BTKEpisode2
===

[00:00:00] Welcome to the latest episode of our breast surgery podcast series On Behind the Knife. We have the same team as last time. I'm your host for the episode, Rashmi Kumar. I'm a general surgery resident at the University of Michigan. Today we're tackling a question that lies at the heart of modern breast cancer care.

Should sentinel lymph node biopsy be emitted in select patients with early breast cancer? It's a challenging but timely question. Balancing the need for accurate staging information with the goals of minimizing patient harm and optimizing quality of life. We're joined again by Dr. Poluski and Dr. Down scanner, both renowned experts in breast surgical oncology.

Dr. Poluski is the co-director of the Wiser Family Center for Breast Cancer at the University of Michigan. Dr. Down scanner joins us from Memorial Sloan Kettering Cancer Center, where she's the fellowship program director for breast surgical oncology. Today we're doing a journal review of trials studying admission of sentinel lymph node biopsy in select patients.

We'll cover the groundbreaking sound and in semi trials [00:01:00] we'll explore what these studies mean for clinical practice, patient counseling, and the future of axillary management. But let's start with the foundation and some historical context. If we look back, breast cancer surgery, historically was very aggressive, not just in removal of the breasts, but also the axillary lymph nodes through radical mastectomy and routine axillary lymph node dissection, or a l and d.

The rationale at the time was that a l and D would help control disease, provide accurate staging and reduce recurrence, but the morbidity was substantial. Patients developed chronic lymphedema, nerve injury and real functional limitations, Dr. Down scanner. Can you walk us through a brief overview of how the field has changed in using A LND to shifting Des Sentinel lymph node biopsy over the past 30 years?

Sure. I think it's important to understand when operations for breast cancer were first described by Halstead in the late 18 hundreds, our understanding of the biology of the disease was different, [00:02:00] and it was felt that the cancer spread by direct extension, so the more radical the surgery, the better the outcomes, or at least that was what was thought at that time.

Not until almost a hundred years later did scientists. Including Bernie Fisher, think about the biology of breast cancer differently, and understood that it didn't necessarily spread by direct extension, but instead through the blood. And so this led to the development of multiple trials to deescalate surgery, beginning with the use of sentinel lymph node biopsy in clinically node negative women, really important randomized trials, many run by the N-S-A-B-P, including N-S-A-B-P 32.

Demonstrated that women had the same outcomes, whether they were treated with sentinel lymph node biopsy or axillary dissection, and this was done in no negative women. Even after that though, there's been further deescalation, including studies such as the AKA AXI 11 study, which demonstrated the safety of sentinel lymph node biopsy for low volume axillary disease.

So this showed us that all patients who were [00:03:00] found to have metastatic. Breast cancer and the lymph nodes did not need to have completion, axillary dissection, and then even more studies looking at certain populations of women in whom any axillary surgery could be omitted. These include multiple studies in women over 70, where it was shown that we don't need to do any axillary staging at all, and this is safe in terms of cancer outcomes and leads to significant improvements in quality of life.

Most listeners know axillary surgery use. To be almost automatic until the results of the trials Dr. Down scanner mentioned changed that paradigm. Now we have used routine sentinel lymph node biopsies in patients instead, but what are the current questions we're grappling with in axillary disease management?

I'd love for experts to weigh in on this.

Thanks. So let me chime in. I wanna just echo some of the comments that Dr. Dons canner made. You know, we've seen this huge. Shift in how we manage the axilla from radical surgery to sentinel node [00:04:00] biopsy for staging and sentinel node biopsy to manage low volume disease.

And the question today is, who can omit even that small nodal staging procedure? Some of the studies that we've had. Such as CL GB 93 43, and others that really showed the safety of omission in older patients with low risk breast cancer led to a campaign called Choosing Wisely, which outlined the recommendation to not do sentinel node biopsy in this cohort of low risk patients.

And what we found is even with strong data supporting the practice, this has been hard to implement into clinical practice and studies are showing that. Over 70% of patients who meet the criteria for those older studies of sentinel node biopsy omission actually are still undergoing nodal staging. And so it really raises the question of why are we not always applying this data into clinical practice?

And I think it really challenges us as surgeons to understand the pros and cons and the nuances of this, of how do we balance. The [00:05:00] morbidity and side effects of a procedure and the potential impact that nodal staging will have on adjuvant therapy. And so that's really the question, um, hopefully that we will tackle.

