Finding and Treating Inactive Breast Cancer Cells

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. My guest today is Dr. Angela DeMichele, who is the Alan and Jill Miller Professor in Breast Cancer Excellence at the Perelman School of Medicine at the University of Pennsylvania. She is also the co-director of the 2-PREVENT Breast Cancer Translational Center of Excellence at the Abramson Cancer Center at Penn Medicine.

At the European Society for Medical Oncology 2023 Congress, Dr. DeMichele presented results from the CLEVER study which looked at ways to treat inactive breast cancer cells that remained in people who were previously treated for breast cancer. The results suggest that it might be possible to find and treat these inactive breast cancer cells, which could help prevent breast cancer recurrence. She’s going to explain the findings to us. 

Dr. DeMichele, welcome to the podcast.

Dr. Angela DeMichele: Thanks so much for having me.

Jamie DePolo: So, first I want to ask, could you explain how these inactive or dormant breast cancer cells survive chemotherapy? How does that work?

Dr. Angela DeMichele: So, we now understand that women who are diagnosed with breast cancer have a tumor in the breast, but there are also these very specialized cells that can leave the breast, travel through the blood stream, and find their way to other parts of the body where they can essentially become dormant or sleep. I think about it like, a bear hibernating in the winter, sort of goes into the cave, goes to sleep, doesn’t really need any external food or energy, and just sort of sits there until such time that they wake up and then travel to other parts of the body. 

During this period of time we don’t see any evidence of cancer anywhere. Patients aren’t having any symptoms, they don’t have any findings on a scan, and honestly, we don’t know, up to this point we’ve never known which patients have these cells and which patients don’t have these cells. Until such time as those cells wake up, travel through the blood stream to another part of the body, and then that is recurrent metastatic breast cancer, which then can lead to symptoms, and of course, be a very serious problem.

Jamie DePolo: And so, when these inactive cells are in their sleeping phase and wherever they are, my understanding is they’re in places in your body where they’re hard to see or hard to find like, bone marrow. Is that correct?

Dr. Angela DeMichele: That’s right, and they are very rare. We don’t know exactly how many of these cells a patient might have, but we know there aren’t a lot of them, and so, finding them can be very difficult. There are laboratory studies using animal models that have told us a lot about how this whole process works, and from there we’ve learned that the bone marrow is a very supportive environment for these cells.

But there can be other places where they may find a supportive environment and be able to maintain this inactive state outside of the bone marrow as well. But they do seem to be more commonly found in the bone marrow, and it’s the easiest place for us to find them as we’re looking for them in the clinic.

Jamie DePolo: Okay, and I want to make sure I understand. You said that it’s not clear yet who has these inactive cells and who doesn’t, right? It’s not everybody has them, as far as we know. 

Dr. Angela DeMichele: That’s right, and so, if you think about it, you know, a patient is diagnosed with a tumor in the breast, they’ll have surgery, usually have the lymph nodes evaluated, and radiation, chemotherapy. The hope is that we’re eliminating all cells, and because we have such a high cure rate from breast cancer, we assume that most patients don’t have the cells. But about 20% to 30% of patients will relapse or recur sometime in their lifetime so, probably about a third of the patients have these cells.

Now, it’s possible that it’s even higher, but that for many women they never wake up so, we never know they have them.

Jamie DePolo: Gotcha. Okay. So, if the cells are inactive, I have to ask, how do they wake up? Do we know what causes that?

Dr. Angela DeMichele: We really don’t, and this is an area that’s of active research, primarily again in the laboratory in these models where the tumor cells can be tagged with fluorescent markers, and then scientists can implant them in the mice, for example, mimic the whole process of treating the cancer, and then see these few cells that survive that treatment and follow what happens to them, see them become dormant and then see them reactivate, and it’s through these types of studies that we’ve learned some of the mechanisms that seem to be responsible for both allowing them to go to sleep to begin with, allow them to survive in that suspended animation, and then ultimately wake up.

So, we are learning a lot, but we don’t know precisely what allows them to wake up.

Jamie DePolo: And are there certain subtypes or breast cancers with specific characteristics that are more likely to have these dormant cells, or doesn’t that matter, or aren’t we there in our knowledge yet?

