Ask the expert: Triple-negative breast cancer with Elaine Walsh, MB BCh BAO, PhD

Making up 15 to 20 percent of all breast cancer diagnoses, triple-negative breast cancer (TNBC) is often seen as a more aggressive subtype that disproportionally affects young, Black, and Latinx communities.

In this video, oncologist Elaine Walsh, MB BCh BAO, PhD, answers questions about TNBC symptoms, side-effects, and treatment options for early-stage and metastatic breast cancer.
 

Elaine Walsh, MB BCh BAO, PhD, is a medical oncologist who specializes in the treatment of people with breast cancer. At Memorial Sloan Kettering Cancer Center, Dr. Walsh works as part of a multidisciplinary team to provide the highest level of care and best treatment options to people with breast cancer, while taking individual preferences and priorities into account. Read more.
 

Janine Guglielmino, MA: 

Good evening, everyone, and welcome to Living Beyond Breast Cancer’s webinar Ask the expert: Triple-negative breast cancer. My name is Janine Guglielmino, and I am vice president of mission delivery at Living Beyond Breast Cancer. I'm very honored to serve as your moderator tonight, along with our distinguished speaker, Dr. Elaine Walsh. If you look at the bottom of your zoom screen, you'll see the chat icon. I know many of you are already using it. Please say hello and where you're joining us from and make sure to mark your message to all attendees and panelists so we can all see it. I'd also like to welcome folks who are with us on Facebook live. I can't see you here, but we're really happy to have you with us. We're excited to spend the next hour getting to all of your questions about triple-negative breast cancer, early-stage, and metastatic disease.

Before we jump in, I do want to thank the community of sponsors who are supporting our work. Tonight, I'd like to thank our signature level sponsors, AstraZeneca and Genentech, as well as our presenting organizational partner, the Triple Negative Breast Cancer Foundation, who has been an amazing partner to us for many years, and we're so proud to be able to bring you this program with them. I'd like to invite the executive director of the foundation, Hayley Dinerman, to say a few words, if you can come on, Hayley, and say hi, that would be great.

Hayley Dinerman:

Thank you so much, Janine. It's always such a pleasure to work with you and your team. On behalf of everyone at the Triple Negative Breast Cancer Foundation, I'd like to welcome all our TNBC thrivers here tonight. We're thrilled to offer this program to you in partnership with LBBC. For those of you who aren't aware, we have a huge menu of education and support services for the TNBC community. You can find out more about them on tnbcfoundation.org and on our Facebook, Instagram, and Twitter accounts. Thank you again for joining us. 

Janine Guglielmino, MA: 

Thank you so much, Hayley, and thanks again to the Triple Negative Breast Cancer Foundation for, for all your years of support and partnership. I also would like to thank Dr. Walsh in advance for donating her time and expertise tonight. And thanks to all of you for taking an hour out of your day to join us and learn more from Dr. Walsh. This hour is dedicated to answering your questions. We already have a few in the queue, and we encourage you to ask throughout.

To submit your questions, I ask you to please use the Q&A icon that's at the bottom of your screen. You'll also be able to chat throughout, but please put your questions in the Q&A area so that Hayley and I can see them just a couple of notes before we get started, Dr. Walsh to not give personalized advice. So please try and ask your questions in as general a fashion as you can, so that as many people as possible can benefit. Also, we're recording tonight's program and we'll make this available on lbbc.org as soon as possible.

Just a few words of introduction about Dr. Walsh. She is a medical oncologist specializing in the treatment of people with breast cancer at Memorial Sloan Kettering Cancer Center in New York. Dr. Walsh works as part of a multi-disciplinary team to provide the highest level of care and treatment while considering personal preferences and priorities. Her research focuses on breast cancer, but she has a special interest in triple-negative disease, particularly triple-negative breast cancers caused by an inability to repair DNA damage. She'll be able to share about that tonight. To read her full bio, please go to lbbc.org. I'd like to invite Dr. Walsh to come on the screen and join us.

Hi, welcome, Dr. Walsh.

Elaine Walsh, MB BCh BAO, PhD: 

Thank you, Janine, for a wonderful introduction and thank you, Hayley, also for the introduction. I'm delighted to be here. I'm happy to have a discussion and answer any questions and see what the evening brings us.

Janine Guglielmino, MA:

Great. Well, we already have a number of really excellent questions. I'm going to start just to level set for everyone. We may have some folks here who are just diagnosed or who are just learning. Could you please just provide a definition of what triple-negative breast cancer is? What is it, and what isn't it?

Elaine Walsh, MB BCh BAO, PhD:

That's a great question. And sometimes we kind of take that for granted when we talk about triple-negative breast cancer. Strictly speaking, the definition is that it's a breast cancer that's not driven by three of the known markers. It's not driven by estrogen. It's not driven by progesterone. It's not driven by HER2. And so that's the triple-negative component. I honestly kind of struggle with that definition. It's the best definition that we have right now, but we're defining it by what it's not rather than what it is. The only other disease really that we have done that in is non-small cell lung cancer. And that was kind of a historical definition in lung cancer. But now we know that, among that subtype, there are 5, 10, 15 different subtypes based on mutations and based on protein expression. So “triple-negative” is the working diagnosis that we have for now, but I'm hoping that over time we can refine that into a more kind of specific diagnosis because it is kind of unsatisfying to call it by something that it's not rather than what it is.

