Dr. Jennifer Litton is a board certified medical oncologist and professor of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston, where she is chief of the Section of Clinical Research and Drug Development for Breast Cancer. She also is a member of the Breast Immuno-Oncology Task Force of the National Cancer Institute.
At the European Society for Medical Oncology 2019 Congress, she presented information on a study she's leading, looking at combining a new type of immunotherapy with a traditional chemotherapy medicine. She joined us to talk about current immunotherapy research for breast cancer in general as well as what is specifically being presented at the congress.
Listen to the podcast to hear Dr. Litton discuss:
- why immunotherapy medicines to treat breast cancer will likely be used with another type of therapy, such as chemotherapy or radiation therapy
- the difference between a "hot" and "cold" tumor and why that is important for immunotherapy
- other biomarkers besides PD-L1 that may help doctors decided if an immunotherapy medicine will work
Running time: 16:50
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This podcast is made possible by the generous support of Lilly Oncology.
Jamie DePolo: Hello, and welcome to the Breastcancer.org podcast. I’m your host Jamie DePolo, senior editor of Breastcancer.org. We’re podcasting live from the European Society for Medical Oncology 2019 Congress in Barcelona, Spain.
My guest is Dr. Jennifer Litton, professor of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston. At the Congress, she’s presenting research about an ongoing study she’s leading that’s looking at combining a novel immunotherapy with Halaven, which is a chemotherapy to treat metastatic triple-negative breast cancer. So, we’re going to talk to her about the state of immunotherapy for breast cancer and what sorts of things are being presented at the conference, as well as her ongoing research.
Dr. Litton, welcome to the podcast.
Jennifer Litton: Oh, thank you so much for inviting me.
Jamie DePolo: So, give us some background on where we are with immunotherapy in breast cancer because there’s one medicine approved, but some of the results have been less than stellar.
Jennifer Litton: So, I am very excited to say that we now have our first breast immunotherapy combination that’s been approved for patients with metastatic triple-negative breast cancer. I think immunotherapy has changed the face of cancer care, especially in the last 5 to 10 years. We’ve certainly seen amazing results in other tumor types, such as melanoma, some lung cancer, some colon cancers, kidney cancer, and it’s been slower in showing its benefit in breast cancer.
A lot of that is just based on some of the basic biological differences of breast cancer when we compare it to the other cancers. There’s not as much of a percentage of the tumors that have immune cells already working against the tumor, and these immunotherapies kind of really help those immune cells increase in number and increase their attack against the tumor cells. And so for breast cancer, we’ve really been trying to look at enhancing those results.
So, there’s been multiple trials of the single-agent immunotherapies that have worked so well in those other tumor types that haven’t been as stellar at helping as many people with breast cancer. I think we saw some early signals where only a few people responded, but when they did it was very durable and long-lasting. So, a lot of work is going into how do we make those breast tumors more responsive to the immunotherapies, and there’s so much going on right now that I’m very excited about.
Jamie DePolo: When people talk about breast cancer tumors they often call them cold tumors versus warm tumors, which seems like that’s what a lung cancer tumor is, so could you talk a little bit about those differences?
Jennifer Litton: So, a couple things. When I’m trying to describe it to a patient, you know, I’ll often draw a picture of the tumor, and if you look at a melanoma tumor, when you see the tumor cells, sitting in those tumor cells there’s already a lot of immune cells that are attacking the tumor but need more help.
You know, these tumors get really smart and they put up shields, so those immune cells might be sitting next to the tumor cells but they’re not attacking them. They’re not seeing the tumor as something it needs to kill off. And these checkpoint inhibitors, of which there are multiple, what they do is they kind of rip that shield off so all of a sudden the immune cells are there, and they start attacking the tumor at a bigger effect.
Now, if you have a tumor where, if you looked at it on a slide, like the vast majority of breast cancers, there’s not a lot of immune cells sitting in there, so you can rip that shield off all you want, but if those cells aren’t sitting there already embedded in the tumor they can’t start fighting it.
So, we do notice from some of the tumor types that tend to have already some more immune cells sitting in them, tend to be the higher grade, more aggressive tumors. So, triple-negative, HER2-positive breast cancers, though not all of them, still a smaller percentage. We know that when we get immune cells in the tumors that they respond better to chemotherapy, they have better outcomes, so really we need to think of not only just ripping that shield off, but how do we get those immune cells to start infiltrating into that tumor, making it a hot tumor.
