Rethinking Axillary Management in Breast Cancer

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a Medical Oncologist and Co-Director of the Sarcoma Program at Cleveland Clinic. Today, I'm happy to be joined by Dr. Lauren Kopicky, a Breast Surgical Oncologist here at Cleveland Clinic. She's here today to talk about changes in the management of the axilla in patients with breast cancer. So welcome.

Lauren Kopicky, DO: Thank you. Very happy to be able to join you today.

Dale Shepard, MD, PhD: So give us a little bit of an idea of what you do here at Cleveland Clinic.

Lauren Kopicky, DO: Sure. So I'm a breast surgical oncologist, which means that I specialize in taking care of patients who have benign or malignant breast disease. I joined the clinic in early 2023 and I work primarily in the west region at Avon and Fairview Hospitals.

Dale Shepard, MD, PhD: Very good. So we're going to talk specifically about management of breast cancer and really managing the axilla. And oftentimes in these podcasts, we're talking about new treatments and how we come up with new things. We're actually going to talk a little bit on the other side how we deescalate treatment perhaps. And so as we think about breast cancer management and the axilla, give us a little bit of a background. There's a lot of different people might be listening in with different backgrounds. What is that all about and why is this important?

Lauren Kopicky, DO: Absolutely. So we traditionally have removed lymph nodes as part of our evaluation in patients with breast cancer to accurately stage them. So staging traditionally is based on the AJCC guidelines, TNM, so T for tumor size, N for lymph node status, and M for presence or absence of metastasis. And so the N standing for lymph nodes, we start with a clinical diagnosis whether or not patients have abnormal lymph nodes detected on exam or by imaging. And then we also have what we call pathologic nodal staging, which we get that result from actually removing some lymph nodes as part of our surgery. So traditionally, our lymph node assessment would always start with a clinical exam that gives us that clinical staging. And then we, historically, really early in breast cancer treatment assess the lymph nodes by a pretty radical approach by removing all of the lymph nodes, what we call an axillary lymph node dissection in all patients, even if they did not have any clinical evidence of lymph node disease.

So we were subjecting women to a pretty extensive surgery without any evidence that the lymph nodes were involved really to use that information to guide additional treatments such as our radiation planning or chemotherapy. And so thankfully, we've over the years developed or improved our processes to reduce the burden of surgery, particularly in the axilla for women. So the sentinel lymph node biopsy was a major improvement allowing us to reduce the amount of surgery on the lymph nodes for patients who did not have any clinical evidence of lymph node disease.

Dale Shepard, MD, PhD: And I guess other than more surgery, extensive surgery, what were the downsides of doing that surgery?

Lauren Kopicky, DO: So the downsides to an axillary lymph node dissection, first and foremost, risk of lymphedema. So our lymph nodes play an important role in draining fluid from both the breast, which is why we remove them for patients with breast cancer because we worry about cancer cells having gone there, but we inadvertently remove lymph nodes underneath the armpit that are draining the arm. So we were subjecting women to an increased risk of developing lymphedema or swelling of the arm, and that could be very symptomatic, ranging from mild to severe, very impactful in terms of negatively impacting quality of life. Additionally, the added risk of a more extensive axillary surgery has to do with pain, decreased range of motion, discomfort.

Dale Shepard, MD, PhD: So there have been some studies now just to suggest that maybe we don't need to do as extensive surgeries with the axilla. Tell us a little bit about how people have looked at this.

Lauren Kopicky, DO: When we look back historically over the originally from axillary lymph node dissection, jumping forward to now where we'll talk here shortly about not even checking lymph nodes at all, we've moved through some good studies. NSABP before told us that our surgery of the axilla did not actually impact survival. So we looked at patients who had the axillary lymph node dissection versus patients who did not. And overall outcomes in terms of survival were the same. We moved forward to assessing our ability to detect nodal disease with sentinel lymph node biopsy. We looked at the data from NSABP B-32 and found that we were able to reduce the extent of axillary surgery without any negative effects on patients' outcomes. And then moving forward, one of our pivotal trials, ACOSOG Z0011 looked at even in patients who did have pathologically positive sentinel lymph nodes that we did not need to return to the OR for an axillary lymph node dissection if it was very limited disease.