Janine Guglielmino, MA:

Thanks for helping us understand that. And just speaking really broadly, what are the treatments available today for triple-negative breast cancer?

Elaine Walsh, MB BCh BAO, PhD:

So that's a great question. So very generally speaking our treatments really are divided into chemotherapy, which is applicable to most patients. We also have treatments like immunotherapy, which may be relevant to a subset of patients. We have PARP inhibitors, more targeted therapy that's also available or recommended for a subset of patients. But really, for the most part, chemotherapy is our main backbone of treatment. And that's because, as we said, it's not driven by estrogen progesterone or HER2, so we don't have great targeted treatment like we may have in other breast cancer types.

Janine Guglielmino, MA:

Thanks for explaining that Dr. Walsh. And I think with that, I'm going to start asking, some of the questions that we're getting here. One of the first questions that we received is about the medicine olaparib, which recently made quite a bit of news at the ASCO meeting. This is a medicine approved in metastatic triple-negative breast cancer. But at the ASCO meeting, we heard about the OlympiA trial in people with early-stage triple-negative breast cancer. Can you talk a little bit about that study, what it found, and whether olaparib is going to be available for people with early-stage breast cancer?

Elaine Walsh, MB BCh BAO, PhD:

It's a great question. To answer that I might take a step back and talk about how we got to olaparib in the first place. Olaparib is a PARP inhibitor, and there are two PARP inhibitors currently approved in metastatic breast cancer: olaparib and talazoparib.

These drugs monopolize on the fact that in some people, DNA damage repair cannot be performed adequately. So for example, we know in patients with a BRACA mutation — BRCA1 or BRCA2 mutation, for example — that they already, because of that mutation, have an impaired ability to repair DNA damage. And so a PARP inhibitor does takes advantage of that inability to repair DNA damage and selects a cancer cell and kills that cancer cell. So the combination of a BRCA mutation with a PARP inhibitor can achieve cell death, basically. PARP inhibitors are approved in other cancers like ovarian cancer, prostate cancer, [pancreatic] cancer, for example, all in the metastatic setting.

And so up until recently, outside of a clinical trial, we considered PARP inhibitors for patients with metastatic breast cancer who had a germline or an inherited BRCA1 or BRCA2 mutation, because, as I've said, we knew that it was an effective treatment strategy. So more recently, as you said, the OlympiA study was presented at ASCO just this year, about a month ago. And basically, it was a study looking at giving patients adjuvant olaparib. So, it was olaparib after surgery for early-stage disease, in patients with a germline or an inherited BRCA1, or BRCA2 mutation. The patients included in this study were what we consider high-risk patients. Some were qualified depending on the size of the tumor, for example — the tumor had to be two centimeters or greater — or have lymph node involvement.

In patients who got neoadjuvant chemotherapy or chemotherapy before surgery, if they had residual disease at the time of surgery, they were also considered high risk. And there were other criteria for estrogen receptor-positive, but I won't go into that this evening. And so that study essentially told us that if we gave olaparib for 1 year in high-risk patients — high-risk, triple-negative, either two centimeters or greater, lymph node positive, or residual disease after chemotherapy — that it improved their survival, essentially. It's still kind of early days in terms of following on, but at 3 years, there was an improvement of between 8 and 9 percent in terms of survival in patients who received olaparib for 1 year. So that really has essentially changed our practice.

It is not yet FDA approved, which is challenging. And I think this is probably what you were alluding to, Janine. Sometimes we get these great study results and we would love to start prescribing these drugs for our patients the next day in clinic, but we are practicing within the constraints of FDA approval and unfortunately, with the way our insurance system works here with insurance approval. However, having said that, most [healthcare practitioners], irrespective of FDA approval, if a patient meets the, criteria are trying to get the drug approved, either through working with insurance companies or working with the provider of the drug itself from a compassionate use perspective.

Janine Guglielmino, MA:

Thanks for that, Dr. Walsh, and just a couple of follow-up questions.

So we have some folks who have early-stage disease and are taking capecitabine, or Xeloda, and are wondering what's, what's the difference between taking olaparib and Xeloda, and how that might be recommended for them.

Elaine Walsh, MB BCh BAO, PhD:

That's a great question. And I wish I had a very straightforward answer, but I don't. The OlympiA study, which is the study I just mentioned using olaparib, is a study that's been going on for a period of time because often in our early-stage studies, people do so well and live so long, it takes time for those studies to mature and for us to get results. That study actually had completed enrollment, meaning patients were no longer being treated and they were just being followed before the CREATE-X study was presented. The CREATE-X study is the study which explored using adjuvant, or after surgery, Xeloda or capecitabine.

The OlympiA was designed not knowing the results of the CREATE-X study. So no patients in the OlympiA actually received capecitabine. And so until this summer, the standard treatment for someone who had residual disease after neoadjuvant chemotherapy was capecitabine. What we don't know is how to navigate both of those. I think most people honestly feel that the margin or the magnitude of benefit in the OlympiA — so, with the olaparib — was actually so compelling and seems to be superior to the results that we saw with capecitabine. Now it's very difficult to do cross-trial comparisons. We normally don't compare one trial to another because they weren't studied that way. But most people would feel that if we have a patient now with a germline BRCA mutation who had residual disease after chemotherapy, if they were starting now, our preference would be olaparib if they have already started.

