Breast cancer is a profoundly personal disease, and blanket approaches may not work for all patients. In fact, some can avoid particular therapies or treatments altogether. BCRF investigators have played a significant role in developing precision medicine and individualized therapies, improving treatment efficacy, and limiting side effects.
This is the area where Dr. Roisin Connolly’s work is centered. Her research is focused on investigating new and innovative biomarkers to support more individualized treatment plans for triple-negative breast cancer (TNBC), which has fewer treatment options than other types of breast cancer. Upcoming work seeks to identify promising biomarkers in blood samples and tumor biopsies from patients who have received chemotherapy with or without immunotherapy. She and her colleagues will examine the tissue environment and breast cancer microbiome to develop further treatment options.
A BCRF investigator since 2022, Dr. Connolly is the Director and Professor Gerald O’Sullivan Chair in cancer research at the University of College Cork and Cork University Hospital in Ireland. Dr. Connolly previously served as an associate professor of medical oncology at Johns Hopkins University. She has also recently received an Irish Cancer Society grant to support a Women’s Cancer Survivorship Clinic in Cork in collaboration with national and international teams.
Chris Riback: Dr. Connolly, thank you for joining me. I appreciate your time.
I thought we might start with the phrase that’s associated with your work. On the surface, it seems like an obvious term, but the more I thought about it, I wondered how much complexity might lie below the surface. The phrase is “individualized treatment.” And we hear it so often, particularly with breast cancer and other types of cancer. But what does individualized treatment look like? I understand, of course, what the words mean, but what exactly might it involve? What are the permutations or potential areas for individualization?
Dr. Roisin Connolly: That’s a really great question, and I suppose we need to think back to the history of cancer treatment when we’re considering this term. I’m a breast cancer physician, so I’m discussing treatment options with my patients in the clinic, and I’m telling them that we are where we are because of decades of clinical trials and clinical research. But as the decades have passed, breast cancer is no longer seen as one disease. It’s been divided and divided into smaller cohorts. And as we do that, we realize that our almost blanket treatment decisions that we might have made in the past may not be suitable for everybody.
So for example, in the past, the majority of women with breast cancer who were coming to see a physician after surgery may have been recommended chemotherapy. And that became a standard of care. What we have learned over the last 15, 20 years is that there are tools we can use that can help us determine which patient may benefit more from chemotherapy. And what we’re doing in many cases is we’re actually omitting or avoiding chemotherapy in many of our patients, which we’re very happy with. And of course, the patients are very happy when they don’t have to go through that.
So I suppose the individualized question is, for the patient sitting in front of you, if you look at all of the tools that you have available to treat the cancer, which one is more relevant for that patient? And it might be in the future that we get even smarter than we are now, and we could do something like a simple blood test and say, “Well, the test that we had available to us already suggests that you are probably going to benefit from chemotherapy.But now I have a blood test that refines this even more to tell me that you specifically may be one of the 10 patients who really is going to get that benefit, and so it’s going to be more worth it for that patient to receive the treatment.
That’s just one example where, again, in the past, we used more chemotherapy than we do now, but we also can make those decisions if we consider other targets in breast cancer, like HER2 or the estrogen receptor. And we are now using those routinely in the clinic to make decisions. But we want to delve even deeper. We want to see even more. Can we choose who needs what therapy, who needs more chemo versus less chemotherapy, who needs none at all? That’s the general sense of individualized therapy, if it makes sense to you.
Chris Riback: It does. And I love that phrase that we will hopefully get smarter in the future. Thanks to work from folks like you, we are exponentially smarter today than we were 5, 10, 20 years ago. And as that continues, those advancements in the ability to then individualize the treatment is really remarkable.
What are immune checkpoints, and how might some cancers evade an immune response by simulating these proteins? We’re getting closer to the heart of the work that you’re actually doing.
Dr. Roisin Connolly: Yes. So I suppose, in general terms, we know that cancers are smart, and they can grow over time to be only a cell at the beginning to be a palpable lump. And they grow because they learn how to, I suppose, live and grow in our human bodies. Some of the mechanisms whereby they have been able to do this is because they have developed ways of evading or avoiding the immune system. And our immune system is very clever. It can fight infections. It can fight cancer and other insults to our body. And there’s probably many cancer cells that are killed or taken away by our immune system, but others learn to evade it.