Right. And I think that also highlights why breast cancer is such a multidisciplinary disease because. These decisions made by surgeons really cannot be made by surgeons alone and without understanding how the entire treatment process happens. I'd make no mistakes though. Sentinel lymph node biopsy is a real surgery with complications, even if they're less than axillary dissection and significantly less.

But there's still a risk of lymphedema of about two to 5% in women who undergo sentinel lymph node biopsy. Probably the most talked about risk, but there's also a risk of wound infection and shoulder dysfunction or dysmotility and pain in up to 20% of patients, at least in some form for some duration of time.

That's not insignificant, and these risks might be especially meaningful for older adults and really for any [00:06:00] adults. So if we can understand if there are a group of patients in whom we can safely omit this operation, we expect that we'd offer a major quality of life benefit. But we need to be certain that when we omit this operation, we are not losing important staging information that might guide adjuvant therapy decisions.

This brings us to our journal club discussion and topic point of the emission of sentinel lymph node biopsy in select patients. I think to start off, it would be very helpful for our listeners and trainees to talk about the pros and cons of sentinel lymph node biopsy. What are the most compelling reasons for and against admission?

So

the benefits are clear. If we think about omitting sentinel node biopsy in doing less surgery, we are clearly reducing the risk of surgical morbidity. And we just heard some of the potential side effects really eliminating the potential risk of lymphedema, which is truly meaningful, potentially shorter recovery, and also potentially avoidance of general anesthesia [00:07:00] if it is your practice that that is routinely used for sentinel node biopsy and it also can.

Really impact potential functional status of upper extremities and more broadly, I would say this is associated with lower healthcare costs, less time under anesthesia. And so all of these risks matter and add up. The benefits of omission are on one side of our scale, and on the flip side, clearly are losing.

Nodal staging. We have good tools, but they're imperfect imaging we're gonna talk about in more detail. But in these studies of omission of sentinel node biopsy, we know that we're missing about 15% of patients who have positive nodes. And so it's in that cohort that we're left with the unanswered questions of how is this going to impact prognosis, treatment selection, and potentially eligibility for clinical trials.

As we deescalate and do less therapy in one modality, this will impact how we think about multimodal care in other aspects. And I think it also begs the question of patient [00:08:00] preference and where do we deescalate therapy, whether that's in surgical care or other aspects of their breast cancer treatment.

Exactly, and that's why shared decision making is really important because as we've touched on axillary staging impacts other aspects of care. For example, radiation and systemic therapy decisions deescalating in one area may result in the need to escalate it in another area. Each patient has probably a different perspective and preference.

And providers, of course have different preferences as well. So it's really key to have shared decision making with our patients as we talk about sentinel lymph node biopsy.

To help you with those conversations and more, today, we have three main objectives for the episode. First, we'll talk about where is it safe and beneficial to emit sentinel lymph node biopsy.

What risks do we run by foregoing the diagnostic as well as the prognostic? Power that it provides specifically for select patients, and how do we balance [00:09:00] patient quality of life with the need for more and robust clinical information? There are currently multiple randomized clinical trials investigating the emission of sentinel lymph node biopsy in clinically node negative.

Patients, the SOUND Trial, Nima Dutch Breast Cancer Research Group, and Nautilus to name a few of these, of all of these trials, the SOUND and Nima trials have published their primary results, which we will cover today in our deep dive. These are the most rigorous and largest studies to date, asking the question, can we emit sentinel lymph node biopsy safely in early stage clinically node negative patients?

So let's start by breaking down the sound trial first. Sound stands for Sentinel lymph node biopsy versus no axillary surgery in patients with negative results on ultrasound of axillary lymph nodes. So this trial was published in gym oncology in 2023. It's a perspective randomized control trial randomizing over 1400 women with small up to two centimeters of disease clinically node [00:10:00] negative breast cancers.

Confirmed to be negative on a preoperative axillary ultrasound of the patients enrolled in the trial any age was eligible. But in the real world population, the cohort tended to be older with the median age of 60. These were ER positive patients and her two negative patients predominantly, and the median tumor size was 1.1 centimeters.

Despite the trial allowing up to two centimeters total. And these patients were distributed across 18 hospitals in Italy, Spain, Switzerland, and Chile. The arms of the trial were sentinel lymph node biopsy, which is the standard of care versus no axillary surgery at all. Both groups received standard adjuvant therapy and whole breast radiation if indicated.