You know, I think it's certainly a conversation between the patient and their oncologist. We don't know whether they are safe to give together. We don't really have any safety data combining capecitabine and olaparib, so most would not recommend that. But I guess the question is, do you continue the 6 months of Xeloda and then start a year of olaparib, or do you maybe stop Xeloda and start olaparib. Again, that's a very personalized conversation between the patient and oncologist. There are no two patients that would have the same approach in that regard. And we don't really yet have good guidelines necessarily from NCCN or ASCO or the FDA, even on how we approach the timing of both of those drugs. But my sense is that for suitable patients, olaparib would probably be the drug of choice.

And then in patients who do not have a germline BRCA mutation, Xeloda would remain the standard of care.

Janine Guglielmino, MA:

Thanks for addressing that Dr. Walsh. And it sounds like there are really still a lot of open research questions. So potentially opportunities for people to get involved through clinical trials.

Elaine Walsh, MB BCh BAO, PhD:

Definitely.

Janine Guglielmino, MA:

So, we have a number of questions, from folks who are asking about tests and testing and the use of scans in triple-negative breast cancer. Talk a little bit about how often scans should be given after an early-stage diagnosis of triple-negative disease to monitor for presence of disease.

Elaine Walsh, MB BCh BAO, PhD:

That's a great question. And it's something, honestly, my patients ask me every week in clinic. And so for early-stage disease, depending on maybe the size of the tumor or the presence of lymph nodes, many people would choose to do what we call a staging scan at diagnosis. And so, a staging scan can be either a PET-CT or a CT bone scan. And really they give us very comparable results. The only difference is that it's two scans or one scan, but really, we wouldn't do a CT bone scan and a PET. We would do CT and bone scan or PET. And so, again, depending on the stage of the disease—in early stage—depending on the size of the tumor and lymph nodes, many people would do a scan at diagnosis or before starting chemotherapy, for example. Now, after finishing chemotherapy, it's not recommended to do routine what we call “surveillance scans,” meaning scans on a schedule. And the reason for that is, I think, historically, people maybe did get scans every 6 months or once a year. And I know in other disease types the tendency was to maybe overlook some symptoms because of a recent scan.

And so what I tell my patients is that if we did a scan in January and then in March, you come to me with new symptoms, the tendency might be to say, “Well, you had a scan two months ago. That scan looked good. I'm sure this is nothing, no need to worry.” Whereas in fact, we know now that if we scan based on symptoms, that we're more likely to pick up something or more likely to detect something. And so the symptoms that we talk about are a new problem that comes and stays, and we do not have a good explanation for it. Because we, we can still get colds and flus, aches, and pains, other things people can get appendicitis, diverticulitis, lots of other medical things can still happen, even though you have a history of breast cancer.

And so if you have a new symptom that comes and stays, and we don't have a good explanation for it, then we recommend doing scans. But apart from that, we do not recommend routinely doing surveillance scans. There is a lot of work and research now being put into liquid biopsies, such as circulating tumor DNA, which can be used to potentially monitor disease in early stages. Now this is still in a research forum. It's not something that is standard of care, and it's not something that we're recommending outside of a clinical trial.

Janine Guglielmino, MA:

Dr. Walsh, could you explain what circulating tumor DNA is for folks who may not be familiar?

Elaine Walsh, MB BCh BAO, PhD:

Of course. Essentially circulating tumor DNA is DNA, or maybe a cell or a DNA that is shed from a tumor. A tumor has to be usually one centimeter or greater in order for us to pick it up on imaging. … And so if a tumor is smaller than that, for example there's a chance that it's shedding off some of its cells and those cells can circulate in your bloodstream and they can be picked up either as circulating tumor DNA (DNA from the tumor) or maybe even what we call CTC (circulating tumor cells). There's research now looking into checking to see if those CT DNA or CTCs are present and then how they evolve or change over time and whether that corresponds to disease recurrence, for example, in early-stage disease. In the research setting, it's still being investigated. I'm presuming that everyone that has dived into this is a motivated patient and interested in new topics. And it's certainly something to consider if there was a clinical trial near you, that's looking at CT DNA, for example.

Janine Guglielmino, MA:

Sure. And Dr. Walsh, before we move on to the next subject, as a rule of thumb for someone who's concerned, at what point would you want to see one of your patients who had had early-stage disease, if they're having a concerning symptom? When would you want to hear from them?

Elaine Walsh, MB BCh BAO, PhD:

That's a great question. If it's something that's new that is unexplained—you weren't in a car accident and now you're sore all over because we can explain that. And I'm not saying I wouldn't want to know about that. I would, but I would be less worried about something like that because we have a good explanation, but I encourage my patients  to contact us, to reach out with any concerns or questions, because most of the time it's something that we have heard of before or seen before. There's often a good explanation, but it's always good for peace of mind to check. And there are many ways to contact providers — calling the office, some centers have online portals where you can send messages, but obviously if it's an emergency we don't recommend using those portals.