And that’s where these immune checkpoints come in. They are, as you said, proteins that can be present on a cancer cell or a normal cell that help it to evade the immune system by it interacting with a partner protein on one of the immune cells. And so scientists have realized that this is a potential mechanism for cancer cells to avoid being killed by our immune system, which is constantly searching for these insults in our body. That is where a new generation of medications has been developed to break down that connection between those proteins and allow the immune system to then fight the cancer.
Chris Riback: And is that next generation? Are those the immunology agents, or is that something else?
Dr. Roisin Connolly: Well, there are medications we call immune checkpoint inhibitors that are specifically targeting those proteins. Some of them are called PD-1 or PD-L1, PD-L2, and they’re sitting between the tumor cells, the normal cells, and the immune cells and interacting. So, the new generation of medications that we’ve heard a lot about over the last few years that have been approved in certain cancers earlier on, approved in melanomas, really revolutionizing their management, approved in lung cancer and other diseases. And then, more recently, there have been approvals in the breast cancer space specifically, TNBC, which is the area that I’ve been working on recently.
Chris Riback: Let’s get into your work, and with that context established, you’re focused, as I understand it, on identifying biomarkers that can help determine which patients would benefit from a combination of adding an immune checkpoint inhibitor to chemotherapy in early stage TNBC. I assume that among the key aspects of that, key qualifiers of that, is early stage. And so maybe we’ll talk about why you’re focused on early stage and the differences between coming in at that opportunity, as opposed to, unfortunately, if one comes in at a later stage.
My first question in thinking about your work is why is that combination not viable or effective for everyone? And maybe that goes back to what you talked about at the beginning around individualized approaches. And what helps determine who might benefit from the combination approach?
And lastly—because there’s no question that I wouldn’t want to just pile onto—, for those who might not benefit as much, is it a question of tumor reduction effectiveness, or is it a question around highly desirable side effects? So, which aspect of outcomes is what drives some of that decision-making? So a lot there. To the extent that I offered you something convoluted, I fully expect that you will straighten it all out and give me nice, clear answers.
Dr. Roisin Connolly: Exactly. So I think what we’ll do is we might go back to the original conversation, about how over time we have developed strategies to treat a certain type of cancer or a certain stage of cancer. And oftentimes, those strategies have built on the past. So, there is a combination of chemotherapy and immunotherapy that is now approved for use in TNBC. And by adding this immune checkpoint inhibitor to the type of combination chemotherapy approach that we’ve had available to us for a long time, the results are better. So, we have added on what we’ve learned in the past, and now we’re in a situation whereby we have a regimen that is really quite effective in terms of preventing the cancer from coming back down the line and saving lives of a proportion of women.
But what we’ve realized is that we are likely not benefitting everybody that we give that regimen to. We, in our heart of hearts, know that there’s probably some women within the triple-negative group that are really going to benefit from that, and others who may not have needed that extra treatment approach, may need two chemotherapies versus three. And so, now that we’ve not quite maxed out on efficacy, but getting closer to that in TNBC with these new combinations, now the community is thinking, “Okay, we have this effective regimen. It’s been given regulatory approval. We’re using it in the clinic. But can we start to tease out now who may benefit more or less from that approach so we can make those individualized decisions?”
Another part of your question was about who could be benefitting from these treatments and who may not benefit from them. And what we think about TNBC and breast cancers is they were not traditionally felt to be as sensitive to these immune agents as other cancers, like, again, the melanoma, the lung cancer, et cetera, possibly because the environment around the cancers was a bit hostile to that effect. And that term has been used to describe sort of a cold environment, whereby maybe the surrounds of the tumor were not so amenable to using these immune checkpoints, or the tumor microenvironment, which is a term that’s used a lot these days.
And so, a lot of efforts have been initiated to see, “Well, can we be more smart with the medications we use with the approaches to almost make triple-negative more hot or more amenable to these immune checkpoint inhibitors?” And so, there’s been a sense that we both need to do better where people aren’t responding, and for people who are going to respond, pick them out so that we’re making sure that we give the treatment to them versus other people who may not benefit as much.
An area that is of interest to mine is looking at this tumor microenvironment, the tumor itself and the microenvironment around it, so we can learn more about what’s happening there as these medications are given so we can, in the future, again, be smarter about the choices that we make, so identify these biomarkers or signals that can tell me that one patient is going to do better than another. So I hope that gives a general answer to your question.
Chris Riback: It certainly does. And what I appreciate so much about the characterization, what’s more personal than cancer, than what an individual is going through? I mean, anyone who goes through it obviously knows she or he are not the first ones in history to have gone through it, and yet, it surely feels, for that person, like, “I am the first one,”. I mean, it’s the most personal.