Dr. Down scanner. Can you give us an overview of the key results from the sound trial?

Sure. One of the key results was distant disease-free survival, which was essentially identical in both arms of the trial. So in the patients who had sentinel lymph node biopsy, distant disease-free survival was [00:11:00] 97.7%, and it was 98% in the omission group.

The other outcomes that were evaluated included overall survival and recurrence. We're not different between the sentinel lymph node and the no axillary surgery group. The authors also reported on adjuvant therapy in the two arms of the group. In the sentinel lymph node biopsy group, 142 women, or about 20% received adjuvant chemotherapy and 17 point a half percent or 122 women in the no axillary surgery group received chemotherapy.

In this study, the decision to use chemotherapy was made mostly based on genomic assays. Particularly in the group that did not have axillary surgery. The study also looked at complications and as expected there was a lower morbidity in the axillary surgery omission group. One thing to note in this study is that in the patients who did have a sentinel lymph node biopsy, and Dr.

Puluski alluded to. 15% or so did have a positive node, which highlights [00:12:00] sort of the importance of this discussion. So in the group of patients who did not undergo any axillary surgery, we'd expect they'd also have about the same percentage of a positive node. So while we see that in this study, there was no difference in the primary outcomes and secondary outcomes, one thing to think about is.

The importance of the information that we're losing from not checking the sentinel lymph node in that group of patients who we expect to have about 15% of the time, a positive lymph node.

Dr. Poluski, when looking at these results, how do we generalize this to our patient population of interest?

I think that this is a really important considerations.

As was mentioned, the trial allowed enrollment of a wide range of patient age and tumor profile and histology. The patients who were enrolled. We're quite select. These tended to be older, most likely postmenopausal patients with hormone receptor positive. HER two negative smaller tumors and lower grades.

So this is really the population where we are potentially considering omission. So it's really [00:13:00] this cohort of patients who were overrepresented in its own trial. I just wanna clarify that it is really important to remember that sentinel node biopsy results strongly impact adjuvant therapy recommendations.

For premenopausal patients and individuals with either triple negative or HER two positive tumors, where the results are still really correlated with chemotherapy decision making and potential. Their treatment recommendations

a fantastic summary of the first trial. So let's compare and contrast that to the NIMA trial, which was published in New England Journal of Medicine in 2020.

Four, these findings were on an even larger cohort. So Dr. Poluski, could you give us an overview of this trial?

Absolutely. So the Sima trial enrolled over 5,500 patients, over 150 sites, which were primarily in European countries. Similarly, the median patient age in this trial was 62 years. Nearly all 90% had T one tumors.

And again. [00:14:00] Most of these were hormone receptor positive tumors. This was a similar randomization between a sentinel node biopsy versus omission with no axillary staging in patients who were clinically node negative with a negative axillary ultrasound. And again, five-year results. We see no difference in disease-free survival.

92% in both groups, and which was really non-inferior by quite rigorous criteria from the trial as we would. Expect the patients who did not have a sentinel node biopsy had fewer complications, lower rates of lymphedema, pain, and restricted shoulder movement. So really in line with what we would anticipate with omission, I would add a novel feature in the anima trials that they tracked morbidity quite carefully.

So this added to the already strong survival data. As we've noted, these side effects are not trivial, but the selection remains paramount. And in both the in semen sound trial, we see a pretty similar patient [00:15:00] population that were enrolled.

Let's discuss candidacy even more deeply here. What subgroups, based off of all of this trial information that we do have should still actually receive no.

Staging and what caveats remain for clinicians

when we're thinking about who should still receive nodal staging and what we need to think about when we're seeing a patient in our clinic. There's a few different things to think about. One is, is there a group of patients in whom the axillary staging information is still really important for making adjuvant therapy decisions?

And the answer is yes. Those are premenopausal patients who have ER positive, HER two negative breast cancer, as well as patients with HER two positive and triple negative breast cancer of any age. The nodal information is extremely important. The second thing we need to think about is, are these patients low risk for nodal metastases?

For example, we wouldn't wanna omit sentinel lymph node biopsy in a group of patients in whom we'd expect a high burden of disease. So who are the low risk patients? And that's related to tumor biology. So patients with low [00:16:00] grade tumors. Without Lymphovascular invasion, and I think age is a little bit also associated with tumor biology, then we wanna think about what are the factors that drive risk for nodal positivity and make sure we're continuing to do nodal staging in these patients.