Dr. Angela DeMichele: Well, initially we thought that estrogen receptor-positive breast cancer would be the type that has these cells because of the latency or the delay between the original diagnosis and when recurrences can happen, right? So, a recurrence, meaning development of disease in the lungs or the bones or the liver, that can happen within months, years, decades. It’s much more likely in an estrogen receptor-positive breast cancer that is going to happen beyond five years.

So, we always thought oh, those are the tumors that have dormant cells, but it turns out that in the laboratory we’ve seen that all subtypes can pass through a dormant phase, it’s just that that phase is very short. Even a HER2-positive breast cancer can have a dormant phase, it’s just that the cells will wake up and recur within that five-year timeframe. So, there is no one way that a cell becomes dormant, there’s not one way in which it wakes up. It’s likely to vary by subtype, but all subtypes have the possibility of becoming dormant.

Jamie DePolo: Oh, wow. That sounds so very complicated. Could you describe the CLEVER study for us?

Dr. Angela DeMichele: So, based on what has been learned in the laboratory by my colleague and research partner, Dr. Lewis Chodosh, who’s really been one of the primary people looking at how these cells function, he was able to identify several different ways in which the cells stay asleep and wake up. One of those is called autophagy. Autophagy is a term that means supporting oneself. It’s a mechanism by which the cells use their own internal energy sources to stay alive.

So, most cancer cells are dividing very rapidly. Dormant tumor cells are not dividing. Most tumor cells that are dividing very rapidly need a lot of glucose. So, we’ve heard people talk about how sugar can fuel cancer cells, right? Dormant cells are not dividing so, they have the ability to stay alive without using any of that sugar, without using any external energy sources. They use their own internal energy sources. So, this is why I think about that bear hibernating in the winter analogy, it really works. 

And so, that’s an important way that the cells stay alive, and there are drugs that can interfere with that. One of the drugs that can do that is hydroxychloroquine. So, we all heard about hydroxychloroquine during the pandemic when it was touted as a potential treatment for COVID, but it’s a drug that’s been around for a very long time. It’s been used for the last several decades to treat malaria, it’s been used for inflammatory conditions, but it turns out that it’s also really good at blocking this process of autophagy. 

So, in the laboratory Dr. Chodash treated the animals with an analog of hydroxychloroquine, and it killed the dormant tumor cells. And so, that was one way we thought, oh, we could try to now see if that could work in patients. 

Another one of these mechanisms is called mTOR. mTOR is a signaling pathway. Signaling pathways in cancer cells are sort of like the electrical system that carry current from different parts of the cells to another, and you can interrupt that electrical current through drugs. So, when Dr. Chodash found mTOR as another mechanism that these cells use, he treated the animals with an mTOR inhibitor, and again, it was able to kill the dormant cells. And with both hydroxychloroquine and an mTOR inhibitor called everolimus, could see that the animal didn’t recur once he treated them with these drugs. 

So, we said okay, we’d like to translate that to the clinic. First thing we have to do is we have to be able to find the patients who have the cells. So how do you do that? Well, we talked about the fact that the cells are residing within the bone marrow. That’s a reservoir if you will, it’s sort of like, a little lake in which these cells can survive. 

So, we do something called a bone marrow aspirate, which is done in the clinic. It’s a little needle that is put into the hip bone and we take out about 10 ccs or 4 tablespoons of the liquid part of the bone marrow. We put it through a sophisticated system of filters, and at the other end of that filter we take what comes out and we look at it under the microscope, and we can tell whether a patient has any of these cells.

So, we first started a study to simply look for the cells in patients who had had breast cancer, had been treated for their breast cancer, finished all their treatment, and were just in their surveillance period. And we’ve enrolled a little over 200 patients into that study so far, and we were able to identify patients who had these cells.

Once we found these cells in the patients, we then offered the patients the opportunity to enter the clinical trial, and that’s the CLEVER trial. So, the CLEVER trial is for patients in whom we have found these cells in the bone marrow. They are treated with either hydroxychloroquine or the mTOR inhibitor, everolimus, or a combination, for six months. There’s another bone marrow halfway through at three months, and another one at the end of six months. 

There’s also a group of patients who waited to start their treatment for three months. That’s our internal control, and they had another bone marrow at the end of that three-month period. So, now we have a group of patients who had no treatment for three months, and then we had the patients who were on each of these treatment arms, and we looked to see after three months of treatment whether we were able to eradicate these cells from the bone marrow. And we compared it to what was happening in the bone marrow of patients who had no treatment, and what we found was that we were able to clear these cells in about 80% of the patients with each of the treatments.