And this has been supported by several other studies, the MrOS trial. We also looked at patients after chemotherapy who had a good response that we were able to say they were clinically lymph node positive up front and then became clinically negative through chemotherapy. We were able to decrease the extent of axillary surgery. We looked at that in the Alliance Z1071 study. And then we have a couple studies that are looking at reducing treatment to the axilla, Alliance A011202, we're waiting on data. And then P51 looked at whether or not we still needed to treat patients who had a complete response in their lymph nodes with radiation to the lymph nodes. And then now with the newest conversation of de-escalation of omitting removal of lymph nodes entirely. We've looked at the SOUND trial and INSEMA trial, and these were really proposed and based off of some good results from CALGB 9343, which looked at women over 70 with small tumors with favorable features of really reducing adjuvant treatments. So it's really been a great advancement in the last 50 years of de-escalating the extent of surgery and minimizing added morbidity from our otherwise well-intended procedure.

Dale Shepard, MD, PhD: So we think about the latest trials, the SOUND trial, the INSEMA trial, looking at really, really minimal intervention. Can you walk through what those trials looked at and the populations and what we learned from those?

Lauren Kopicky, DO: Absolutely. And one thing I'll add before I dive into those is about eight years ago now, the Society of Surgical Oncology had published their Choosing Wisely guidelines, one of which pertained to breast cancer patients. And based on that CALGB 9343 data actually proposed not routinely using sentinel lymph node biopsy in clinically no negative women over 70 with a small hormone receptor positive breast cancer. So that's been a part of our practice for a number of years now. And then most recently with the results of SOUND and INSEMA studies, they looked at pretty similar types of patients, but did extend the age range. Median age for each study was in the early 60s, but they did look at ranges outside of just 70 and older. SOUND study looked at women with up to two centimeters.

So a clinically T1N0 breast cancer, vast majority estrogen positive HER2-negative. INSEMA allowed up to five centimeters. But interestingly in their T2 group, which would be two to five centimeters, their median size was still 2.5 centimeters. So we're largely talking about the tumor size being really up to two, two and a half centimeters. So on the smaller size. So these studies looked at patients who were randomized to undergoing a routine sentinel lymph node biopsy versus no sentinel lymph node biopsy and really looked at overall outcomes in terms of survival or axillary recurrence, and then even some secondary outcomes looking at risk of negative outcomes of the sentinel node procedures such as limited range of motion lymphedema.

Dale Shepard, MD, PhD: If you think about these trials, as we think about who we can deescalate therapy with. You mentioned the INSEMA trial. Really patients could have tumors up to five centimeter on average. They stayed a little closer to that two centimeter. When you're thinking about patients and minimizing lymph node sampling, what are the biggest factors that you're currently using? You've mentioned age, size of tumor, hormonal status. What are the factors that go into those decisions?

Lauren Kopicky, DO: So all of the women in each study had a negative axillary ultrasound. So axillary ultrasound is an important adjunct to our clinical exam to make sure that we're not seeing any abnormalities. Now, certainly that won't preclude maybe presence of a micrometastasis or a small focus of tumor, but we want to make sure we're not missing something that even though our exam doesn't detect an abnormal lymph node, that we're not seeing anything abnormal on their diagnostic workup. And at least here at the Cleveland Clinic, our diagnostic studies include axillary ultrasound as part of a workup for an abnormal mammogram. So we're screening our patients that way to make sure not only do we have a negative clinical exam, but a negative axillary ultrasound. You mentioned age. Age is something that I think based on the Choosing Wisely guidelines, very comfortable applying these studies to 70 and older.