But I think if there's something on your mind, if there's something that you're concerned about, it's better to be safe than sorry. And I always tell people, please reach out. What I would hate is to see you at your next routine visit, and find out that you've been miserable or sick since our last visit. I would rather know in advance so that we can investigate as we need to.

Janine Guglielmino, MA:

Thank you for answering that. We have a number of questions being asked in different ways about if you have early-stage, triple-negative breast cancer, and you do not experience disease recurrence, or evidence of disease growth in 3 years or 5 years, is it true that you can consider yourself cured?

Elaine Walsh, MB BCh BAO, PhD:

It's a great question. And so, you're absolutely right. Typically, if a triple-negative breast cancer does recur, it tends to recur within the first 2 to 3 years, which is very different from other breast cancer subtypes.

So, when we think about estrogen receptor-positive breast cancer, or hormone receptor-positive breast cancer, for example, they can often recur 5, 10, 15 years after diagnosis. Whereas we know with triple-negative breast cancer, just because of the nature of the disease, it does tend to recur earlier. And so the 5-year mark is kind of an antiquated benchmark, honestly, for a lot of people because our treatments have changed. And especially now, when we're talking about maybe giving olaparib for a year after standard treatment. So I think that the actual numbers become kind of less of a benchmark, honestly, but yes, … there was one study in particular that after 8 years, the likelihood of recurrence from triple-negative breast cancer is essentially — I mean, it's never zero — but it's essentially very, very rare to recur after 8 years. But yes, typically kind of from 5 years on you know, I think we don't always use the word “cure” like we do in other cancers.

But we definitely consider this disease hopefully will not cause you a problem again, if we haven't heard from it in the first 3 years or so.

Janine Guglielmino, MA:

Thanks for addressing that extremely common question among members of our community. I wanted to transition to answer some of the questions that we have [from] a number of our metastatic thrivers here on, on the call. So why don't we start with just one sort of generalized question: What are the current options and emerging options for people with metastatic triple-negative disease?

Elaine Walsh, MB BCh BAO, PhD:

Great question. So, I kind of alluded to it at the beginning. So our standard treatment for triple-negative breast cancer remains chemotherapy in some shape or form. And then we always look to see, do we have any other targets that we can maybe take advantage of?

One such target is PD-L1, which is a test of the tumor itself. It's a test of immune cells on the tumor. And if a tumor has PD-L1 expression, it’s more likely to respond to immunotherapy. And so in terms of immunotherapy, we have two drugs that are approved. We have pembrolizumab and atezolizumab, and they're given slightly differently with different chemotherapies, but they are both given with chemotherapy. And so the first thing I would check, if someone presented to me with newly metastatic, triple-negative breast cancer, would be PD-L1 status. And our pathologists are very comfortable doing that. It’s almost done now as reflex. We don't even have to ask for it because they know that it changes our treatment options.

So, if a tumor was PD-L1 positive, meaning it expressed PD-L1, our treatments would be chemotherapy combined with immunotherapy. In those that do not express PD-L1, other things that we look at are androgen receptor, for example. So that's almost like a hormone, like an estrogen. But we see it most commonly in prostate cancer, but there's a subtype of triple-negative breast cancers that express androgen receptor. And so that's something else that we typically check for on a newly metastatic, triple-negative breast cancer, because if they do express androgen receptor, we have trials that we could give an anti-androgen treatment. So, it's kind of the closest thing to a hormone treatment that we have for triple-negative breast cancer.

The next thing then we check for, if it hasn't already been done, is BRCA testing. So we do germline BRCA testing, meaning testing of the person themselves to see if they have inherited a mutation in BRCA1 or BRCA2, or maybe another gene, for example, and that caused this breast cancer to develop. We also recommend genetic testing of the tumor itself. So I tell my patients, we're testing you to see if this is something that has been passed on from one generation to the next, but we're also testing the tumor for genes to see. Maybe that can give us some more information about why this breast cancer developed for you. And it might actually open up other potential treatment options. So for example, we talked about BRCA1 and BRCA2 mutations in the person. Sometimes we don't see them in the person, but we see them in the tumor. So, there are what we call somatic BRCA1 or BRCA2 mutations.

And there's a study going on at the moment that was reported at ASCO of last year, ASCO 2020, and that looked at giving PARP inhibitors to patients with a somatic BRCA mutation. So the person themselves had not inherited a mutation, but the tumor for whatever reason has acquired this mutation. And fundamentally the way that the PARP inhibitor works is similar. The study was looking at giving PARP inhibitor to those patients, and they had very good responses. And so that's another potential targeted treatment. So they're kind of the first places that we start: we check for PD-L1 status, we check for androgen receptor, and then we sequence or do genetic testing of the tumor to see if they have maybe a somatic BRCA mutation or maybe another mutation that we could manipulate with treatment in some way.

Janine Guglielmino, MA:

Thank you, Dr. Walsh. And can you just talk for a minute about the type of tests that would be given to identify those mutations in the tumor? So, you're talking about molecular biomarker testing. How is that different than testing the DNA of a person?

Elaine Walsh, MB BCh BAO, PhD:

Great question. So when we do germline or inherited testing, it's a test essentially of our own DNA. So that could be a blood test. It can be saliva. Sometimes we can do it on hair or nail clippings. So it's kind of what you think of in forensics. So you're testing the DNA of the person. When we're doing what we call next generation sequencing, genomic profiling, somatic testing, they're all kind of terminology for the same type of tests, but they're specifically testing the gene makeup of the tumor.