Now, the combination treatment was a little bit better than each of the treatments alone, but they were all in that 80, 81% range, and we then followed these patients and looked at what was happening in the bone marrow six months later and six months after that, and in fact, we saw that it was persistently cleared in these patients.

So, it’s early data. There were 51 patients who were treated on the trial. So far only two patients have had their breast cancer come back, and we’ve been following these patients for about three and a half years at this point. And those two patients who’ve had their breast cancer come back did not clear the dormant cells. None of the patients who cleared their dormant cells have had a recurrence up to this point. 

Now, I will tell you that a little over half of the patients in the trial actually had triple-negative breast cancer, about a third of the patients had estrogen receptor-positive breast cancer, and 20% had HER2-positive breast cancer. So, we had all different subtypes of breast cancer. All of the patients had very high-risk features of their disease like, positive lymph nodes, or still had residual cancer after preoperative therapy, things that would put them at high risk of recurrence. But we really saw this effect across all of these different subtypes.

So, this is really the very first study that has ever targeted specifically these inactive, sleeping cells, these dormant cells. We’re hopeful that this is really a way that we can move forward, but it’s early and I think it’s important to recognize that before any treatment can become part of standard of care, we need a lot of evidence that it really works, and we don’t want to expose people to therapies before they’re ready.

So, while this is very positive early data, we have two other trials actually that are going on that will help us to confirm these findings. We’ll continue to follow these patients who’ve been treated on the CLEVER trial for many years, actually. Recently got a large grant from the Department of Defense that will enable us to continue to follow patients, continue to screen patients, and treat them, really to try to build our body of evidence that this can be a successful way to prevent breast cancer recurrence. 

Jamie DePolo: Oh, that’s great, and the new grant I think is especially great because as you said, we know that hormone receptor-positive breast cancer can come back decades after the initial diagnosis so, I think the longer you could follow the people in the CLEVER trial, the more information we’ve had. 

Dr. Angela DeMichele: And this grant allows us another four years of follow-up. These patients will continue to have bone marrow aspirates intermittently, they’ll have CT scans, and PET scans to make sure that there’s no evidence of cancer, and then concurrently we’re looking for circulating tumor DNA in the blood stream as well. 

We haven’t talked about that yet, but that’s another very important area, and those are the cells that have woken up. Those are the cells that now have left that protected area where they were dormant, are now back into the blood stream and are on their way to another place. So, we’ll be monitoring that in these patients as well, because that gives us yet another opportunity to intervene. 

So, my vision and my hope for the future is that we will now start to be monitoring patients for both the dormant sleeping cells as well as the reactivating circulating cells and have trials and eventually treatment for patients regardless of whatever stage of recurrence they may be in to prevent it from ever getting to the organs. 

And I think this would really represent an important advance because up to this point surveillance has really been about watchful waiting, and I got into this because, you know, for gosh, 15 years I was taking care of patients and we’d get to the end of that initial treatment and they would say well, how do you know it worked, and what are we going to do now, and when am I having my scans? And I would say, look, I don’t really have a way to know that and I don’t really have a way to monitor you, and that’s very, very stressful for patients. 

And I think that even though we have cure rates now that are over 80%, until we get to 100%, every patient who gets breast cancer is going to worry about this. 

So, one of the other goals that we have is not only to be able to find and treat these cells that might come back, but also develop a strategy to test patients proactively and be able to tell them hey, you’re clear, everything’s okay, you don’t have these cells. I think that would also be an enormous step forward to alleviate a lot of that anxiety that patients are feeling, you know, over the course of their lifetimes, even though they’ve already been treated for breast cancer. 

Jamie DePolo: Oh, yeah, and I am wondering, you talked about the results from both treatments, the everolimus and the hydroxychloroquine, and then the combo, they were all about the same. I guess I’m wondering, since each of those treatments works on a different pathway or a different method that the cell might keep itself alive while it’s dormant, does that suggest that for those 20% that maybe they’re using another method to stay alive when they’re dormant?

Dr. Angela DeMichele: Yes, and you know, there are many, many different parts of this. I mean, it’s as complicated as initial therapy, initial biology. It is complicated. So, we know of other mechanism and our other studies are starting to test some of those as well. An important part of this is the immune system. You know, one question is, why are these cells allowed to exist in the body? Why is the immune system not recognizing them and destroying them because they’re foreign. They shouldn’t be there, they are not your normal cells.