I think we have a little less comfort and we're currently discussing internally, do we drop that to 60? Do we drop it to 50, things like grade? So predominantly grade one and two were included in these studies. A much smaller number of patients with grade three. We exclude patients who have multifocal or multicentric disease. And one of the key components I think that we talk about often in the surgical realm is we don't want to deescalate our surgery and inadvertently escalate something else. So we have a lot of concurrent studies looking at de-escalation or decreasing the extent of adjuvant radiation using a lot of partial breast radiation. So I have to mention that in both of these studies, patients got whole breast radiation. So in my mind, if somebody could be a good candidate for partial breast radiation, we reduce the side effects of whole breast radiation.

We reduce the small but present potential exposure to the underlying heart and lungs, and so does our small risk of the surgery of a sentinel lymph node biopsy is that preferred to the increased risk of whole breast radiation. And I think we have to balance those things. The other component to keep in mind is what that nodal information would give us with regards to adjuvant systemic therapy. We put a lot more emphasis on our genomic tests these days, our MammaPrint and Oncotype to give us that data. So our lymph nodes are less important, but there are some studies that we looked at not wanting to undertreat patients. So does this not identify patients eligible for other systemic therapies like CDK4/6 inhibitors if we haven't checked the lymph nodes?

And I think when we really look at some of these patient populations, we look at, well, how many patients with a really high lymph node burden are we actually missing? And it's very, very low. So I think we have to really look at all of these components when we're applying it. So it's definitely not a blanket application to all patients. And so very much depends on multidisciplinary discussion. I think that axillary management has been a very common theme at our multidisciplinary tumor boards. Just because we can do additional surgery doesn't mean we should or need to, but we don't want to not do that and inadvertently escalate somewhere else.

Dale Shepard, MD, PhD: And then I guess the other part of multidisciplinary would be the patient themselves. So this is...

Lauren Kopicky, DO: Absolutely.

Dale Shepard, MD, PhD: Yeah, I mean, this is a disease where we have patients who say, "Well, I have breast cancer in one breast. I want to lose the other breast as well, just in case." What do those discussions look like sometimes with patients in terms of saying, well, we're not going to get pathology from your axillary lymph nodes?

Lauren Kopicky, DO: I think it depends on what the patient brings to the table in terms of their experiences or maybe any friends or family that have had breast cancer. I've had patients that say, "I don't care what the data says, I just want to know. I want to know their negative." And I do think that our surgical technique has helped to minimize the negative side effects of lymph node surgery. We have a lot of different techniques of how we perform the sentinel lymph node biopsy, how we inject the radiotracer or dye, how we minimize the number of lymph nodes that we remove. We're probably less aggressive with our dissection in order to try to minimize disrupting the remaining lymph node drainage channels.

So I do think that that has changed a lot over the years as well, even with our axillary lymph node dissections. So I think our technique has improved to minimize side effects. But you're absolutely right. I think so much of our breast cancer care has shifted into individualized and personalized treatment. And at the crux of that is shared decision-making. So if I think somebody qualifies, I bring up the studies, we discuss it, I get their input, discuss that with their other medical providers, their medical oncologists and radiation oncologists just to make sure we're all on the same page.

Dale Shepard, MD, PhD: So the studies the more recent with the SOUND study, the INSEMA trial primarily, as I recall, looked at patients who were having breast conserving surgeries. What differences are there in terms of how we think through this for patients having mastectomies?

Lauren Kopicky, DO: So that's a great question, and I think that also gives us some pause as surgeons, because technically speaking, when we're doing a mastectomy, we're exposing the base of the axilla. So to remove the sentinel lymph nodes, we're right there. We have that open versus a lumpectomy where we're making an incision on or around the breast, we have to make a separate incision for the lymph nodes. So it's really two separate incisions for breast conservation versus with the mastectomy where we would say we're right there. But I think that we can still apply this data because the decision for mastectomy may not be really extent or size of tumor or anything more concerning. It may simply be a patient choice. And so we really need to focus in and make our decisions based on the tumor biology or behavior of the tumor rather than the extent of surgery.