And so they will identify typically if there are any alterations, mutations, or abnormalities in genes. So, they don't necessarily comment on the normal genes, but they will comment on if anything looks unusual. And so that is a test on the tumor itself. Some hospitals do it in house. So here at Memorial, we do that in house, meaning that our own pathologists can do those tests. In many other places they're sent out to commercial labs. Some labs that we talk about are like Foundation Medicine. We have, like Guardant, for example, you know, there's many other commercially available, platforms, so that if your pathologists in house don't do it, you can physically send the tumor out to one of these labs that will test the tumor and send a report back to you.

Janine Guglielmino, MA:

Thanks for explaining that. It's a very common question. Another very common question that we received is: For people have had chemotherapy and had progression on those chemotherapies in the past, what is the value of going back to those treatments again? Is that something that might be recommended in the, in the metastatic setting?

Elaine Walsh, MB BCh BAO, PhD:

That's another great question. And so, we have a pretty long list of drugs available — of chemotherapy drugs, for example — available for triple-negative breast cancer, but it's not an infinite list. You know, it is a finite list. And so sometimes we do wonder: if you had a treatment in the past that you responded well to at the time, maybe you stayed on a particular chemo regimen for a year or maybe 2 years, and then we stopped it maybe because the tumor grew, or maybe we stopped it because you were having side effects, like your blood counts were dropping, or maybe you had some other physical side effects from the treatment…

So, in those cases, after a period of time has passed, it may be reasonable to reconsider what we call rechallenging with that same chemo drug. We usually would not do it necessarily back to back. Now, there are some exceptions to that as well. But in general terms, we would normally, if you had progressed on a drug or needed to stop a drug because of toxicities, we would like to give you a different type of drug next. But if it had been a period of time since you had that first drug, and if you responded well to it at the time, then it's definitely something to reconsider. We would not typically do it if you had been on that drug maybe for 3 or 6 months and needed to change at that point, because that tells us that maybe we'd like to try something that we could get a bit more mileage out of. What we do know about rechallenging with drugs is that sometimes be you might have gotten a year or 2 years the first time, but the next time we give you that drug, we would expect it to be a little bit shorter. And so that's why we would typically only rechallenge with drugs that you maybe had a good length of time with stable or responding disease first time around, and then we may consider rechallenging in the future. But that's a great question.

Janine Guglielmino, MA:

Thanks. Thanks for addressing that. And, I have a question that just came in. I think it's an important one. So this is a person who had an early-stage, triple-negative breast cancer and has had a metastatic recurrence and has been advised not to have the recurrence biopsied and test it to see if it remains triple negative. What would you suggest in a situation like this? Should someone with a metastatic recurrence after triple-negative breast cancer have the metastasis biopsy if that's possible?

Elaine Walsh, MB BCh BAO, PhD:

Another great question. So, I typically do recommend biopsying the first time that someone develops metastatic disease. And there are a couple of reasons for that. First of all, we want to make sure that we're dealing with breast cancer, [and] that we're not dealing with some other process. You know, people can get sarcoidosis, for example, which can present with lymph nodes, so there are other conditions and there are other cancers that can present.

So, the first thing we would want to confirm is, is this in fact, breast cancer. If it is confirmed to be recurrent or metastatic breast cancer, exactly, to your point, we do want to confirm that this is still triple-negative breast cancer. It doesn't happen very often, but occasionally we can see a tumor that changes its hormone status. We more often see it in tumors that maybe were estrogen positive at diagnosis, and then lose their estrogen sensitivity and become triple-negative. But the reverse is also hypothetically possible. And so, we would want to confirm not only that it's breast cancer, but also that it's triple-negative breast cancer. In addition, I think both of those are really important things to do, I think in terms of treatments,  genetic testing of the tumor itself, that's typically what we would do that on the metastatic biopsy, because we know that the mutation profile can differ between the primary cancer and the metastatic cancer. In order to do that, we need a biopsy of the metastatic site.

And so for all of those three reasons normally at first diagnosis of metastatic disease, I would do a biopsy but, there are some caveats to that. Maybe a biopsy is not safe; maybe it's technically very difficult. And so there are some nuances there, for example, like bone biopsies can be difficult to do. And sometimes genetic testing on the bone biopsy can also be difficult just because of the way that they process the bone. And so maybe there are more nuanced or more individual reasons that that was not recommended, but if it was a safe and feasible biopsy, it's certainly something that I would recommend.

Janine Guglielmino, MA:

Thanks for answering that and also really pointing out if you're not sure why, if the test hasn't been recommended that it might be possible to find out the reasons. What are your some questions that you might be able to ask your doctor? So, we have many questions about breast cancer recurrence, triple-negative recurrence. And, and as you know, this is a really big concern for people who have had early-stage disease. Talk a little bit about the chances of a metastatic recurrence after having a pathological complete response. And if you could just explain, how does the doctor determine that you've had a pathological complete response? What does that mean? And what are the chances of recurrence after that?

