Chapters Transcript Video Local Control in IDC and DCIS Thank you Angela for organizing and for the staff for doing this. So, um in the next 20 minutes, we're going to talk about local control and DC is and infiltrating ductal carcinoma and uh buckle your seatbelts because we got 20 minutes and we're gonna talk about six abstracts. So, so, first of all disclosures, I'm a consultant for a Len, but that has nothing to do with any of these talks. All right. So the first thing we're gonna talk about is we're going to be talking about a review and meta analysis of long term outcomes of sentinel biopsy for patients who were initially node positive. Um prior to having their neoadjuvant chemotherapy, we'll then review an abstract looking at uh circulating tumor DNA uh for the detection of minimal residual disease uh using an assay and seeing the evaluation of that. We'll then look at the CAC trial which is similar to Z 11 and we'll review those studies. We'll talk about whether a nodal uh isolated tumor cells after neoadjuvant chemotherapy. When you find them in a sentinel node is an indication or not. For axillary dissection. We'll talk about the evaluation of bilateral mastectomies on survival for individuals who have a BRC, a one pathogenic mutation. And then finally, we'll be looking at the impact of race and ethnicity on recurrence for patients who have breast conserving surgery for DC. Is all right. Now, the first thing is I'll just tell you the poster spotlights in San Antonio are four slides, four minutes but so very brief. So this one was a poster spotlight that looked at long term outcomes of sentinel node biopsy after neoadjuvant chemotherapy for patients who were initially node positive. This was a systematic review and meta analysis. The purpose of this was to evaluate the data that existed for sentinel node patients who were node positive, who were stage 2 to 3 that converted after um neoadjuvant to node negative, the primary outcomes were axillary recurrence and the secondary were local regional recurrence, disease free survival and overall survival. The authors searched several data sets and came up with 2500 studies. The poor two reviewers that had to review 2 2500 studies ended up finally looking at 100 and 68 that had a full text review. 58 were included, six had follow up greater than three years. Um They did a meta analysis and all of these were observational studies. The median um age across all of these were between 4060 the follow up was between 20 100 and eight months. There were 2500 patients in total in these studies. And in short, they really noted no significant difference for Axo recurrence, whether or not the patients ended up having a sentinel biopsy versus an Axo dissection. They also noted no local regional recurrences or any event or between the two sets study inclusions. Interestingly included, not just clinical T one or T two, but clinical T 1 to 4 and also not just low nodal disease, but those who started with clinical and 1 to 3 disease. Of course, none of these patients have metastatic disease. When they evaluated this, the, the long and the short of it was the patients who converted from node positive clinically to node negative after neoadjuvant chemotherapy, um for those sentinel biopsy didn't result in a different recurrence um or survival versus if you didn't a or dissection. So the point being that if those patients start out with nodal disease and they end up becoming clinically node negative uh ultimately and pathologically node negative, it's fine to do a sentinel node. You don't need to do an ax dissection. The discussion basically said, you know, this is pretty much what we do now. But this was a good study to evaluate all the literature put it together. And in fact, yes, we can de escalate patients who become pathologically node negative after being clinically node positive uh prior to neoadjuvant from our situation from our standpoint, if you look at this critically, one of the things that was missing from this poster discussion was sort of what are the details in these studies. So there wasn't any difference between them. How were the sentinel nodes done? One substrate or two? Did they do targeted a or dissection? How many nodes did they take? And what would have been based upon these data, the false negative rate that we would expect? So some of these would have been interesting to know, but in this short presentation, that data was not elaborated. Um Basically the conclusion should say if these patients confer from clinically node positive to clinically node negative and then pathologically no negative, then it's fine to specifically omit a or dissection. Afterwards. The next one was a poster spotlight. Again, this was evaluating circulating tumor DNA for detection of minimal residual disease using a tissue free multi omic assay. And in this, they evaluated what was known as the success a