And really that's sort of the opposite of the low risk patients. So high K 67, if that's done at your institution, larger tumor sizes. Lymphovascular invasion, younger age, these patients all have a higher likelihood of having positive node. And then lastly, we need to remember that in these studies, all of the patients who were included were clinically node negative.

So this means that on physical exam, they did not have any abnormally palpated nodes. And they had axillary imaging, typically an axillary ultrasound, which did not show any abnormal nodes. Keeping those things in mind will help us understand how we can apply this in our clinical practice.

Just to emphasize, a point that keeps coming up is nodal status gives us information to help us decide on different forms of adjuvant therapy.

So let's pivot [00:17:00] to adjuvant therapy. How do these shifts in emitting sentinel lymph node biopsies affect chemotherapy selection, endocrine therapy, duration. Radiation and even eligibility for newer agents like CDK four six inhibitors. I'm gonna

start and focus on the chemotherapy question. So I think that this was really one of the initial questions and potential concerns about.

Omitting sentinel node biopsy. As we just heard, for certain patients, this is still a main driver for decision making for systemic chemotherapy. In particular, if there's a positive node in a triple negative, HER two positive or premenopausal patient, that is typically an indication for chemo. If we have a cohort.

Postmenopausal ER-positive, HER two negative patients. We have now seen a big shift in decision making for chemotherapy, and that's based on the results of the RX ponder trial. We have had strong data looking at utilizing genomic profiling for [00:18:00] determining the benefit of chemotherapy in no negative patients, and RX responder found that in postmenopausal women.

Even with N one disease, so whether they were no negative or had one to three positive nodes, it was still the genomic profiling results from an Oncotype DX recurrent score that was the most predictive and prognostic for benefit of chemotherapy. And so that has really changed a huge paradigm in decision making Now.

Where it's genomic profiling rather than nodal staging. That is the primary driver for chemotherapy decision making in postmenopausal patients.

In addition to chemotherapy decision making, there are newer agents that we need to think about whether or not the nodal status would be important for determining eligibility.

Mostly talking about cell cycle inhibitors, which are called CDK 46 inhibitors. There's three on the market right now. Those drugs are used in women with high risk. ER positive, HER two negative disease. And when I say high [00:19:00] risk, that can be defined in many ways, but basically we're talking about patients who are at high risk for relapse, for distant relapse, and in whom we think the addition of this medication would improve overall survival for some of these CDK four six inhibitors, nodal status.

Was important in determining eligibility for the use of this medication. So omission of sentinel lymph node biopsy may reduce access to these drugs for some patients who otherwise would've been eligible if they were found to have a positive node on a sentinel lymph node biopsy.

So it seems as though in the current world, there is risk ratification that's dependent on both imaging and also molecular biology through these molecular assays and not just.

Surgical staging. So let's also touch briefly on radiation. How does the mission of sentinel lymph node biopsy impact the multidisciplinary planning for postoperative radiation?

Let's first remember that we're talking about patients under 70 because we do have data about omitting sentinel [00:20:00] node and radiation decisions in those over 70 with small hormone receptor positive, HER two negative cancers.

But omitting a sentinel lymph node biopsy in a younger group of women means. That in most cases, they're going to be committed to whole breast radiation. While there are many women who might be candidates for partial breast radiation, which is a shorter course, and generally easier from a at least short-term quality of life perspective, most of those patients who would be deemed eligible for partial breast radiation had.

A sentinel lymph node staging with negative nodes. So right now, that is one consideration for when we are omitting sentinel lymph node biopsy, which I think raises again, the importance of shared decision making and thinking about the whole picture and the whole treatment for your patient.

That brings us to our next segment where we're thinking about how do institutions incorporate these changes.

If both of you could speak to institutional adoption of these. Trials and these trial results, and then as well as what barriers [00:21:00] remain in a broader context for across the country in terms of adopting these practices.

Happy to start here. I mean, it's clear that practices vary, um, across the region, across the country.

I can share that. Here at Michigan Medicine, we have partnered with our radiation oncologist and medical oncology colleagues to come up with a patient population where collectively as a group, we were comfortable applying this data and expanding sentinel node biopsy omission to patients under the age of 70.

