Can Chemotherapy Before Surgery Eliminate the Need for Surgery?

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. I’m podcasting from the European Society for Medical Oncology 2023 Congress in Madrid, Spain. My guest is Dr. Henry Kuerer, a breast cancer surgeon at MD Anderson in Houston, Texas, who is the Robinson Endowed Distinguished Professor of Surgery in Cancer Research and serves as executive director of the MD Anderson Cancer Network Breast Programs. He just presented results from his study looking at whether some women diagnosed with early stage triple-negative breast cancer, or early stage HER2-positive breast cancer could skip surgery if they had a pathologic complete response to chemotherapy before surgery.

Dr. Kuerer welcome to the podcast.

Henry Kuerer: Thanks a lot. 

Jamie DePolo: So, before we start talking about the research, just so all our listeners are aware, could you please explain what a pathologic complete response is? Because most of our listeners are patients and they may not be aware.

Henry Kuerer: Sure. So, for certain types of breast cancer there’s a higher risk, potentially, of recurrence both locally and somewhere else in the body. Those used to be triple-negative breast cancer and what we call HER2-positive breast cancer, where, when I said used to, now we’ve got really effective agents, and better and better agents actually, that improve survival and prevent distant as well as local recurrences.

At MD Anderson Cancer Center, over the last 25 years and more, we’ve tended to do a lot of our clinical trials, as well as now much more commonly is standard, giving the systemic therapy and this is chemotherapy and targeted therapies before surgery. 

And over the years we found that when we did the surgery, sometimes a mastectomy and certainly extensive axillary surgery called axillary lymph node dissection, the pathologists, when looking for the disease to characterize it, found oftentimes none. No evidence of cancer. And this makes sense because patients derive an increase in survival because chemotherapy and systemic targeted therapies actually can kill cells that we don’t know about, and why wouldn’t it kill the cells in the breast and the lymph nodes. So, pathologic complete response means the pathologists under microscopic review cannot find any cancer left.

Jamie DePolo: Okay, perfect, thank you. And I want to confirm, too, the women in your study, they were diagnosed with either early-stage triple-negative or HER2-positive [breast cancer], so there was no hormone receptor-positive disease in this study, and I’m just wondering why was that?

Henry Kuerer: So, if we give systemic chemotherapy, or what’s called endocrine therapy, to estrogen receptor-positive, pure estrogen receptor-positive cancers, the chance of having a complete pathologic response is pretty low, in the 5% range. And we felt that because of the technique we developed to select patients where there’s no more cancer that to put patients on trial it would take one out of 20 patients for us to find such a case. And this is all new, this whole concept of eliminating breast cancer surgery, and we wanted to go with a group of patients where the chances were extremely high and for triple-negative breast cancer and HER2-positive breast cancer with these optimal therapies is in the 50% to 70% range that no cancer cells -- pathologic response -- will occur.

Jamie DePolo: Okay, thank you. So, now could you explain the study for us? What did you set out to do?

Henry Kuerer: I want to say that, I will tell you what made me and my group and other investigators think about such a, or specifically why I thought that this might be an option.

So, first we were looking at patients who had lymph node spread, or what we call axillary lymph node metastases, and we proved it. We did an ultrasound, we stuck a needle in and these patients had cancer in their lymph nodes. And we know that axillary lymph node dissection is associated with a side effect called lymphedema, which occurs in about 20% to 25% of our patients. 

So, we were working and working because we were finding that 50% to 70% of these patients, we do this very radical surgery and there’s nothing left. So, we spent quite a long time figuring out a way, or we actually designed a procedure called targeted axillary dissection, where the hypothesis was that we could just test a lymph node that was, that had cancer in it, and avoid that complete dissection if no disease was found. Because obviously how on earth is surgery going to help those patients if there isn’t any breast cancer? And it turned out that, that was a pretty accurate method, in the range of 98%. The false negative rate, that we might miss some cells, was very low in that scenario. 

So, after we designed, tested, and implemented that new procedure that we were sparing this extensive axillary dissection, about 40% of our patients, I said, well, why can’t we just biopsy the breast cancer with you know standard needle, image-guided needle biopsy, like we do for all diagnostic procedures in breast cancer? So, we said, well, why don’t we take a look if we could accurately predict which of those patients had no residual without actually having to pull them into surgery? And we did that study and again these patients, you could imagine these women, we told them and you could imagine we’re following these women over five or six months and we’re looking at the breast imaging and their lymph nodes and they’re shrinking and they’re getting smaller. 

And I would talk to them and say, you know, I have a vision that maybe someday we might be able to determine which of you actually are not going to have any cancer left without doing the surgery, and we’re doing a clinical trial to figure out who those patients are. This will not benefit you, but it might benefit other patients. And it was real interesting to me, it amazed me how the women went through this additional procedure going, after they took all their chemo, got that needle biopsy just to help other, potentially help other patients. Because a lot of our research never helps anybody, but we were able to show that these women, in that first pivotal study at MD Anderson, that we could accurately identify these patients with one needle stick and 98% accuracy. 

