormone receptor positive breast cancers, triple-negative breast cancer cells divide and turn over faster and are more efficient at invading and moving around. They also, and there are always exceptions within every subgroup, so there may be hormone-receptor positive breast cancers that act more triple-negative, so just to clarify that, but triple-negative breast cancer seem to be more plastic in their biology, so that under the pressure of treatment, they can develop mechanisms that allow them to grow under the treatment you’re giving that originally caused the tumor to shrink, so there’s more plasticity or instability, as well as the absence of receptors. Now, within the triple-negative breast cancer, there are subsets that are quite different.
There are subsets that look more like connective tissue, as opposed to looking like breast cells. In older women and sometimes in younger women, less commonly, we see a subset of breast cancers that are slower-growing, look a lot like hormone receptor–positive breast cancers, except for they don’t have the hormone receptors. Those cancers actually behave differently, and there may be differences between racial and ethnic subgroups in terms of the frequency of these different subtypes of breast cancer, but for all intents and purposes, when we’re speaking about triple-negative breast cancer, we’re talking about this more aggressive subtype that seems to predominate in the population we see.
Chris Riback: If I understand correctly, one of your set of studies is around trying to determine how the triple-negative breast cancer cells are able to avoid attack by the immune system with your goal, of course, being to develop new and better immunotherapies. Is that related to the plasticity that you just mentioned or is that related to something else? I know it’s at the heart of your own questions, but why are triple-negative breast cancer cells able to frustrate attacks by the immune system?
Dr. Hope Rugo: That’s an interesting question. It’s a little sort of to the side of our project because there are so many aspects to the answer to your question, so one is, “How can triple-negative breast cancers escape the immune system?” And there seem to be many mechanisms. One of which is part of our project, first project within the BCRF grant. One area is that as the burden of cancer increases, the cancer is able to turn down the host immune response, so the more cancer you have, and potentially this is related to these drivers of cancer growth, which is part of our projects, that drive the cancer to be larger sooner, and then suppress the host immune response. The mechanism of suppressing the host immune response is not simply the mutations within the cancer.
It has to do with multiple different mechanisms, and trying to overcome that with immunotherapy is a major aspect of treatment, I think, of treatment investigations now for a triple-negative breast cancer, and there’s a reason why immunotherapy works better in early stage breast cancer than as breast cancer starts growing and being larger, more invasive, and eventually metastasizing. Again, it has to do with this better immune response in smaller tumors, even the immune cells that can infiltrate the tumor decrease, as well as the immune markers as the tumor continues to grow. Why that happens is not clear, but it is definitely an important part of this escape of the immune system. Now, the instability of the cancer seems to come from many aspects, so we can’t just look at mutations, so looking at alterations in DNA or the RNA that comes from DNA changes in protein, that doesn’t by itself explain how the cancer becomes more resistant. Although, as the cancer becomes more resistant, it develops more and more instability mutations, et cetera, but there are major initial drivers that reprogram the ability of the cancer cell to grow and change the stops and the controls.
As those mutations occur, they make a lot of other changes in the cancer cell, and part of that is the ability to suppress your body’s immune system from recognizing the cancer and contributing to the ability to suppress its growth.
Chris Riback: Now, as I understand it in a parallel study, and I’m wondering to what extent this relates to the point that you were just making. You’re looking at not necessarily, let’s call it the front end of cancer that a patient is diagnosed, so now, how can we implement the most effective immunotherapies, but rather, what felt to me like the other side of the coin, how can we better predict metastatic relapse? What is the status of your work around the serial analysis of circulating tumor DNA, I guess ctDNA, in blood samples?