However, that being said, I think returning to the OR to sample lymph nodes after a mastectomy may be a little bit more challenging than after breast conservation. And so we take that into account. There are some new technologies. There's a type of iron oxide material that we can actually inject at the time of mastectomy that will stay in the lymph nodes up to 30 days in case somebody's diagnosis changes and we need to go back. That's been looked at in patients with stage zero breast cancer where we don't routinely check lymph nodes, but there's a lot of advancement there, I think to help us feel comfortable if we do need to go back. And so sometimes that's part of the conversation. Certainly, we make some decisions based on our biopsy pathology, and that could change once the whole tumor is removed, grade might change, final size might change. We kind of look at that two centimeter threshold. And if somebody comes back 2.1 or 2.2, it's not an automatic return to check lymph nodes. We look at all of those factors.

Dale Shepard, MD, PhD: How has management of the axilla changed in patients who get neoadjuvant treatment?

Lauren Kopicky, DO: It's changed a lot. So we have looked at historically patients who had lymph nodes involved, even though they went through neoadjuvant chemotherapy, were still subjected to a bigger axillary surgery. And now, we're looking at patients through treatment and saying, "Okay, who's responding?" So I frequently check patients during chemotherapy reassessing with imaging to look at those lymph nodes and say, "Okay, are they normalizing? Are they responding?" And if we are getting a good clinical response, then now we can do what we call a targeted sentinel lymph node biopsy. So a lot of these patients who have had lymph nodes positive before chemotherapy have had that node biopsied and had a clip placed. So fast-forward, go through chemotherapy, get a good response. We do this targeted sentinel lymph node excision and map the lymph nodes the same way we do with radiotracer, dyes or combination, and really just remove those couple and reassess them.

So what we're looking for is, are there any gross bits of tumor left? Are there microscopic cells left or have we had a complete response? And now, we're waiting on some data from Alliance 11202 study looking at, okay, if somebody does have residual microscopic disease after chemotherapy, meaning that we did not get a complete response in the lymph nodes, are those patients still needing to be subjected to a completion x-ray lymph node dissection or can they go on to planned nodal radiation? And so I think there's a lot of discussion there of, say somebody had four abnormal nodes by imaging, we get a really great response.

They have a micrometastasis left and one lymph node, the others are negative, meaning they completely responded. Do we feel that that's an accurate representation of the lymph nodes that remain? Meaning we don't need to go and remove the rest of them to know for sure that they're negative. And again, a lot of the data from these studies have also looked at quality of life, morbidity. And we know that with less axillary surgery, we see less lymphedema and less negative side effects, such as decreased range of motion and pain.

Dale Shepard, MD, PhD: So as someone who doesn't treat breast cancer, you think about breast cancer, you don't really think about the axilla as much, but as you've outlined, there's a tremendous amount of work that's going into how we can optimize care for these patients. So is there anything else you're looking forward to seeing the results of ongoing trials or trials that are coming up that you'll think will be significant changes to how we're managing?

Lauren Kopicky, DO: Well, 11202 is one that we are all really eagerly awaiting. I think that some apply some of those principles, but we really don't have the data yet. And then there are a couple studies. So the National Cancer Database, NCDB, has actually announced that for patients over 70 grade one to two hormone receptor positive, HER2-negative, tumor size less than two centimeters. So really those Choosing Wisely guideline, they now actually have announced that that's a quality improvement measure looking at we should not be checking lymph nodes in those patients. So there are some pending studies, BOOG 2013-08 should result later this year.

And then the NAUTILUS study are kind of the next steps after SOUND and INSEMA and looking at those. And so I'd be excited to just look forward to more of this data to come out to be able to apply, because not every patient's going to fit perfectly into a box for a study. And so we do a little bit of extrapolating. And again, at the end of the day, we don't want to de-escalate something and escalate somewhere else. And so it's very much shared decision making and multidisciplinary discussion.

Dale Shepard, MD, PhD: Well, it's some fascinating insights you've shared with us today and appreciate you being with us.

Lauren Kopicky, DO: Thank you very much for having me. Appreciate it.

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