So, that’s, that’s kind of what led to the clinical trial that was presented here at the European Society of Medical Oncology. We presented the three-year results of what we call a phase II, very early, small trial, but a remarkable trial where we did that and we just biopsied the breast and there was no cancer after the chemotherapy. And these patients agreed to participate in a trial where we skipped actually the breast surgery, and they went on to have their standard radiotherapy and their results were pretty remarkable. Because at three years, which was presented today here at ESMO, there was a 100% disease-free survival. That is no recurrences in the breast, and we’re following these patients closely every six months, and their survival is a 100%, as well as distant, that is it spread somewhere else. 

So, why is this? How can we not do surgery and they’re doing so well? You know, I don’t know why we would be surprised about this. We already knew that in 60% of these patients there is nothing going to be there and we selected these patients appropriately. It’s early, three years, but it’s very promising. Why? Because if we had missed disease, these types of tumors, which you don’t have a good response, tend to recur very early. But again I caution, particularly if patients are listening to this, this is the very beginning of this new field where we’re trying to avoid, not only the lymph node surgery, but the breast surgery. And I think the message really needs to be, for patients, that it’s new, it has not been proven in large studies and it cannot be considered a standard. 

But I do believe, and I am biased, that this is, this is the way of the future. Why? Because we’re developing better and better agents for breast cancer constantly. You, there was so many clinical studies that were presented at this meeting and all around the world that are showing better, newer, more effective drugs and not only for breast cancer, you can imagine this would work for other high-risk cancers, colon cancer, bladder, renal, brain, lung, prostate. You can imagine we’re developing better and better agents and we are trying to what’s called de-escalate some of our therapies. That is, if it proves that the patients have a high survival with limited toxicity why wouldn’t we skip surgery?

Jamie DePolo: Absolutely, that’s so promising. I’m curious, you followed -- the results that you presented -- the women were followed for three years, how long do you plan to follow them?

Henry Kuerer: Initially, we designed the trial to follow them for five years, and based on increasing interest as more time goes by, we had closed the, this trial that started in 2017, but we have now our institutional review board has agreed to expansion of 100 patients, additional patients. And along with that change in the clinical trial, we have requested the patients to be followed for 10 years. And we have consented quite a few of the patients on the initial study and we plan to ask them when they finish their five years if they would mind follow us along, because I think that information is going to be really interesting for patients.

Jamie DePolo: Oh, absolutely. So, just to make sure I understand. The initial study had 50 women in it and now it sounds like you want to expand it to 150 women, is that correct?

Henry Kuerer: A hundred patients. We have expanded it to 100 patients.

Jamie DePolo: Okay, gotcha. 

Henry Kuerer: Because of patient interest, yeah.

Jamie DePolo: Sure. 

Henry Kuerer: I wanted to mention one thing. I mentioned the toxicity, but I think because it is a new field you know we make these assumptions that, you know, women are going to prefer no surgery for breast cancer. You know it’s obvious, well, why wouldn’t they? You know who wants to have cuts on the breasts, cuts anywhere, you know.

But we didn’t know. We, we didn’t know if the patients would be nervous, afraid that their cancer is going to recur, so we designed several …to include several validated patient surveys looking at their comfort with participating in this clinical trial, patient health reported outcomes. Are they having anxiety? How is their physical health? How is their psychological well-being, their sexual health? What is their perception of their breasts, of their arm function, lymphedema, all of this? It’s so many questions that the patients have agreed to be followed. 

And I can tell you my colleague Helen Johnson published in JAMA Network a few weeks ago, it’s available online for anyone who wants to read about it, looking specifically at how are these patients feeling? And it’s pretty remarkable that these patients felt really good. They were comfortable participating in the study and I think, and this is my hypothesis is that they were looking at the imaging, the tumors were shrinking very, shrinking very a lot, down to 2 centimeters or less and the biopsy showed there was no cancer. So, maybe they felt, you know, that this probably would be safe, but the decisional comfort was pretty high and it increased over the three years, and the broad overall health quality-related indicators also were pretty high and increased with time. We will continue to follow these patients and we have also asked could we follow all these parameters for the next 10 years as well. 

Jamie DePolo: Oh, that’s great, yeah. And I can definitely understand if, you know, someone’s been diagnosed with cancer, I think the immediate reaction is you know let’s get it out, you know, I don’t want this in me. But that’s wonderful that everyone was comfortable, the quality of life was good, and certainly, as you said, you know, yes chemotherapy, targeted therapy, Herceptin can be tough, there are side effects, but to not have surgery and then deal with those side effects, like potentially lymphedema as you said, that’s, that’s pretty amazing.

So, you know, you’ve added more women to this study, this, you know it’s a small early study as you said, not standard of care of yet, but where do you see this going? Do you see like larger phase III trials coming in?