And so, the work that you’re describing to personalize, individualize the evaluation and then obviously, the approach and what gets done to help that patient, the ability to personalize or individualize that, to me, is a line moving towards the reality that that individual is feeling, that this is highly personal, highly individualized, so, “Doc, could you please tell me what I need, not what the general population needs? Could you tell me what I need?” And in listening to you, that’s what you, and others, are really striving towards. So, describe for me, then, if you would, please, your study, the work that you’re actively under right now. What is your hypothesis? What’s the status? What happens next?
Dr. Roisin Connolly: The reason that this area is so important to me is because I am prescribing these medications in the clinic. And when patients are experiencing side effects, either from the chemotherapy or the immunotherapy, that disappoints us to have to put patients through that if we don’t need to, and balancing, again, the benefits and the risks. So, this idea that some patients as well as maybe the immune system attacking the cancer cell, the immune checkpoint agents might also be causing these unwanted side effects. And that’s a whole other area of research, is the immune-related adverse events. So, my research in TNBC and other cancers in other projects is to try and, again, maximize efficacy and minimize toxicity, that balance. So for this specific project, we’re deciding to focus on the tumor microenvironment and explore it further.
One of the main areas of interest is a very topical scientific area in oncology right now, and that’s the area of the microbiome. There’s been a lot of interest in bacteria that are living in us that might actually be influencing how we are responding to treatments given to us. And there’s been a lot of work done in the gut microbiome, so the bacteria that are living in our guts that might then be passed in our stool. There is some evidence that these bacteria may influence response or side effects from immunotherapy.
Some collaborators of mine here in Cork in Ireland have gone a little bit beyond the stool microbiome. They have a particular interest in what’s happening in the tumor itself, and they have identified that bacteria are also residing in the tumor.
So how do we best identify them and determine what’s tumor-related bacteria versus normal bacteria that might just be there because of contamination or living in other tissue? And we need to look at whether those bacteria might be able to influence response to treatment and the drugs that might be present treating the cancer, and how they interact with the surrounding immune system.
So, we are going to try to tease this out in this project in a number of different ways. One is by using samples that are already available that have been stored in a biobank, a breast cancer biobank, and looking at those samples. And how do we look at the bacteria in those stored samples? How are they interfacing with immune cells locally, and is there a better way to identify those bacteria in other ways? And so we have not only taken a look at samples that are already in the lab that have been taken with patient consent but also developing a new protocol, whereby we’re looking to see if there are better ways to identify these bacteria and to link them with both the local immune cells and immune environment. And then in an early sense, what is the association between those and how the patient is doing in regards to the response to the treatment, which we call the pathological response, and also their survival outcomes?
This very topical area really has potential to influence our decisions if we can follow through on this, and may also be a way for usto identify new treatments, like treatments that might actually target those bacteria if they’re not helping us in treating cancer by virtue of how they’re acting in the tumor.
Chris Riback: Is your work focusing on all of those different stages—first IDing what bacteria are in there, but then also testing the impact of that bacteria, and then testing the pathological response of that bacteria to various, I guess medications is what one might say? Are you investigating all, let’s just call it three or four of those stages? It looks like you are. And then, if so, what’s your status? Where are you now? And do those happen in parallel path, or do you have to take it stage by stage?
Dr. Roisin Connolly: Yes,we are doing this in what we’re calling a careful step-wise approach to looking at these potential biomarkers, because if we’re going to use something to make a treatment decision, there’s a very clear and careful pathway that we have to follow.. We would never want to use a biomarker or assay unless we were very sure that we knew exactly how it was behaving, exactly how we should identify it, exactly how it associated with response.
Where we are right now is we’re doing this in parallel, not sequentially. So we have access. We’ve identified the samples that are linked to these patients with a history of TNBC who’ve received these treatments. And, at the moment, they’re on their way to the laboratory. And then, in parallel, we’re working out the final details of the new protocol that will enroll new patients. And those patients will consent. Then they’ll have their blood sampling, their tissue sampling. We’ll be collecting their clinical data. And so, it is a parallel effort to look at a variety of ways of measuring these bacteria and the tumor microenvironment. And, we believe that then adding this information together will strengthen what we can learn about the field.