And so this includes. Again, postmenopausal women with tumors that are one centimeter or smaller of ductal histology, estrogen receptor positive, HER two negative low grade without lymphovascular invasion. So again, highlighting all of these low risk features. How can we identify a cohort of patients that we think are at lowest likelihood for missing microscopic nodal disease?

These patients are clinically no negative with a negative. Ultrasound. So that has become now a part of our practice that we are [00:22:00] routinely imaging patients to see if they're eligible for potential omission. And then I will comment that one of the biggest challenges I face is, you know, how do we integrate this, as we've talked about with radiation planning, I think that that's the biggest barrier that we face, not only for potential consideration of partial breast radiation, which is a bit of extrapolation from the data.

Almost all of the patients in sound and Nima did receive whole breast radiation and so it, it is a challenge for some providers to move to partial breast. But if we go one step further, we also have clinical trials right now assessing the safety of omission of radiation therapy. In the lowest risk patient populations.

One study that we have open is the Debra Study, but eligibility for that trial requires a negative sentinel node biopsy. So we have competing interest of deescalation in our local therapy trials right now. And so that's really a lot of patient preference and shared decision [00:23:00] making of how we think about which would we rather omit.

That's a great point, Dr. Poluski. I'll say that our implementation of the results of the sound and in some studies were quite similar to what was already described, and we, after first several hundred patients looked at our data and we sort of expanded our criteria. And so currently we. Consider omission of a sentinel lymph node biopsy in postmenopausal women with ER at least 10% grade one or grade two, up to two and a half centimeters of invasive cancer.

In patients who are found to have either high grade disease or tumors greater than three centimeters on final pathology, we typically will offer sentinel lymph node biopsy based on a multidisciplinary consensus. And just like mentioned by Dr. Poluski, these criteria were decided upon by our multidisciplinary group of medical oncologists and radiation oncologists to be certain that they were comfortable with our decision and how that might impact their [00:24:00] decision making.

Given everything we've heard so far, what's next for axillary management and breast cancer, and also any last words of advice for listeners, whether clinicians or trainees navigating these decisions?

Sure. So I think these studies are very well done and in some ways are very groundbreaking and also relatively in some patient populations easy to implement.

However, I think we'll need to continue fine tuning patient selection. For example, one particular issue that we are evaluating is whether or not these patients truly need a negative axillary ultrasound in order to be potentially eligible for omission of a sentinel lymph node biopsy. And as Dr. Poluski mentioned, thinking about how to harmonize trial eligibility to prevent exclusions who might benefit from new therapies but wouldn't be eligible without traditional sentinel lymph node biopsy staging.

Thanks. I guess my take home here for folks in practice or [00:25:00] trainees is that we do have robust surgical. Trial data, looking at a very specific patient population showing the oncologic safety of omission of sentinel node biopsy. So the benefit there is clear, but I wouldn't take this approach without a discussion with your medical oncologist and radiation oncologist, right, so that we're all on the same page and identifying patients who we feel like we can safely treat with multimodal therapy.

That patients are on board with that. You know, the two big question marks here really remain how we implement data from the Natalie trial for CDK four six inhibitors and potential deescalation of radiation therapy. And so, you know, reiterating that in the future as we design trials, it really should take into consideration deescalation across the board.

And I, I think that we will have better opportunity to use. Biology rather than anatomic, nodal staging for this decision making. But in current practice, [00:26:00] it really is making sure that the team is comfortable with those decision makings and our patients. I mean, I, I still will go back to one of the first comments I made that in data that we've had for over a decade showing the safety of omission of sentinel node biopsy in women over 70, most patients across the country are still undergoing the procedure.

That doesn't mean it's right, right? We, we want, as a group to stop doing low value procedures and being cognizant of that, but there is data showing that there is both patient and provider nuances to how we educate and disseminate this information. And so this trial data is exciting, but it's gonna take a lot of work to understand how this is really implemented into practice every day.

With that, we wrap our episode today. We've covered how axillary surgery is changing in breast surgical oncology. We've reviewed key clinical trials, including the sound and Nima studies and unpacked how evidence is driving change towards less invasive but [00:27:00] equally safe breast cancer care in select patients.

We hope you found this deep dive, informative and thought provoking are thanks to Dr. Down scanner and Dr. Poluski for their expert insights and to all our listeners for joining us. Please join us again for more clinical conversations at the cutting edge of breast cancer care at Behind the Knife. But before you do that, don't forget to dominate the day.