Dr. Hope Rugo: This is such an incredibly interesting and cool area and going back to my interest in that chemistry set, when you have tumor, and you have to have some tumor, but you might not have any visible tumor by imaging or exam, the tumor actually will put fragments of DNA into the blood, and we had started our evaluation of circulating markers of tumor, which might be much more sensitive to both detecting tumor, as well as providing a rich source of tumor to interrogate the cancer about what’s going on that’s making it act so differently, so we started that whole process looking at circulating tumor cells, so tumor cells that were shed into the blood. The problem with that was that it required special processing. These all do, but the cells themselves, they had to be analyzed very quickly because otherwise, they would fall apart, and then not everybody has circulating tumor cells, so only about 50 percent of patients, even in the metastatic setting where patients have quite a lot of visible cancer. The whole new field of looking at what happens when those cells fall apart and just in patients who have even early stage cancer is that you can find this cell-free or circulating tumor DNA in the blood, and using special techniques in the blood, you can actually find these cells even in patients who have early stage breast cancer.
Chris Riback: Wow.
Dr. Hope Rugo: You could understand in metastatic disease where you had cancer in the liver, lung or wherever the cancer was, that there would be shed circulating tumor DNA, but in early stage breast cancer, this has been really a remarkable finding, and it is something that we can then use to understand the tumor biology, what’s driving the tumor, but also, to try and figure out how therapies work and what we could do to intervene to change outcome in a more sensitive way than simply following the size of the tumor.
Chris Riback: Yes. Again, as a layperson in reading about ctDNA, it felt almost like a cancer thermometer of sorts, potentially like an early warning system. Is that an appropriate way to think about it or is that too simplistic?
Dr. Hope Rugo: I think that that’s a good terminology to use. I want to separate the use of cell-free DNA in metastatic versus early stage breast cancer.
Chris Riback: Please.
Dr. Hope Rugo: Cell-free DNA in the metastatic setting in cancers that are generally considered to be incurable, treatable but incurable, is used right now as a very important test to help us understand mutations that drive cancer growth that we could potentially target with new therapies, and that’s a way, for example, to find mutations that can be targeted by drugs called PI3-Kinase inhibitors or tumors that have mutations in the estrogen receptor, called ESR1, and the importance of ctDNA in this setting is that not only could it tell you new changes that are occurring in the cancer, but also, it means that patients might not have to have biopsies of their tumor that are more invasive, uncomfortable, and risky.
Chris Riback: Yes.
Dr. Hope Rugo: Biopsies still have a really important role, but ctDNA has been this tremendous advance in giving us a little bit more window into potential targets in the treatment of cancer. There are also studies that are looking to see whether or not if you were to change therapy based on ctDNA numbers alone, so the fraction of tumor burden evidenced by blood measurements. If you were to change therapy based on that alone, no evidence of cancer progression could you change outcome.
Dr. Hope Rugo: To date, there’s no evidence that that’s the case, but there are studies that are looking at this, but certainly would not change based on that now. In the early stage setting, we have one overlapping and one very different rationale, so one is, could the ctDNA give you a better window into the prognosis of the cancer compared to looking at the tumor shrink by itself? For larger, more aggressive cancers, we want to give treatment before surgery, called Neoadjuvant treatment, because one of the most frustrating aspects of treating early stage cancer have been you treat the cancer after surgery, so there’s nothing you can see anywhere, and then you just wait to see if it worked, right?
Chris Riback: Yes. Yes.
Dr. Hope Rugo: What you’re waiting for is, does the cancer come back? It never really made sense to me, and so now, we are treating before surgery because that response to treatment before surgery gives us a big window into prognosis, or what the potential outcome is, and more recently, it’s allowed us to individualize treatment based on response with evidence of improvement in outcome where we’ve changed that treatment approach in subsets of patients and subset of tumors, so how could ctDNA help us in addition to the response? Well, once you have a response to treatment and you go to surgery, you could have no cancer left, invasive cancer, or you could have a little bit left or a lot. Now, the ctDNA, we believe, adds into that information to give you more data about potential outcomes, so some patients who have cell-free DNA at the time of surgery won’t have recurrent cancer. Other patients, even those who have no invasive cancer at the time of surgery who have cell-free DNA, they might still have a substantial risk of recurrence.