trial. Now, this was a chemotherapy trial. The details of the chemo are not important, but what they did was they looked at blood draws before, immediately after two and five years after chemotherapy. And so specifically, the authors wanted to know what is the impact of finding circulating tumor DNA in these patients. They have 311 patients stage 1 to 3. And in this study, they specifically looked at one time point, the two year time point out of those 311 patients. They used to study specifically the Garden reveal assay, which I will define for you, which is a tumor agnostic test, looking at breast cancer, specific alterations and methylation patterns. They evaluated the sensitivity and specificity for recurrence. In order to determine whether there was some prognostic significance to the circulating tumor DNA after post neoadjuvant patients in the surveillance time, specifically pointing this out some of the things we should glean from this study was the the number of patients who were detected before distant recurrence was only 34%. So, while the authors didn't focus on the sensitivity of this, it turned out it really wasn't very sensitive at the same time. However, 60% of those where it was detected were detected within a year of recurrence and the specificity was quite high at 98%. It interestingly also this essay detected a recurrence up to over two years or 28 months prior to detecting the distant recurrence. The association of risk um in terms of distant recurrence when this stuff was detected was 14 fold. And the risk of death when CT DNA was present was 17 fold. They concluded that CT DNA was a highly prognostic and specific in breast cancer. But more research was warranted. And again, I think it's important for us to understand that it was not very sensitive, at least when you use one time point. Um Also, I would say kudos to the authors who are now moving ahead with this and they're now doing what's known as the survive study where they're randomizing 3500 patients to standard care versus evaluating patients with circulating tumor cells and CT DNA screening. So it'll be very interesting to see if that provides any benefit or a survival benefit. The next session we're going to look at is recurrence free survival after sentinel node positive breast cancer without a completion. A dissection which is the results from the international Cemac trial. Now, we know that um uh we've had prior studies um where we've looked at whether or not a dissection is appropriate um when we have positive sentinel nodes in limited disease in patients who are not having neoadjuvant chemotherapy. So this study was a 1 to 1 randomized clinical non inferiority trial. Looking at completion dissection versus node dissection, they had 2500 patients split between a or dissection and observation arms. So similar to Z 11, you have positive nodes, you do a dissection or you do an observation. Oddly, they started allowing neoadjuvant in this trial and then they stopped it. So that's a little bit of a Bugaboo here. But it was only 55 patients out of the total. The primary endpoint was overall survival 1 to 2 years and the target accrual was 3000 patients. The secondary end point was relapse free survival. Interestingly, while most of these studies have looked at T one and two patients, this study allowed T 12 and T three patients primary invasive breast cancers and they had to be clinically no negative by palpation. Interestingly also, they allowed preoperative axillary ultrasound. Actually, it wasn't just allowed, it was mandatory but didn't matter if it was negative, didn't matter if it was positive. If it was positive, you did biopsy didn't matter what the result was, it was positive or negative, they just required it and whatever those results were, it was just part of the study. They included men and women, breast conservation and mastectomy. And in this study, we they allowed up to two sentinel node macro mets, but they were also on top of that allowed to have micro mets in additional nodes. Now, these are the characteristics I'm putting this up here just to say that I showed them to you. But take it from me, there was nothing particularly unique or important about the um uh nothing novel about the characteristics of the arms. This is the data from the arms that's important. Um If we look at the recurrence events, the recurrence events were similar between the ax dissection arm and the observation arm. The five year relapse free survival was also similar. If you look at the non inferiority hazard ratio, you can see, although it says 0.89 it spans one. So that was not significant and the non inferiority uh P value was significant showing that these two arms were identical. They also did several sensitivity analyses which I've listed here and subgroup analyses, none of which ended up showing a difference between the arms. Now, I want to just take a minute to sort of review