Triple-Negative Breast Cancer Treatment: Where Are We?

This podcast is supported, in part, by Gilead. 

Welcome to The Breastcancer.org Podcast, the podcast that brings you the latest information on breast cancer research, treatments, side effects, and survivorship issues through expert interviews, as well as personal stories from people affected by breast cancer. Here’s your host, Breastcancer.org Senior Editor, Jamie DePolo.

Jamie DePolo: Hello, thanks for listening. About 10% to 15% of breast cancers are triple-negative. This means they don’t have receptors for the hormones estrogen or progesterone, and don’t have too many HER2 proteins. So, hormonal therapy medicines and medicines that target the HER2 protein aren’t effective against triple-negative breast cancer. 

Chemotherapy, often given before and after surgery, is used to treat triple-negative breast cancer, as is the immunotherapy medicine Keytruda, also called pembrolizumab.

I’m joined by Dr. Lisa Carey, the L. Richardson and Marilyn Jacobs Preyer Distinguished Professor for Breast Cancer Research at the University of North Carolina School of Medicine. She is also the deputy director of clinical sciences and director of the Center for Triple-Negative Breast Cancer, both at the UNC Lineberger Comprehensive Cancer Center. 

Dr. Carey is known around the world for her expertise on triple-negative breast cancer. She joins us to discuss the latest treatments and research on this type of breast cancer. Dr. Carey, welcome to the podcast.

Dr. Lisa Carey: Thank you. It’s a pleasure to be here.

Jamie DePolo: Am I correct in saying that triple-negative breast cancer is considered one of the most difficult subtypes to treat because it doesn’t have those proteins and hormone receptors that can be targeted? Is that correct?

Dr. Lisa Carey: Yeah, that is correct. It’s a shame because it’s really named by the things it doesn’t have, which is emblematic of the fact that when we have drugs that go after particular, maybe, for want of a better word, we’ll say, Achilles heels of the cancer, those are the targeted therapies, and triple-negative simply doesn’t have any of the ones that we currently have available, but that’s hopefully going to change in the near future.

Jamie DePolo: Yes, I hope so. Well, that’s the perfect lead-in to my next question. You are one of the top researchers on this type of breast cancer. What is the state of the research on triple-negative disease? What are you all looking at?

Dr. Lisa Carey: Well, you know there’s sort of two big arenas for research in triple-negative disease.

The first is trying to figure out what exactly it is because it’s probably a bunch of biologically distinct subsets that just happen to fit into the triple-negative umbrella. By teasing that out, that’s where you might find subsets that, in fact, have targetability and that might uniquely respond to drugs when, you know, in aggregate triple-negative breast cancer may not respond, but once you start teasing it out you may find groups that would be very effectively treated by drugs, some that we have already. 

The second arena, you know, is kind of what I’m alluding to, which is trying to improve treatments. So, some of the treatment improvements have to do with being smarter about how we treat triple-negative breast cancer currently. Like, being more tailored in the use of the chemotherapy drugs and immunotherapy drugs that we use. And some are going after novel approaches, right? Either totally novel drugs, you know, antibody-drug conjugates are one step in that direction, but also better immunotherapies and better ways to get the immune system to contribute and participate in treating the cancer.

Jamie DePolo: So, from the first part of your question there, it almost sounds like if we consider triple-negative a subtype, then there might be a, for lack of a better term, a sort of a sub-subtype, sort of distinct types of triple-negative breast cancer? Am I understanding that correctly?

Dr. Lisa Carey: Yeah. I mean, I would take it one step further. I’d say there almost certainly are sub-subtypes within triple-negative. 

Jamie DePolo: Okay. Okay, and you mentioned antibody drug conjugates. I’ve talked to some other researchers about, specifically Enhertu and Dato-DXd, and now I guess...yeah, no, that was the one that was just approved. Sorry. But possibly being effective against triple-negative breast cancer because they do seem to work on cancers with very low-levels of HER2 proteins. What is your take on that?

Dr. Lisa Carey: Well, you know, these are really exciting drugs. So, the antibody-drug conjugates, if you don’t mind my just saying briefly, you take an antibody against some protein that is typically found on the cancer cell, and they attach something to it.

Now, most of them, the ones that we have available, attach chemotherapy to it. So, it’s basically making chemotherapy smarter. You know, essentially the granddaddy of this is a drug called sacituzumab govitecan, also known as Trodelvy, it’s an antibody against a protein called Trop-2 and it attaches to chemotherapy, and actually that was the first one that was tested and shown to be effective in triple-negative breast cancer. 