And so, one of our trials which is called PALAVY and is open across the country actually right now, also incorporates immunotherapy in an effort to try to teach the immune system to recognize these cells and destroy them. 

So, as you were saying, you know, if we have lots of different ways that we can attack these cells, maybe the strategy should be that you try one, if that doesn’t work that you could move to another and another until we find the one that works. So, that’s another way we’re thinking about this is to develop what’s called a platform trial where you could try multiple therapies for an individual patient because we know that it’s not going to be the same for everybody, we know there might be lots of different therapies that can work.

And then, of course, we also need to develop better and better technologies to find the cells. Not only find them, but be able to profile them, to really understand, oh, well, what kind of cell is this and what mechanism is this cell using? 

Jamie DePolo: Yeah, that was actually going to be my next question. I could see looking at, how is this cell staying alive so, when you found them, it’s staying alive with the mTOR pathway. We know that everolimus is the treatment for this one, but there’s also some of these other ones in there that we need to use this medicine for. So, that sounds very exciting, too. 

Dr. Angela DeMichele: Right, because that would be a more precision approach. So, just like we measure estrogen and progesterone receptor and HER2 when the patient is initially diagnosed and we match the treatment to that, we could envision a scenario where we now can profile the dormant cells and match the treatment to those.

Obviously that’s several steps down the line, but, you know, I think it’s entirely possible that that will happen eventually. My colleague, Dr. Chodash, is working on a technology that would enable us to do that so, that we could really interrogate these cells, understand, you know, what flavor per se of dormant cell the patient has, or maybe it’s a mixture, and then we could tailor the therapy to that.

Jamie DePolo: Oh, that would be so, so incredibly exciting, and I’m assuming, this is probably out of your purview of research, but this could be applicable to other types of cancer as well.

Dr. Angela DeMichele: Yes. So, this is starting to be investigated in other cancer types. There’s work with both dormancy and with the circulating tumor cells or circulating tumor DNA. In fact, with colon cancer there was a large, really amazing study that showed that circulating tumor DNA, the cells that are in the blood stream, could be used as a way to figure out if patients needed additional therapy after surgery and which patients did not. 

And so, not only can this be a method to find patients who might have a recurrence later, but it also could be used as they did in this study, as a way to figure out who might not need as much therapy. So, this is another really exciting aspect of this research which is if you know the patient doesn’t have these cells, could you avoid some of the more toxic therapy that we give as adjuvant or insurance? 

So, I think you’re going to see more and more of this being discussed over the coming years and decades, and I think it will really transform how we treat all kinds of cancers. 

Jamie DePolo: Oh, yeah. I could see if somebody was diagnosed with hormone receptor-positive breast cancer and they did not have these dormant cells, the possibility of not having to take tamoxifen or an aromatase inhibitor for five to 10 years would be incredible for a lot of people if they didn’t have to do that.

Dr. Angela DeMichele: That’s right, and I think really that what we’re limited by now is how sensitive the tests are. So, remember, I said that, you know, these cells are very rare and so, you have to have really, really sensitive ways to find them because, of course, we would never want to forego treatment in someone because we tested them and they were negative but we just missed the cells. So, I think that’s a little bit further down the line as the tests get more sensitive, but I think what we have now are very specific tests that can say yes, you have these cells and we should do something about it. 

And this could be, you know, we’ve been also working on designing a trial for women with estrogen receptor-positive breast cancer who’ve been on their anti-estrogens for several years. We know that those drugs can stop working after a while, and so, now we’re looking at a potential trial where we would measure the blood for these cells and see if they are still there, and then think about switching the anti-estrogen because perhaps the one they’re on isn’t working.

So, you can see all kinds of different opportunities here to direct therapy in a setting where there’s nothing you see on a scan, there’s nothing you can see on physical exam, the cells are there. Now we would have these very sensitive, specific ways to find them and to be able to give therapies that prevent them from ever really causing harm or limiting a lifespan.

Jamie DePolo: It’s amazing. Dr. DeMichele, thank you so much. I know, as you’ve stressed, this is early research, we don’t have all the pieces in place yet, but so, so, exciting and encouraging to think that one day this could be possible so, thank you so much for sharing this with us.

Dr. Angela DeMichele: Well, I really appreciate the opportunity to come speak with you and appreciate all you do to educate patients, it’s really important so, thank you, too.

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