what we know in terms of the axilla. We have now four prospective randomized trials. Basically looking at the same thing. We have Z 11 that had no mastectomy patients. We have IB CS G 23 01 that had 9%. We had sidar one that had 22% mastectomy patients. And we now have CAC which has 36% mastectomy patients. So you can sort of start to see we're now not just doing what the 11 did in breast conservation, but we're doing it in mastectomies as well with consistent results. We also, if we look at the burden of disease in the axilla we've got in the 11, we had 1 to 2 micro or macro metastatic nodes, sentinel nodes in IB CS G, we had any number of micro metastatic sentinel nodes in Synod one, we had 1 to 2 positive micro or macro metastatic sentinel nodes. And in simac, we have 1 to 2 macro metastatic sentinel nodes with any additional micro metastatic sentinel nodes. So I think at this point, it's safe to say that pretty much even the Z 11 skeptics now have to admit if you've got a limited burden of disease in the axilla, you just in the non neoadjuvant setting, you just simply do not need to do an ax dissection, it provides no benefit. So what I would say is a couple of things. First of all, this is yet again, confirmation of the 11 for upfront surgical patients, not the neoadjuvant setting biopsy. Proven nodes and positive sentinel nodes do not require an ax or dissection. And I'm gonna just be like, what's her name? Sus Orman and say stop the madness with the ultrasounds. OK. We do ultras people do ultrasounds if there's no clinical adenopathy, they say in the non neoadjuvant setting and they're like, let's just scan the axilla in um in Synod one, they had all, they mandated ultrasounds, they could be positive negative, they all had positive nodes. So they were falsely actually, they had to be actually in Synod one, they had to be negative but they required them. So they were all falsely negative. In this trial cinema, they could be positive or negative. You could do biopsies or not do biopsy, they could be positive. And I mean, the ultrasounds do not help us. So I would just say please people in the non neoadjuvant setting where there's no clinical adenopathy do not do an ultrasound. It does not help you. All right, let's move on our no isolated tumor cells. After neoadjuvant chemotherapy, an indication for axillary dissection. The icaro study um run by Giacomo Montana and I believe Dr Williams at our own institution contributed some patients in this as well. After a section after neoadjuvant, we all know is standard for positive sentinel nodes. Um and when patients have residual micro metastatic disease or macro metastatic disease, once they've had neoadjuvant and we do a sentinel node. Um The additional positive nodes, there are additional positive nodes in more than 60% of cases. When we look at those non sentinel nodes, um isolated tumor cells, it turns out are found in sentinel nodes in 1.5% of cases after neoadjuvant chemotherapy. But the reality is people don't act on that uniformly. And so we really never knew what the non sentinel node burden is in these cases. And whether there was a benefit to doing an a dissection when your sentinel nodes after neoadjuvant just have it CS. So the aims of this study was to see how often are non sentinel nodes positive in those with sentinel node. It CS after neoadjuvant and what is the rate of a or an invasive recurrence and the benefit of a dissection? So, this study was very broad in its inclusion T 1 to 4 and 0 to 3 surgery after neoadjuvant chemotherapy, having isolated tumor cells at from frozen or permanent section were included. Um patients had to have dual tracer if they had a sentinel biopsy performed where there seemed to be disease or they could have tad or they could have married. But if they ended up being clinically and zero, it was ok for them to have a single agent used for their sentinel biopsy. They excluded those who didn't have a sentinel biopsy or T ad those who had an inflammatory breast cancer or those who were stage four and those who had neoadjuvant endocrine therapy. This was a multinational multi center trial and people uh basically contributed to this by including data from their own data sets. Um 694 patients, 583 had isolated tumor cells on sentinel node biopsy. Um 100 and 82 had the dissections and 401 in these data sets that people contributed did not have dissections. Median fault was just after 3/3 years. Um There were additional positive nodes in those having a or dissection for isolated tumor cells in 30%. And among those 5% were macro mets, 7% were micro mets and 18% were yet more isolated tumor cells. Ultimately, what they found between the two arms was that there was no difference uh in a recurrence, no difference in local or distant recurrence and any invasive recurrence was no different at five years either. So the conclusions which are actually quite appropriate