Jamie DePolo: Well, that was going to be my question. So, how does that research even look? Like, how do you get more immune cells into a tumor?
Jennifer Litton: So, I think that what I’m excited about is there is a ton of research going into it, and there are a lot of trials, not just in breast but across the board, looking at these immunotherapy agents. Either pairing them together, not just to rip the shields off checkpoint inhibitors that we have, but also the kind that rev up and put more of the attack immune cells sitting in the tumor. We’re looking at different dosing of radiation therapy.
We’re looking at ways to directly inject into the tumor to start to cause a local reaction in there as well. We’re looking at so many different ways, vaccines that we can start revving up the immune system and then helping with those medicines that rip off the shield. And I think for breast cancer, I don’t have as much enthusiasm for the single agent. And so that is why I’m excited to look at different ways to do it or different immunotherapy agents that are trying to do those simultaneously.
Jamie DePolo: Okay, so it sounds like for breast cancer, we have the one medicine approved, but it’s in combination with another.
Jennifer Litton: With the chemotherapy, with the standard chemotherapy. And I think, you know, we do know that as we kill off tumor cells that they do express antigens, and we can kind of spur the immune system that way. Also, with triple-negative breast cancer that’s metastatic and fast-growing, those immune medications need some time in your system to really work. And so part of it is not just making it more of a hot tumor, but also giving us the time to get enough time for the immune part to really start revving up as well.
So, you know, right now we have nab-paclitaxel and atezolizumab for first-line metastatic triple-negative breast cancer patients. For this combination, the FDA did approve it with the specific requirement of looking for PD-L1 staining on the tumor-infiltrating immune cells. And so for patients with metastatic breast cancer that’s triple negative, that is something their doctors will be talking with them and doing the staining that before we didn’t routinely do for every patient. And that would give us an idea of if you were eligible for that particular combination.
But there’s some patients that don’t have that PD-L1 staining. How do we get it there, and can we induce that, and so a lot of different trials. I am presenting at this meeting a trial in progress where we’re looking at eribulin, which is a standard chemotherapy that we give for patients with metastatic cancer both ER-positive and triple negative. We’re pairing it with a brand new pharmaceutical that has that shield-removing part of the checkpoint inhibitor, but it has a second head to it. It’s a fused protein, and the second actually blocks TGF-beta, and by blocking TGF-beta...
Jamie DePolo: That’s a protein?
Jennifer Litton: Yes.
Jamie DePolo: Sorry to interrupt.
Jennifer Litton: And so what it’s doing is also trying to block some of the other ways that the tumor can respond to shut down the immune system, right? We have all of these feedback loops, so this really helps us not only try to rev up the immune system with the chemotherapy, take the shields off, and then block the feedback loop of turning off the immune in that tumor. And so, we’re looking at that particular drug for the first time in combination.
So it’s a phase 1 trial, and we do have a poster showing that trial in progress, but I think that we’re really looking at how do we improve this across the board. And I’m very excited about looking at all the different ways that we’re going to use immunotherapy in the future. I think Jim Allison rightly — and I say this with full disclosure because he is at my institution — but he has changed the face of cancer care, and now it’s… that was the beginning, and I still feel it’s only scratching the surface of where we’re going to go in cancer care.
Jamie DePolo: Okay. One last question for you, I’m curious, most of the immunotherapies or in my limited knowledge, they do target, as you said, the PD-L1. Are there other targets that are being looked at or why is that... is that just the first one?
Jennifer Litton: So many, you know, as far as scratching the surface. So, there’s so many other ways to target the immune system, both the kind that rev it up, the agonist, as well as the antagonist that shut down that shield. And my friend, Beth Mittendorf, who is a phenomenal doctor in the world of immunotherapy, she’s constantly talking about using pedals in your car, your brake and your acceleration and constantly moving between those.
And I think that, although to date we have not had the huge responses yet in breast cancer, I don’t think every person needs immunotherapy. I think there’s a lot of people we can do less for without the toxicity, because to date immunotherapy does have serious side effects that we have to monitor differently than we’re used to in chemo. But I still think that we are scratching the surface of where we’re going, and I’m very hopeful.