If someone gets a diagnosis of triple-negative breast cancer [sometimes] they're recommended to undergo chemotherapy before their surgery, so that's what we call neoadjuvant chemotherapy. There are a number of reasons we do that. And I can talk about that after if that's helpful, but if someone is undergoing neoadjuvant chemotherapy, our hope is that we are treating the cancer, causing that cancer to shrink down and hopefully become undetectable to clinical exam and to our mammogram, ultrasound, MRI, whatever the imaging might be. The person will still have surgery. And at the time of surgery maybe all we see is scar tissue and dead cancer cells in the breast and the lymph node. And that's really the best result that we had hoped for, with giving you that chemo first.

And that's what we call a pathological complete response. So it means our pathologist has examined the tumor bed. Where the tumor was under the microscope, they have found no active cancer cells, meaning that the chemo killed all of the cancer cells. And we know that patients who achieve a pathological complete response — meaning that with their chemo, there's no active cancer cells at the time of surgery — their outcomes are better than those who do not get a complete response to treatment.

Now the figure is kind of vary in terms of what we mean by “outcomes.” … There was a recent study of pembrolizumab, for example, a new immunotherapy drug in neoadjuvant, triple-negative breast cancer. In that study — and I'm just referencing my paper here because it was just presented last week. In patients who achieved a pathological complete response in that study, and it's a short follow-up, so this will evolve over time, but after 3 years, 85 percent of patients who were treated with pembrolizumab and got a pathological complete response had no evidence of cancer at 3 years, meaning that about 15 percent of patients did develop an event of some kind. Now that event can be maybe a local recurrence, or it could be metastatic disease.

That's kind of the benchmark in terms of events. Now importantly in that study, they found that — I'm digressing a little bit — but they found that survival was increased irrespective of whether patients achieve a pathological complete response. But typically, patients who achieve a complete response have better survival and better outcomes than those who do not. And that's where we try to kind of escalate our treatments, like we talked about with Xeloda, and like we talked about with olaparib for those patients who do not achieve a pathological complete response. And so for a lot of people, maybe 85 percent doesn't seem that wonderful, and I would agree. But with any of our treatments with any of our breast cancer subtypes, it's never 100 percent. So even in the smallest hormone receptor-positive breast cancer with no lymph nodes involved, we can never guarantee 100 percent that this will not come back.

And so really, with kind of all of our subtypes, what we talk about is usually between the like 80 to high 90s percentage. So, I'm not sure if that answers your question, Janine. I think I digressed a little bit.

Janine Guglielmino, MA:

I think you gave a lot of really helpful information and it, and it also feeds into a follow-up question that we're getting from a number of people. In addition to some of the strategies you've talked about with potentially Xeloda or olaparib, do you recommend any sort of lifestyle interventions to help decrease the chances of recurrence, and what's the evidence base for some of those lifestyle interventions?

 

Elaine Walsh, MB BCh BAO, PhD:

That's another great question. So, what I typically tell people is when you're undergoing treatment, whatever that treatment might be — maybe it's neoadjuvant chemo, adjuvant Xeloda, olaparib — whatever it might be. I don't typically recommend major lifestyle changes at that point in time, because you're already going through so much. And if you develop a side effect, we don't know if that side effect is from your treatment or whether it's because you have cut out dairy, gluten, sugar, all of the kind of foods that you normally get. And so, it can be difficult to separate out. Do you have headaches because you have changed your diet dramatically, or do you have headaches because of the chemo, for example? And so I typically don't recommend that people make major lifestyle changes while on treatment. And I get asked this all the time: After treatment, are there any lifestyle modifications that we should do? And the answer is probably not really what people want to hear, but the best lifestyle modification that we know of, honestly, is maintaining a healthy body weight and exercise.

We know that women who maintain a healthy body weight are at a lower risk of developing breast cancer in the first place. And that obviously is not absolute. We know plenty of women that are normal body weight that develop breast cancer, but compared to women that are overweight or obese, they're less likely to develop breast cancer. And your outcomes from breast cancer point of view we know are better if you are normal body weight compared to those that are overweight or obese. We do not have any good data about dairy, for example, about red meat. Red meat has been shown in colon cancer, pretty convincingly, but we don't have any great data in breast cancer. So, what I tell people typically is healthy, balanced diet; nothing in excess; and just try and maintain a healthy body weight and exercise.

And I'm not supposed to read the chats, but I see a few questions about alcohol. So again, it's hard to make a direct correlation between alcohol and cancer, but what we do know is that alcohol can promote a pro-estrogenic state, for example. So there has been some suggestions that alcohol can increase your risk of developing a hormone receptor-positive breast cancer, but not, to my knowledge, triple-negative breast cancer. We also know that excess alcohol is associated with body weight. And then, body weight is associated with breast cancer development and survival. So, all of that, kind of in keeping with healthy body weight exercise, and then everything else in moderation. Nothing in excess would be my recommendation.

Janine Guglielmino, MA:

Thank you for addressing that. And we have actually a number of questions about whether there's progress on the development of a breast cancer vaccine that can be used in triple-negative. And a couple of folks have seen some clinical trials at several institutions. Could you please speak to that?