Henry Kuerer: Yeah.

Jamie DePolo: And you know and then I’m assuming that to do this the people have to be selected very carefully, as you said. 

Henry Kuerer: Right. So, with the new field we had to be exquisitely super selective in which patients where we felt that it probably, more likely than not, would be safe or just as good. We think it could be better with toxicity, surgical toxicity, which we’ve mentioned lymphedema, pain, syndromes, infection, psychological impact of scars, things like that.

What are the next steps? You know I have personal opinions about the next step. I will tell you certainly we’re expanding the multicenter study at MD Anderson Cancer Center, but we’re going to need a lot more of these other trials in diverse populations of patients. 

And I will tell you that there is a very large study, which is essentially trying to replicate our clinical trial with large, with much larger patients in the number of patients in Korea, 530 patients, so 10 times as large a study. That trial is doing really well. I happen to know Dr. Lee from Seoul and it’s a multi, of course, we’re colleagues and in contact about this quite a bit. That trial is doing really well, open I’m going to guess about five months, and 10% of the patients have already been accrued on that study. I think, you know, the real interesting question you know as a clinical researcher, you know, the gold standard is for clinical trials are these randomized controlled trials. That is I don’t decide, the patient doesn’t decide what treatment they’re going to get and sometimes we don’t know what they’re going to get. 

This one obviously the patient’s going to know and so is the doctor, but I really don’t believe, I’m predicting this, that patients would agree to be randomized if several of these studies with long-term, five- 10-year, show that their local recurrence and their survival was high, just as high as just doing standard surgery. I don’t think they would agree to be in this study because they may not have equipoise. That is they may think based on those results from several of these larger studies that that’s really what they care about the toxicity, the recurrence. But the gold standard you know, for example, you know, 45 years ago the standard was radical mastectomy, and the randomized trials had to be done with lumpectomy versus a very radical procedure. 

That was done at a time of 100 years of radical mastectomy and what allowed that to move forward, at that time period, was that there were smaller studies, that several smaller studies that showed the lumpectomy, even before we had breast imaging by the way, which is remarkable, might be effective. But I think we’re new, in a new era, much better breast imaging, better pathologic processing, ultra-processing of looking carefully at tissues, and systemic therapies are so much improved, I’m not sure if patients would agree to get standard, just that they wouldn’t be able to make a decision. And this is controversial. 

We talk about this among other clinical trial people and research, you know, the gold standard. Sure, I would prefer to have no bias, that is, a computer decides what the treatment is and let’s see how these patients are doing with their toxicity and recurrence. That would be probably the strongest evidence that it has as good, or better or worse efficacy and toxicity, but I don’t think patients will agree. So, I predict that we will have larger studies from multiple different centers around the world, and that this might be an option for some patients who would prefer not to undergo surgery. 

Jamie DePolo: Well, I just want to ask one more question, that suggests a question to me. Because the people for the study have to be selected so carefully, could you get a large enough group to randomize them? 

Henry Kuerer: Right. Yeah, you hit it. That is one of the challenges in all clinical research, not just cancer research, is selection of these, of these patients. You know we think about this, of course we’ve been working on this for a decade or so or longer, so about 40% of women with invasive breast cancer will have this HER2-poitive disease or triple-negative, so that’s a large number. But when I said selected, for example if a patient had many, many tumors in the breast, I don’t think it would be feasible for us to biopsy all of them, you know, under image guidance with a needle. I would say in the United States, at least, and places where there are screening, where there is, excuse me, screening mammography, that we are seeing very small triple-negative and HER2-positive breast cancers. 

But you’re right, stringent criteria and you know there’s all these, there are, there are… we are going to have to get better, let me just say, at our, at our breast imaging and other methods. Because lots of times the imaging will look like there is residual cancer, but it could be scar, and those in that clinical scenario, we do the surgery and there’s no cancer left in those patients either. So, we have a lot to do in clinical research over the next several years to figure out all of those potentials where we could use better predictive imaging to help us select the patients who may or may not need surgery or more radical surgery. 

So, not all patients can have a lumpectomy and there are patients where the disease looks very extensive still, and not to upset patients but this is the real world, it looks very dangerous, there’s suspicious microcalcifications, masses, abnormalities on MRI that look dangerous. But the problem is our current imaging can overestimate disease. We are working on this. This, we’ve, like you said we just had to hone down on patients where we felt that it might be the safest, but those other patients, we’re thinking about, constantly, and figuring out what can we do better and how in those clinical scenarios?

Jamie DePolo: Dr. Kuerer, thank you so much. This is so promising, again, emphasizing that this is early, not standard of care, but very, very, I think hopeful and encouraging, that down the road this could be a possibility for some women. So, thank you very much. I appreciate you sharing your research and your time.

Henry Kuerer: Thank you, Jamie, and I was delighted to speak with you today about our study.

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