This may give us more of an information that will help us tailor treatment for patients, and you could follow these tumors over time and get an idea of if something was going to be at risk for recurrence, maybe not today, but in two years or three years, you could potentially, and this is our pipe dream, change therapy to change outcome. Then, the second aspect of this is, could you use that cell-free DNA to individualize treatment? If that tells you there’s an emerging mutation, for example, that makes the hormone treatment that you’re using not effective, or does that tell you that a new mutation has evolved that would help you use a targeted agent more effectively? Those are the two aspects of looking at cell-free DNA. It’s been fascinating actually because, I think our early data suggests that this information may really help us in understanding prognosis, but more importantly, changing outcome.
Chris Riback: So much potential, and thank you for that really clear and, as you said, fascinating to hear the possibilities and the hopes. I have one other area that I want to ask you about quickly before I let you go, but before I get to that, is there anything else about your studies that I should be asking you about or that you wanted to cover that we didn’t get to talk about?
Dr. Hope Rugo: I think the studies that we’re doing are, I think, really exciting and forward-thinking. I’m so even more excited about the data that’s come out over the last year and our prospects over the next year. I think there are two things to mention that make this all possible.
Dr. Hope Rugo: One is BCRF funding allows exploration of areas that wouldn’t be funded by other mechanisms, and I think that’s important to keep in mind because it’s actually a really interesting thing. I mean, you need data to get funding and to move forward, and many of these explorations, new information that’s kind about BCRF funding, would’ve taken decades longer without that funding, so that’s really important. Then, just in terms of my projects, nothing would happen without collaboration, and I’m so fortunate to have amazing colleagues in the clinic and in the laboratory, and my funding supports these really very smart people’s work in the laboratory, and then allows us to move that laboratory work into the clinic, and we wouldn’t be able to do that without BCRF funding.
Chris Riback: Well, thank you for those points, and yes, the people that you work with and the extension of what you are able to do surely connects with all sorts of innovation and scientists and researchers, and so yes, it’s a wide net that gets to be cast. I guess to close out then, I was also fascinated to read that you remained committed to education and regular lecturing, which is even more amazing now that you’ve discussed all of the studies and potential and the data and all the things that you’re kind of balancing/juggling on that hand, and that you run, I assume you still run the Breast Forum, an open bimonthly evening educational session for breast cancer patients, families and friends throughout the Bay Area. First of all, do I have that right? Is that still something that you do, but also, just your committed effort to education and regular lecturing?
Dr. Hope Rugo: Yes. The forum, yes, continues, and it’s actually been amazing, the few, little silver linings of the pandemic, and so we changed our in-person forum to a Zoom meeting in order to continue it during the pandemic.
Chris Riback: Of course.
Dr. Hope Rugo: I mean, it was kind of funny because we never would’ve thought about that or really understood we could achieve that, but we were able to open up the forum to people who obviously couldn’t drive in and park into San Francisco in the middle of the week in the evening, and so we now have a huge number of attendees who come, and we’re also able to focus on specific aspects of breast cancer that our audience is interested in, but the forum has been a great program where patients can ask questions and we have my tremendously gracious colleagues who will donate an hour and a half of their time to talk about their work and how it applies to the clinic to make the new information coming out digestible for our patients. One of the things we do in the forum, other than talking about specific areas of patient interest is we review the results from all major international meetings at the forum. My colleagues come. Again, they routinely donate their time.
They talk about the new data and how it applies to the clinics, most importantly, and patients can ask questions about these areas, which, I think is so important. Being knowledgeable gives people power and really helps them with hope, and also being able to ask appropriate questions of their own physicians. Then, the education for practitioners providers is as important because, I think the general oncologist is a tough job to have right now because there’s so much to learn in different areas of oncology, but if you’re practicing outside of an area where you have people talking to you all the time about the new advances and hearing these information and participating in these studies, you can’t keep up, so understanding how this data can be applied to the clinic when new studies result, but also, and really importantly, understanding how that data applies to the individual patient is the key importance of medical education, and medical education nationally and internationally is what drives excellence in patient care and allows new developments, and it’s not just drugs, but new understanding of treatment of cancer into the hands of the patients.
Chris Riback: Dr. Rugo, thank you. Thank you for your time, and thank you for the work that you do every day with and for patients.
Dr. Hope Rugo: Thank you so much.
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