The more recent ones, and that datopotamab deruxtecan, which is a Dato-DXd you just mentioned, also goes after that Trop-2 protein, but it attaches a different chemotherapy drug to it. 

Enhertu, which is the real name of that is trastuzumab deruxtecan or T-DXd is what we call it, is a little different because it goes after HER2, and the reason it’s interesting, and it is still something that we, you know, we’re wrestling a little bit with exactly how effective it is in triple-negative breast cancer, but I think it’s pretty clear that it has some effectiveness. Is that it grabs onto HER2, and traditionally things that target HER2, you have to have a lot of HER2 for them to work. 

What’s unique about these antibody-drug conjugates, specifically the trastuzumab deruxtecan, Enhertu, is that it doesn’t seem to need very much because it’s not actually using the antibody to treat the cancer, the antibody is basically grabbing the cancer and delivering with chemotherapy. 

So, that kind of, to be frank, it’s an example of how the antibody-drug conjugates kind of open up the arena of targeting where you don’t actually need a lot of the protein that you’re going after, you just need something that the drug can grab onto. Does that make sense?

Jamie DePolo: It does, yes. Well, and I’m also curious, and I talked to Dr. Bardia about this, who did a lot of the research on Dato-DXd. I just wonder, given how these just work, you know, we have triple-negative breast cancer, but it seems like now it may not matter if the cancer is HER2 negative or positive, and maybe we’re kind of going in the same direction with hormone receptors with these kind of new drugs that seem to work on cancers with very low levels of everything, which I’m assuming is a real positive for triple-negative disease, but could this…and I don’t know, maybe this is too far out, but I’m wondering if this kind of testing is going to sort of become less important for breast cancer. 

Dr. Lisa Carey: You know, that’s an incredibly important question. So, you know, I mentioned the first one in the, you know, group of drugs called sacituzumab govitecan. You know, there is no test that’s required to give a drug like that because Trop-2, low levels are sort of, you know, on most cancer cells, and so, there’s no requirement to test for it because, you know, it’d be kind of a useless effort because most of the time you’re going to find it. And as I mentioned, the drug doesn’t need a lot to work.

The more recent ones that have HER2 as the target, I think, you know, essentially had they realized how they worked with very low levels because, and frankly the way we test for HER2 is not designed well for this particular purpose, meaning immunostains, you stain it and look at it under a microscope. And it’s not really designed to look at low versus even lower levels of things. 

But using that technology, almost all — like, 85% have some amount of HER2 — and frankly, the FDA doesn’t usually require, you know, an extra test if it’s that common. Essentially, we’re arriving at this sense of not, you know, gaining much value of special tests to look for the targets, because the drugs are still effective even at low levels. 

Jamie DePolo: Okay, and I’ve read about some studies, too, that are combining these antibody drug conjugates like, Enhertu, Dato-DXd, and Trodelvy with an immunotherapy. And I think the one I saw was Imfinzi, if I’m remembering correctly, but Imfinzi isn’t approved for breast cancer. So, what is the idea behind those kinds of studies? 

Dr. Lisa Carey: Well, to some degree the idea of combining with immunotherapy is because you have a drug that’s delivering chemotherapy and causing, you know, the cells themselves to, you know, kind of die and have proteins get elaborated that the immune system might be able to see and to react against. So, you remember, the whole idea here is you’ve got things on the cancer cell that can be targeted, you also have the opportunity to get the immune system, the patient’s own immune system, to start to recognize the cancer as foreign and to attack it, just the same way as it would attack an infection, right? 

So, these drugs, because of their effectiveness and because of the way in which they kill the cancer cells, may in fact, get the immune system, you know, kind of present things to the immune system, the immune system making it more likely to react.

Now, the only drug that we have that’s approved for immunotherapy as you mentioned at the very beginning, is this drug called pembrolizumab. But durvalumab, which is the real name of Imfinzi, you know, it’s something that’s approved in other, in lung cancers and you know, endometrial and biliary, and things like that, but not in breast cancer. 

However, you know, it’s not unreasonable to try, you know, a variety of these immunotherapies. You know, I’m talking about clinical trials, of course. 

You know, interestingly, the idea of trying to use an antibody-drug conjugate combined with immunotherapy is actually something that the cooperative group that I work with, the NCI sponsor group, is studying, right? In early breast cancer we give immunotherapy both before and after surgery. It’s given with chemotherapy before and then typically with a different chemotherapy if there’s cancer left over afterwards. And we’re testing whether or not substituting that regular chemotherapy for the drug sacituzumab, or Trodelvy, works better when you’re giving it in combination with pembrolizumab.