Chris Riback: This might be just a hyper-naive question, but you mentioned earlier the potential around the blood testing. I know there’s work being done around that. If you do this work and are able to identify which bacteria might be creating or affecting what aspects of cancer and, perhaps as well, what medication or treatments might work against those, is there then a simple test for bacteria? Or is the ultimate outcome something that is potentially as uninvasive as a blood test in terms of testing? Or no, I’m thinking about it wrong, that testing blood is very, very different than bacteria because you have to see if the bacteria in the tumor, et cetera? So I might be conflating things, but I’m wondering if that’s potentially a direction where you’re headed.
Dr. Roisin Connolly: I think it’s a really good question. I think it will be most ideal if down the line, we can do a simple, non-invasive test to make these decisions. There is certainly some interest in the idea of picking up these bacteria in the blood. That is not a focus of our project right now, but certainly that is where the future may go.
We are actually collecting blood in our current project for a different interesting area, which is called the area of tumor exosomes. So these are little vesicles that can be secreted out of cancer cells and maybe float in the blood. And that’s another very novel potential area. We’ve heard a lot about circulating tumor DNA, plasma tumor DNA, circulating tumor cells. There’s been a lot of research over a long period of time trying to look and see whether these help us predict response to treatment and help us make treatment decisions. They haven’t quite reached the clinic yet in breast cancer, but another area that is being explored is these extracellular vesicles.
So oftentimes, when we’re doing these projects where we are collecting biospecimens, we’re thinking, “How can we maximize what we can learn in this project?” And we may be working with scientists in different fields, but then, the benefit is that we can look at that data in aggregate when we have the final numbers.
Chris Riback: And, of course, we want to offer eternal patience in waiting for your results, but at the same time, we’re all just a little bit anxious. So, where would you say you are and what’s next?
Dr. Roisin Connolly: In the next few months we’re going to be actively collecting these samples from new patients coming in the door. And I hope that towards the end of next year, we’ll have some early readout from those patients. In terms of correlation with the clinical outcomes, that’s going to take a little bit longer. And then, for the samples that are already available, I hope that early next year we’ll have some early readout on that and we will have the clinical data available. But again, this is a step-wise approach, and our hope is that once we have information from these two sort of parallel cohorts, we’ll be designing larger studies that will really move us towards the point whereby we can use these in the clinic for patients. But that does take some time.
Chris Riback: You indicated a couple of times that this is very current work. What’s pushing it in that direction? Is it new hypotheses? Why are you characterizing it in that way?
Dr. Roisin Connolly: Some of what we do as clinical trialists is we move things along that pathway towards the patient. And we may have projects at different stages. For example, another area that I’ve got some interest in is imaging with PET scans and other modalities to help make better choices. I have a new large clinical trial that has opened in the US which is at a later stage, whereby we have decided that this biomarker or potential biomarker in HER2-positive breast cancer is at the point where we can do a larger study and try to get more definitive answers for patients.
In the triple-negative stage, immunotherapy is so new that we’re trying to figure out these best biomarkers. And as a clinical researcher, I need to work with the best laboratory scientists to make these new findings relevant. With all of the interest in the area of the microbiome, this is a space that has a lot of excitement, but there is a lot more work to do. It’s at a very early time point. So I am just very happy that I work with folks in Cork who have a slightly different spin on this and can bring something novel, and similarly in the blood phase.
We want to take better developed biomarkers to the final stages, where we can be closer to impacting patients. And then, for new, emerging technologies, they need to go through the step-wise fashion. For the triple-negative group of patients, that’s where the focus is at the moment for me.
Chris Riback: Interesting. So, you indicated earlier something about the fact that colleagues of yours, in Cork, I believe you had said, had been doing some work with bacteria. So, when you just said a moment ago, very fortunate to be working with these folks, am I interpreting you correctly that you are kind of sitting a little bit in the, maybe not the only center of the universe, but close to the center of the universe for this kind of work?Or is it being done in a number of places, and you just happen to be in one of the solar systems, let’s say?
Dr. Roisin Connolly: I think from the perspective of the actual tumor itself and the presence of the bacteria in breast tumors, I would have to say that we’re one of the few areas in the world that is doing this level of research. The gut microbiome has been extensively investigated now by many, and so many have developed expertise in that area. But from a tumor microbiome perspective, I believe my colleagues here are really at the cutting edge.
Chris Riback: That’s got to be incredibly exciting. I mean, for someone who has dedicated her life to the type of work that you have, to get to be affiliated with that type of energy and excitement has got to be very inspiring I should say.
Dr. Roisin Connolly: I would see huge potential, again, for trying to individualize in the setting of immunotherapy, because it really has revolutionized many other cancer types. It’s developing its space in the breast cancer arena, mainly the TNBC. But as a clinician, half of my job is helping to make these treatment decisions and half of it is the research. I really want us to be in a situation whereby we are making those right choices for patients. So it’s that partnership between the clinical need and the great science that’s happening in the labs.