in this and I suspect we sort of uh we could have probably predicted this but the conclusions were that when we have patients with who the additional positive nodes in patients who have isolated tumor cells is actually lower than when you have micro macro mets. Well, there's less disease that makes sense macro mets were found in 5% in the non sentinel nodes. For those having sentinel nodes containing isolated tumor cells. And there was no impact when we looked at the original nodal status of presentation. So, in patients having sentinel nodes after neoadjuvant where they've just got isolated tumor cells, there's no difference in the rate of acts or an invasive recurrence. And so it really does not support the idea that if you're giving patients neoadjuvant chemotherapy, you find isolated tumor cells in your sentinel nodes, don't do a dissection. It does not provide any benefit. All right, moving forward in this rapidly moving train, we've got now be patients with a BRC A one mutation. And what is the impact of bilateral mastectomy on survival? So, it's well known that um individuals who have pathogenic variants um uh or excuse me, I should say individuals who have breast cancer end up having pathogenic variants in BRC A one and two and about 3 to 4% of patients. And oftentimes we consider contralateral prophylactic mastectomy in these uh deleterious mutation carriers um as part of their treatment when we operate on them. So the question was, what exactly is the impact and how do we um how do we assess what we're currently doing? So, they wanted to evaluate the contralateral breast cancer risk and also breast cancer specific mortality uh by surgical treatment. And BRC A one carriers who have non metastatic breast cancer. They did an inter uh national collaboration and people contributed from their charts again, from their institutions. They included patients with stage 1 to 3 breast cancer and they focused specifically on BRC A one carriers. Um They did not allow patients who had synchronous bilateral cancers. They had a total of 2400 and 82 eligible patients at 26 centers in 11 countries. The median fault was about nine years now um at the median age was about 43 years. Now, when they looked at their cohorts, the breast conservation group and the unilateral mastectomy groups were pretty similar for both of these things. But in bilateral mastectomy patients, they tended to have shorter follow up and they tended to be younger in total for the surgical uh performance of what was done. Breast conservation was done in about a third of patients. Unilateral mastectomy was done in just half and bilateral mastectomy was done in about 20%. There were some differences in pathology, but it wasn't anything really that contributes to our understanding of this. So for time, I'm not going to go into it and I would just let you know that 11.5% of patients developed a contralateral breast cancer. Sort of makes sense. Those who ended up having breast conservation and unilateral mastectomy had similar rates of contralateral breast cancer and certainly makes sense that those who had bilateral mastectomy had very few contralateral breast cancers. But it still wasn't zero. Um Those who ended up developing a contralateral breast cancer had twice the risk of mortality 2.22 was the uh hazard ratio and the 15 year breast cancer specific survival was 83%. Now, this was kind of interesting because they had, if you look at the curves and I'm sorry that the numbers are very small, but if you look at the curves, the two curves that are similar are lumpectomy and bilateral mastectomy, unilateral mastectomy actually had a higher mortality. Um So we'll talk about that in a second. But ultimately, the conclusions were that prophylactic mastectomy is in fact preventative. We saw that because of the 0.8% likelihood of having a contralateral cancer as versus those who didn't have it. And that BRC A one carriers are twice as likely to die with a hazard ratio of 2.22 when a contralateral breast cancer develops their conclusion regarding this was very simply bilateral mastectomy does not reduce mortality compared to breast conservation therapy. It's a little unclear what's going on with there with the unilateral mastectomy. However, um and so what I would say is there's a couple of things, first of all, um I think this data really needs to be compared to non carriers overall. I think we need some sort of frame of reference here. We have one very specific group. Um It may also be helpful to have um uh you know, other pathogenic mutations specifically here, but we sort of don't have a context. So it's not exactly clear why the unilateral mastectomy patients had a much worse result than breast conservation and bilateral mastectomy. At the same time, the authors also said they had screening data, they had radiotherapy data, there was other things but they hadn't analyzed it yet. So