So, that’s one example, but there’s a bunch of studies that are actively looking at this. It is a very rational thing to test and I think we’ll have some answers about it in the not-too-distant future.

Jamie DePolo: Well, that would be great. That would be great. 

Dr. Lisa Carey: So, that trial, which is open right now around the world, is called ASCENT-05, or it’s also called OptimICE-RD, with the RD standing for residual disease, and it’s available for patients who have had chemotherapy, immunotherapy, surgery, and are now going to receive the completion of their immunotherapy. And so, I hope patients will, you know, enroll in it so we get this answer quickly.

Jamie DePolo: Oh, that would be great. So, you’re enrolling right now, so, somebody if they’re listening and they have been diagnosed with triple-negative disease, they could contact their doctor about enrolling in the trial?

Dr. Lisa Carey: Yes. ASCENT-05, or it has two names, OptimICE-RD. 

Jamie DePolo: Okay. Excellent. Now, I’ve also read about some studies that are starting on vaccines for triple-negative breast cancer. And it seems like there are a couple, and the vaccines are more so for triple-negative disease than I guess other types. And I’m wondering, is there something specifically about triple-negative breast cancer that lends itself to a vaccine? Or is it because, you know, the other treatment options are somewhat limited?

Dr. Lisa Carey: Yes, and yes. You know, so, vaccines are a super-hot area and you know, while this has been proved for, you know, decades, we now have a better understanding of how the immune system reacts to cancer than we ever did before. You know, immunotherapy didn’t exist for a long time, although everybody was working on it, until there was enough information to actually allow the drugs to be designed so that they work.

For vaccination, there’s a few things that make it of particular interest in triple-negative. The first is, as you just alluded, our options are far more limited in triple-negative than they are in any other clinical subtype of breast cancer. 

The second is that there’s a lot of immune cells in and around triple-negative breast cancers characteristically, so, not all but many more than the average breast cancer. So, those immune cells are sort of in the area, meaning, you know, you might be able to get them to start working on behalf of keeping the cancer at bay.

The third has to do with the nature of triple-negative, which as I mentioned earlier, we think is, you know, going to end up being a bunch of subtypes, but among the characteristics of it, is it has a lot of mutations. It tends to have more mutations and the capability to form new mutations than the average breast cancers, some of which are a little bit quieter from a mutational standpoint. In general, having more mutations and abnormal proteins and things that get created by the cancer increases the likelihood of a strategy like vaccination working. 

Jamie DePolo: Oh, and why is that?

Dr. Lisa Carey: Well, you know, it has to show the vaccine, has to be able to see something on the cancer cell that looks abnormal, that it’s going to inoculate you against, right? Just like in an infectious disease, if the infectious disease looks exactly like your body, it’s not going to work very well. They have to look for things that are on the infection that the vaccine is designed to recognize and you know, prevent. 

The same is true for cancers, right? You need the cancers, these are things, proteins that are either called neoantigens, that’s a long word for saying a protein that’s kind of a new protein, it’s not normal in your body, or old proteins that were part of you when you were developing, you know, in utero, right? That get, as you come into being, they get turned off, but sometimes in a cancer they get turned back on, and it differentiates the cancer from normal. Because what you don’t want is to use immunotherapy that gets confused between cancer and the rest of the body, right? That’s where autoimmune diseases come from. 

Jamie DePolo: Right. Right. And my understanding is, too, that’s what’s always been the problem with breast cancer, but cancer in general, and both immunotherapy and vaccines, is because the cancer cells start from your own cell but then mutates. The body is like, oh, well, no. That’s you, that’s just a weird cell of you and I’m not going to attack it.

Dr. Lisa Carey: That’s exactly right. Yes. There’s a lot of systems in your body to keep your immune system from attacking you and unfortunately, and cancer is very good at hiding within the normal cells. And so, you know, part of it is, it hides from the immune system by basically covering itself in invisibility cloaks, and as you mentioned, it’s also true that it arose from normal tissues of the body. It’s not a totally foreign being like an infection would be. 

Jamie DePolo: Okay, and then I do want to make sure I understand correctly when you talked about triple-negative disease having more mutations, on average, than other types of breast cancer. And just to be clear, these are mutations that are within the cancer cell. It wouldn’t be something that is throughout someone’s body. So, genetic testing would not find these type of mutations. These are just in the cancer itself and it’s constantly changing and mutating. Am I understanding that correctly?