Chris Riback: Yes, the translational aspect of medicine is one of great learnings that I’ve had in these conversations. That and speaking to many people like you who have learned so much from cancer type A and have then made hypotheses and then advancements in cancer type B—all those cross-pollinization opportunities and the way people like you have both the opportunity and then the responsibility to think and bring learnings from one environment to another. It’s always really interesting to hear about.
Quickly, if you would, tell me about you. Was it always it was evident that you were going to be a scientist? Was there ever the potential that we could have lost you to creative writing or anything else in your life?
Dr. Roisin Connolly: I’m the only physician in my family, and I made the decision to go down this pathway early when I was a child. I had a history of childhood asthma and spent a lot of time in hospital at one point. And it was a place that I actually felt very happy, actually.
Chris Riback: Wow.
Dr. Roisin Connolly: I loved being in the hospital. I loved going to school in the hospital—hey had a little school—and I loved talking to the nurses. And I just actually really loved that environment, which isn’t everybody’s experience. So I knew pretty early on that I wanted to go down the medical route. Initially, I thought I might want to be a pediatrician and then changed to adult medicine. In medical school, I had the experience of working with the oncology service in one of our training hospitals and I suppose I just recognized the real, unique relationship that an oncologist has with their patients, to be supporting them through a really difficult time.
I worked with very inspiring attendings at that time, and so I then made the decision to go down the oncology route and did some of my training in Ireland. But then I was lucky enough to start the fellowship program as well at Johns Hopkins subsequently. And that’s where I was more exposed to the academic side of oncology and really enjoyed, “growing up” to some degree in the breast cancer program with absolutely amazing physicians, and then being able to interact with experts in cancer immunotherapy and other scientific areas, the imaging side of things as well. And that opened my eyes to the importance of research in cancer medicine.
My position now is a little similar to my position at Hopkins, whereby I have the clinical component to my work and then the protected time for research. It allows me to maintain my academic interests, to collaborate with pathologists, laboratory scientists, biostatisticians not only in Ireland but in the US and Europe. And so, it is very, very exciting, and it’s probably what keeps me going week to week, is all the new changes and trying to develop new ideas and working with this multidisciplinary group of people who all want to make things better, ultimately, for patients with cancer.
Chris Riback: That’s quite a pathway. And two thoughts are coming to mind. One is incredible, great credit to the doctors and nurses and administrators who ran a child school in the hospital that gave us you in this field now and didn’t turn you off of that. I’m also just slightly curious, if you’re the only one in your family who took this path, what is their reaction to you today? Do they think you’re crazy and whacked out and talking about all sorts of things that aren’t top of mind for them, or I assume that they’re also extremely excited and proud. What’s the family reaction you get today?
Dr. Roisin Connolly: I think they’ve always been very happy with me being happy in my career choice, and obviously proud. It’s an honor to have trained and worked at an internationally recognized center like Johns Hopkins. So I think my family are proud of me, but they probably don’t really understand a lot of what I do. They’re in very different fields but recognize the importance of it.
Chris Riback: Well, maybe they’ll listen to this, and you explained everything so extremely clearly that maybe this will help. Lastly, what role has BCRF played in your research?
Dr. Roisin Connolly: I’ve been so grateful to have been taken on as a BCRF investigator. I feel it’s hugely important for me as well, having moved institutions and having moved countries. BCRF is supporting investigators all over the world, and their support is really giving me the kickstart and the seed funding to get this type of exciting project up and running in a new location with new collaborators and a new patient cohort. And that, to me, has been the most important benefit here. So I’m really grateful to them for believing in what I’m doing, believing in me, and enabling this work. Getting this off the ground would not have been possible without them. And I hope that it spurs on additional support from other places when the early readouts are seen. I think we can probably make BCRF continuously excited about this type of work, as well as other funders and donors.
Chris Riback: Wow, that’s terrific, and I’m sure that they and others will feel similarly. Dr. Connolly, thank you. Thank you for your time, and thank you for the work that you do every day.
Dr. Roisin Connolly: Thank you so much, Chris, nice to speak to you today.
Chris Riback: That was my conversation with Dr. Roisin Connolly. My thanks to Dr. Connolly for joining – and you for listening. To learn more about breast cancer research or to subscribe to our podcast, go to BCRF.org/podcasts.
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