really, all of those things I think are going to be needed to really put a lot of this in context. All right. And finally, we're wrapping up here. Um The impact of race of it and the impact of race and ethnicity on recurrence risk in patients with DC is who were treated with breast conservation surgery. So the objectives in this was to compare local recurrence in women who have DC is having breast conservation surgery across racial and ethnic groups. And they wanted to identify factors that were associated with local recurrence. What they did was they looked at patients who again had breast conservation for DC is between the years that I've listed on this slide and race and ethnicity as typical is self reported. This is the data in summary. So there were 4200 cases and 4100 women with a median follow up of almost nine years, median age was 57. Um there were 6% Asians, 9% blacks, 5% Hispanics and 80% whites. If you look at the overall differences between the groups, the Asians tended to be younger. The blacks in this group tended to be older. The blacks tended and tended to have a more likely clinical presentation. Meaning something was found on clinical exam. Hispanics ended up having a, uh, greater use of radiotherapy and Asians were less likely to have three or more excisions. When we look at the, um, data that they give, you can see that there is the lowest rate for recurrence was with the Asian population higher with whites at 14%. Hispanics at 15% and blacks at 25% so much higher. And a significant difference when this was broken down by radiotherapy. When patients were not given radiotherapy, uh you can see that there was a significant difference between them with, again, Asians having the lowest rate of occurrence. Um next up is whites, then Hispanics and then blacks at 31% in those who had radiotherapy, that sort of seemed to be the statistical equalizer. It wasn't significant, but you can still see the rates and so the rates for blacks were still 21%. So it's not clear whether this was a power issue or why this became nonsignificant. They also tried to sort of hone down on the factors that were predictive. And when you look at, you can see the second column I've listed here, basically the reference values, all of the reference ranges um uh and the values uh related to them showed a decrease in recurrence, the only two factors that would were sort of related to an increase in recurrence were black race and Hispanic ethnicity, but Hispanic ethnicity, as you can see in the confidence interval spans one. So that really left only black race when looking at these and adjusting for all these factors. So their conclusion was that in black women, um there was a higher local recurrence rate in women having breast conservation surgery for their DC is, and this was adjusted for clinical pathologic and treatment risk factors. And so they said to con consider these decisions about radiotherapy. Um So as I mentioned, couple considerations for us. Well, you know, radiotherapy equalized it statistically, but the rate was higher is that a power issue. Further study is needed. The other thing is that endocrine therapy and radiotherapy did reduce the risk in their model, but only 26% got endocrine therapy and only 56% got radiotherapy. So they didn't give specifics. So I think we need to delve into that to sort of interpret some of this better. And then there was no data on factors length or type of endocrine therapy or compliance. All right. So to wrap this up, what can we learn from these? Well, patients who convert from clinically node positive to clinically node negative after neoadjuvant can and pathologically node negative can have a sentinel node biopsy alone. You don't have to do an a dissection circulating tumor DNA is in fact, prognostic but not very sensitive and it is specific for recurrence. More work is needed to see how we should be using that in the surveillance period. Cinema again, confirms the Z 11 paradigm and please stop doing ultrasounds in that setting. Isolated tumor cells when you find them as the sole disease after uh neoadjuvant chemotherapy and your sentinel nodes do not necessitate an A dissection. BRC A one pathogenic mutation carriers have equivalent survival for breast conservation versus bilateral mastectomy. But goodness knows what's going on in the unilateral mastectomy setting. And then for black women, there seems to be a higher local recurrence risk when they have breast conservation surgery for DC is. So I would say further study is clearly needed, but I would say it at least gives us thought to perhaps we should be cautious in this group about de escalation. So, thank you and I will relinquish the podium. Created by Related Presenters Richard Bleicher, MD, FACS Director, Breast Fellowship Program Professor, Department of Surgical OncologyAttending SurgeonLeader, Breast Cancer ProgramDirector, Breast Fellowship Program