Dr. Lisa Carey: Yeah, and thank you so much for clarifying that because I think it’s very confusing. When we talk about mutations in the cancer universe, there are mutations that people can inherit like BRCA1 and 2, and those are some of the inherited forms of breast cancer and other cancers. Those are relatively uncommon, but you know, they are certainly real, they make up about 5% to 10% of breast cancers. 

But…and those are, if you inherit that so, that’s true in all the cells of your body, it’s a propensity gene. It’s a gene that causes a higher likelihood of getting cancer. These are like, just in the cancer. The other group are only in the cancer, they’re what make it a cancer, frankly, right?

Cancers are characterized by genetically abnormal stuff, right? So, these are mutations that are not in any other cell of the body, they are only in the cancer, and they give us an opportunity to develop, you know, a vaccine or other strategies to target them because of their differences from the normal parts of the body.

Jamie DePolo: Okay. Okay. Thank you for explaining that.

And then I guess finally, are there any future directions that we haven’t talked about as far as treatments for triple-negative disease? And do you think, roughly, I won’t hold you to this, but say like, in 10 years would we see some new treatments, five years? Where are we on that kind of spectrum or timeline?

Dr. Lisa Carey: Well, to be frank, we’re seeing new things every day, right? Datopotamab deruxtecan was just approved a few days ago, right? So, new drugs are emerging for triple-negative and other kinds of breast cancer, and remember, several of the drugs we’ve talked about work in triple-negative but they also work in other breast cancer types, and there is some overlap of many of these drugs. 

But what would I say are the future directions? I think there’s sort of three things.

The first is improving the way we deliver the kind of drugs that we have right now. We talked about that in the antibody-drug conjugate which basically takes chemo and allows you to give chemo in a more targeted fashion. But remember, those antibody-drug conjugates, the conjugate part, meaning the thing that’s attached to the antibody, right now it’s chemo because that’s the easiest thing to do. But some day it may be other kinds of targeted agents, right? It could go to much more novel drugs and so, you’re basically a targeted mechanism to get to the cancer, something that’s, you know, much more precise than chemotherapy. 

I think that’s going to also require that we get much smarter about the subtypes, the treatment-relevant subtypes within triple-negative breast cancer. I don’t think it’s all that helpful to identify a subtype for which there’s no treatment possibility. But most people who are doing research in this arena are really focusing on subsets within triple-negative that actually have therapeutic importance or potential therapeutic importance so that we can start teasing that out and treating in a more precise way. This is precision medicine.

The third is actually recognizing that at the moment, we’re taking a pretty blunt instrument to treating triple-negative breast cancer, right? If you think about, you know, most triple-negative breast cancer is at diagnosis, right? It’s not metastatic, it’s you know, it’s shown up as stages I, II, or III, when the effort is at using surgery, radiation, chemotherapy, immunotherapy to cure it, right? And so it, you know, goes away and never comes back in the lifetime of a person who lives a long, healthy life without cancer. 

However, the medical part of that involves four chemotherapy drugs, five if there’s cancer left over at surgery, and a year’s worth of immunotherapy. We know that not all of the cancers need that, and some of the cancers need more than that. And so, trying to sort out resistance and sensitivity and who we need to be that aggressive with and who we can be a little less aggressive, because all of these drugs have side effects and can have sometimes long-term, you know, toxicities that, you know, that the patient suffers. 

We want to make sure that we’re being super rational about treating the people who need treatment and not treating those that don’t need it or won’t benefit from it. 

Jamie DePolo: Sure, and does that kind of depend, as you’ve talked about, this sort of subtypes of triple-negative disease, would that be part of understanding that, who needs more, who needs less?

Dr. Lisa Carey: Yeah. You know, some of it is simply size of the cancer, how big it is, whether it’s gotten involved in the lymph nodes, whether the immune system is already participating in controlling the cancer, right? Because some breast cancers actually seem to have better prognosis because the immune system is actually already working on it. 

So, I think it’s going to be a variety of things, including those kind of efforts. But I think right now people are just trying to say, let’s use the simple stuff like is the immune system already activated, how big is the cancer, and are the lymph nodes involved? 

Jamie DePolo: Okay. Okay. Dr. Carey, thank you so much. This has been very informative. I really appreciate your insights and letting us know what’s going on. 

Dr. Lisa Carey: It’s been such a pleasure. Thank you so much.

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