Elaine Walsh, MB BCh BAO, PhD:

Sure. So this is an area that's still under development. It's not as far along as our immunotherapy understanding or knowledge in triple-negative breast cancer, but … there is some suggestion that vaccine either maybe into the tumor itself or into the person can help stimulate your immune system in the same way that we're trying to do with immunotherapy. And so they're very comparable in terms of their biologics and the reason that we were testing those. So I would say that outside of a clinical trial, it would not be recommended treatment, but as you said, there are clinical trials ongoing in that right now. I know, for example, a colleague here is looking at doing intratumoral vaccine. So, it's kind of injecting an antibody into the tumor itself and someone who has maybe a skin lesion, but that's certainly an area under development. And again, I would encourage people if it's something you're interested in, maybe try and look for clinical trials in your area. And I would hope — watch this space — that it would be coming in the future, but we're not quite there just yet.

Janine Guglielmino, MA:

Thank you. So we have a number of questions that are follow-ups to the conversation we were having earlier about immunotherapy when it can be used, how it can be used. Does the amount of PD-L1 expression influence your treatment options to use immunotherapy?

Elaine Walsh, MB BCh BAO, PhD:

That's a great question. So, in metastatic disease, the short answer is yes. There are two drugs, as I mentioned, that are approved for metastatic triple-negative breast cancer. So, two immunotherapy drugs: pembrolizumab and atezolizumab. For both of those, you need to have positive for the presence of PD-L1 expression. We know, for example, I think in, with atezolizumab, I believe it's anything above one, so one or higher, the drug can be used. With pembrolizumab, the study looked up both 1 percent positivity or higher or 10 percent or higher, and there were more benefits seen with those with 10% or higher. So, we do inherently feel that the more PD-L1 expression that a tumor has, the more targets are available and the better the drug would work.

And that has also been the case in other cancers that were kind of faster to study and adopt immunotherapy, such as lung cancer, for example. We know in lung cancer, the higher the PD-L1 expression, the more likely the tumor is to respond to immunotherapy. The challenge is in early-stage disease. So again, we mentioned the KEYNOTE study — KEYNOTE-522 — that was just presented last week. And in that study, patients were given immunotherapy irrespective of PD-L1 status. And actually they found that there were responses, even if the PD-L1 was negative.

Now, I don't have a good biological explanation for that, honestly. We're not necessarily using it in early-stage to guide our treatment, but we are using it in metastatic. And, the higher the expression, we feel, the more likely you are to respond to that particular immunotherapy drug.

Janine Guglielmino, MA:

Dr. Walsh, could you briefly explain what PD-L1 is?

Elaine Walsh, MB BCh BAO, PhD:

Sure. Oh, I'm sorry. I should've said that at the beginning. PD-L1 is short for programmed cell death-ligand 1, and it's basically a protein but it's a protein that represents an immune cell, so it's seen on immune cells. And so the idea is that normally, if our immune system is fully functioning and working at 100 percent, if it noticed any foreign body like a cancer cell, our own immune system should be able to recognize that cancer cell, realize it doesn't belong in our body, and kill it. For whatever reason that we still don't know, in some patients, the immune system doesn't recognize that cell, and so the cancer is allowed to grow. And we know then that your body still makes the immune cells, and the immune cells are attracted to the cancer, but they're just not able to kill it off. And so the PD-L1 is this receptor or marker of expression of immune cells, meaning that all your immune cells have clustered to this, but for whatever reason, they're just not quite able to kill off this cancer cell. And so that's the fundamental behind immunotherapy where we try to waken up or stimulate your own natural immune system to kill off these cancer cells. So, we're basically just giving your immune system some extra power to recognize the cancer cells and then try to kill them off.

Janine Guglielmino, MA:

Thanks for explaining that Dr. Walsh we're, we're going to run out of time soon, so I'm going to try and get to two or three more questions that I've seen repeated a few times. One person is asking about one of the newer agents in triple-negative breast cancer called Trodelvy. Could you explain in what settings that medication is used and, and where it is most effective?

Elaine Walsh, MB BCh BAO, PhD:

Sure. So, Trodelvy, the other name is sacituzumab, so that's a mouthful. But basically, it's a new type of chemotherapy agent. It's what we call an antibody drug conjugate, and it's kind of a smarter way of delivering chemotherapy into the cancer cells. The agent binds to the cancer cell and releases the chemo drug into the cancer cell. And that simply means that we're able to give higher doses of that particular chemo, because it has less side effects on the non-cancer cells in the body.

So it's currently FDA approved, so that's kind of another advance in the last year. Strictly speaking it's third-line metastatic, meaning that you've had two chemo regimens or two treatment regimens for metastatic disease. And this is your third treatment that you're having. The FDA has recently changed that to include to be second line, if you have received chemotherapy for early-stage disease. So, if you had prior for your early-stage, and then you develop metastatic disease, you can get the sacituzumab as your second line of treatment. And so that's another excellent drug that we've seen great response rates and  we kind of still consider that in our chemotherapy label, but it is kind of a novel way of administering the chemotherapy.

Janine Guglielmino, MA:

Thank you, Dr. Walsh. So, we have a number of questions where people are asking what causes triple-negative breast cancer.

Why does triple-negative breast cancer disproportionally affect younger people diagnosed with breast cancer, Black women, Latinx women? Do we have any idea why certain groups of people are more likely to be diagnosed with triple-negative breast cancer than others?