Jamie DePolo: Okay, and one other question. When you talked about side effects that reminded me. It seems like with immunotherapy, the result is a little bit different mindset for both the oncologist and the person who’s been diagnosed because it’s almost like the immunotherapy is sort of halting the disease. It may not eradicate it completely, but it’s preventing it from growing, so it’s almost like a condition you live with. Is that fair to say?
Jennifer Litton: Well, I don’t think we know yet. I think it’s fair to say that in the land of metastatic cancer that’s where we’ve been for decades, right? There’s a small percentage of patients, mostly in the HER2-positive or untreated triple-negative that we can get to a stage IV, what we call no evidence of disease.
But for the vast majority of patients with metastatic cancer, I do feel that we’re slowing down the growth, hopefully prolonging life, and improving quality of life with our therapies. But we use one therapy for as long as it works until it stops working, and then you move on, with the knowledge that one of the hardest conversations we have as oncologists is there’s certainly a time in patients with stage IV cancer where we do more harm if we just keep treating. And so that’s been the paradigm of the treatment for metastatic cancer.
When we look at those patients with melanoma and other immunologically hot tumors, again, not curing everyone. But what we saw in those tumors, and what we’re hoping to get to in breast cancer, is there’s a certain percentage of patients where they don’t see disease anymore and it lasts for years and years, and that would be paradigm-changing for a patient. So, again, it’s… we’re not there yet. We’re not smart enough yet to figure out who exactly needs it, who’s going to have the long-term... I mean, that’s what we’re working on in a lot of those trials.
We’re not smart enough in a lot of ways that we need to be, I mean, to be really quite honest. And I am somewhat reluctant to say that everyone needs immunotherapy in the metastatic setting because we might do more harm than good. We need to really find those biomarkers that tells us who’s going to respond and to what agent than the all comers.
In the early-stage patients with triple negative — and the reason I’m bringing this up is because at this meeting we’re going to hear data of immunotherapy in the preoperative curative setting — that one of the biggest issues with triple-negative breast cancer is it’s not a disease. It is a group of tumors that are lumped together by what they are not versus what they are. And one of the biggest benefits that I see in the preoperative chemotherapy is we really can separate those folks who do fantastically well. They have a super chemotherapy-sensitive tumor and their outcome is fantastic.
There’s another group of patients where it’s just very resistant to chemo. These are the folks that we need to concentrate and do more and figure out what’s biologically driving their tumor and how we react to them.
I have yet to see — and we’re all looking for it — that perfect biomarker that tells us ahead of time who’s going to respond to chemotherapy and not, because I really think we need to start thinking more of, there’s a group of people who are going to do great, and we need to figure how little we can do to them to have them do great, and decrease their toxicity. And I think we can, even in triple negative. And then identify the folks that are going to be chemotherapy-resistant, and these are the folks we need to spend more time with targeted therapies against their tumors.
And so, I think the idea of just put everyone together in one big trial and throw a drug at them needs to be over.
Jamie DePolo: Okay. That makes sense. And I guess the one other thing I was wondering, it doesn’t seem like we know yet, either, how long people need to be on immunotherapy because, you know, it is like...
Jennifer Litton: Is it one year or is it two years...?
Jamie DePolo: Yeah. Is it for the rest of your life? We don’t know.
Jennifer Litton: We don’t know yet, you know? I would be thrilled that that’s our next question, right? That would be ideal. I was just with a group of colleagues recently, and we were talking about trastuzumab and the same question. You know, transforming drug for HER2-positive breast cancer patients, and we all in our practice have those folks that showed up with metastatic cancer untreated, had never seen an antibody, and are 10 years, 12 years, 14 years out with no evidence of disease.
I never say the word cure because I’m very superstitious. No evidence of disease is the [barometer], and how long do we keep Herceptin on, you know? And there’s no data. We’ll never be able to do a trial, and we all still debate it. What a wonderful debate. What a wonderful debate to be having.
And so those things do need to be done. I think those trials, as we get better treating patients with metastatic cancer, and hopefully make it a much more chronic disease than it is, this is where public funding for the large trials, and cooperative groups, and international cooperative groups are going to have to be the one set up to answer those questions.
Jamie DePolo: Okay. Thank you very much. I appreciate your time.
Jennifer Litton: Oh, thank you.