Elaine Walsh, MB BCh BAO, PhD:

Unfortunately we don't have a great answer or a great reason why exactly, as you said, this disproportionally affects younger women, African American, Latinx. And that can be where the tumor sequencing that we talked about can help us maybe find some of that information. We do know that BRCA mutations, for example, are more commonly seen in women of African American descent or women of Ashkenazi Jewish descent. And so, some of it is kind of like the gene pool and maybe this was passed on from one generation to the next, but they're a minority of cases.

And for most people we don't have a good explanation as to why this developed. What I do tell my patients is this is nothing that you did or didn't do. This could not have been necessarily prevented in any way, because we don't know what caused it. And because we don't know what caused it, we couldn't have prevented it, which is not satisfying for the patients or for us. But hopefully over time we will have more information, more knowledge about what causes this.

Janine Guglielmino, MA:

Thank you for addressing that, Dr. Walsh. And so, with that, I think I'll ask the last question about clinical trials, because that is how we've learned everything we do know and how we'll learn anything in the future. Would you mind speaking to just some of the common myths about clinical trials that might keep people from participating who might have an interest in it?

Elaine Walsh, MB BCh BAO, PhD:

That's a great question. So, exactly to your point, we wouldn't have the advances that we do today — the recent pembrolizumab data, the olaparib data, the sacituzumab, the Trodelvy data that I spoke about — without patient participation in clinical trials. And so the first thing, thank you to all of you that have been, or are considering clinical trials. It really helps to make progress for this disease. I think some of the myths around clinical trials are that it's pure experimentation and that very much isn't true essentially, but it can be interpreted based on the phase of clinical trials.

So, very briefly, a phase I clinical trial is testing a drug. It's probably a new drug, or maybe a new drug in breast cancer. … so, a new drug or a new combination of drugs, and we're testing that they're safe and tolerable. So that's a phase I, an early-phase trial. A phase II, we've shown that it's safe, we've shown that it's tolerable, and we're trying to test how effective it is. And then a phase III is kind of our gold standard, where we compare the new drug to standard of care. And so, for example, all of the studies that we've spoken about—with the PARP inhibitors, pembrolizumab, sacituzumab—now they're all phase III studies where they're compared to standard of care treatment. And that's really the best way that we know how this drug fares compared to what else we have.

And so, I know a lot of patients think, “well, it's experimental,” and that might be the case. And maybe it's a first-in-human study, and that could be considered experimental. But most of the time it's actually a drug that has been used and shown to be effective in other cancers, but we've never studied it in breast cancer. For biological reasons, we think it's a good thing to do.

The other thing that people talk about and people worry about with clinical trials is that you do a clinical trial when you have no hope. So when all the other standard treatments have failed you, then maybe you consider a clinical trial. But, you know, honestly, that might be the case — maybe you've exhausted standard of care options. And you're looking for clinical trials, but many of our trials are looking or studying patients with newly metastatic disease.

And so you haven't had any treatments yet, but we're trying a new combination of treatment, or maybe a new drug. And so, in that case, you certainly haven't exhausted your other options. It's just maybe a nice way to get access to a drug that maybe you wouldn't get otherwise. We talked a lot about immunotherapy. If there were a study of immunotherapy and you didn't meet the criteria because your tumor was not PD-L1 positive, meaning it was unlikely to respond. … Sometimes clinical trials are a nice avenue to get access to those drugs that you would not otherwise be eligible for.

Janine Guglielmino, MA:

Thank you so much for answering that question, Dr. Walsh, and thank you very much for sharing your expertise with our community today.

Elaine Walsh, MB BCh BAO, PhD:

It's a pleasure. It's been an absolute pleasure. I can't believe how quickly the hour has gone. I'm sorry if I talk too much.

Janine Guglielmino, MA:

Not at all, you did an amazing job. And all of you who are with us did an amazing job. I think asked about 150 questions, and I want to thank my colleague Hayley Dinerman for doing such an amazing job, going through the questions and helping us to figure out which ones to ask. I did see a number of things in the chat. And what I think we would like to do is download your questions, see what we can do to answer more of them at a later time, and be in touch with you. And I also pledged to make a transcript of this program, because a number of you were asking about the spellings of the medications and the tests, and that is a way that we can get that information to you.

So, we will do that. I want to thank all of you for your amazing questions. And again, we thank our sponsors for their support today, AstraZeneca and Genentech. And of course, thanking again, our presenting organizational partner, the Triple Negative Breast Cancer Foundation. After this program, you're going to receive a link from us with an evaluation. We read every single one of them. Please do let us know how we did. And we will post a video of this program on lbbc.org, as soon as possible. In the meantime, I hope you'll follow both Living Beyond Breast Cancer and the Triple Negative Breast Cancer Foundation on our social channels and let us know how we're doing. Living Beyond Breast Cancer and TNBCF are both here to help you cope with the medical, emotional, and practical challenges of living with breast cancer. Please don't hesitate to reach out to us to provide support and to connect you with other people who are coping with this disease.

I want to thank you again, Dr. Walsh, and thank everyone. I wish you all happiness, peace, and good health through the summer and beyond. And I hope that someday soon, we're going to be able to see one another in person. Have a wonderful night.

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