Next is a 43 year old female who presents to the office with a 2.7 right breast mass. This time, she is a clinically positive note as well. But the biopsy this time shows an er 90% pr 90% her 21 plus bihc invasive ductal cell carcinoma. Her last menstrual period was two weeks ago. What do you think that was kind of fun? Right. Well, it seems like a majority want to do some neoadjuvant chemo with dos dense ac followed by paclitaxel and then surgery plus or minus radiation. But we have some that want to do surgery first followed by chemo or followed by the gene expression. Now say it sh shows that even among a group of, of experts and, and really smart, smart people that we don't all agree on what to do here. All right. Can we move on to the presentation? Ok. This is case number two. Ok. So, you know, when I think about, you know, a patient in front of me, she's premenopausal, she has breast mass, she also has a node that's positive. There's a couple things that I think about for neoadjuvant therapy and actually, Doctor Leicher like beautifully like kind of gave me this introduction here that I'm gonna kind of continue on. So the first thing I think about is can do I need to think about surgical downs staging. So is there is there a possibility of being able to, to uh get a great axillary response that we can reduce the need for an axillary dissection? Um Is this a patient that was only a candidate for a mastectomy? And she really desires breast conservation therapy and we can use neoadjuvant therapy to maybe make her more eligible for that. And from studies in the past, we've seen that breast conservation therapy was able to be achieved in about 40% of patients when they used endocrine therapy alone and almost 60% of patients when they used chemotherapy. It comes with some cautions that we need to think about and are we potentially overtreating these patients, maybe they would not have needed chemotherapy in the adjuvant setting when we're using it in the neoadjuvant setting? And are we unders staging this pa these patients which has kind of come up before, especially in the axilla? Are we missing out on some lymph nodes that are positive that we're not otherwise gonna find because we're not doing the Axillary ultrasound? I don't know. Um And you know, is there a chance that some of these patients are actually gonna have progression of their disease during their neoadjuvant therapy? And and for those of you, you know, that have been through this before, that is one of the scariest things that, you know, that we go through. Um, but we do know that for those patients that need chemotherapy, we can give it to them in the neoadjuvant setting or in the adjuvant setting and it, uh, it doesn't affect their long term outcomes. Um It's when we think about this question of the pathological response rate from um neoadjuvant therapy that we know that there can be some improved overall survival and disease free survival. The B 27 trials showed us that the addition of taxing to Adriamycin Cytoxan improved the pathological cr rate to 26%. Nothing like the numbers that doctor mcshane just showed us but not zero as letrozole and a GNRH analog only showed pathological response rates at about 5%. So, yes, we can convert these patients from a mastectomy to have being able to get breast conservation therapy. But are we, are we actually changing the amount of disease that's there? And you guys know what are, what are, what chemo are we giving these patients? These, these are drugs that we have been using for a very long time. And so when I, when we looked at the studies that were presented this year at San Antonio, there were two different trends that I saw looking at neoadjuvant therapy. One was the addition of Sylvester to chemotherapy. And so this was a small study. 36 patients um of patients aged 18 to 70 they were ear positive, her two negative with uh invasive ductal cell carcinoma. Stage two B to three C. Um They had not had any prior therapy. They had one measurable lesion. These patients got their loading, full vrant followed by six cycles of therapy along with um epiRUBicin and cyclophosphamide for four cycles followed by dosa Taxol for four cycles. This study looked at the overall response rate for their primary endpoint but also did look at pathological responses. Interesting. This this uh trial also looked at the use of Fes pet to look at uh whether or not that could be used uh to predict response uh to new adjuvant therapy. Um They did see an 80% response rate um but only three patients out of the 36 which comes out to about 8% of patients had a pathological response, um complete response, so didn't do that much better. Um But they did find that the Fes pet that was uh did seem to be a good predictor of response. Um But this is a small study as, as you can see. And there's still more research to be done. I think the authors were most excited about how the Fes pet might be able to be used in the future for determining response. But still more uh information to determine whether or not endocrine therapy can really help to improve the pathological response rate. The checkmate study, biomarker study was also presented at San Antonio this year. This was a study that looked at the uh uh uh looked at the combination of um nivolumab along with chemotherapy. This was in patients with er positive her two negative cancer. These patients were able to have a T one C tumor with a uh clinically positive lymph node or could have a T three T four disease with a clinically negative or positive lymph node. Um These patients had to have at least an er 1% of disease um or grade two with er 1 to 10% uh with adequate organ function and uh tissue available for biomarker assessment. This is an interesting trial that they also, in terms of the biomarker study looked at different ways to determine the patients that were PDL one positive, whether they used the traditional ventana study, whether they looked at CPS, the also looked at stromal tills, um their er status as well as the key 67 proliferation index. Um These patients in treatment um either received novo or placebo along with paclitaxel for the first four cycles followed by Novoa or placebo, um with Adriamycin and Cytoxan for the next four cycles followed by surgery. Um And so in this, in this study, they found that the pathological response rate when nivolumab was added, improved from 20% to 44% in those patients that were PDL one positive determined by the ventana sp 142 assay when they looked at patients, um about 34% of the patients were PDL one positive by the SP 142 assay. When they used CPS, they found that 51% of the patients were positive with the CPS score of one. And that um that rate went down to patients, for example, whose CPS score was 10, only 18% of those patients um were considered positive. They did use stromal tills as well and at a point of 3% positive, um 46 3% tills, 46% of those patients were considered positive and there was a lot of discordance between um the positivity of the tills versus the ventana essay. So they didn't seem to, to um be coordinate um when they looked at the pathological response rate, when they looked at CPS, scores of 3 to 20 the pathological response rate was actually 53 to 78%. Those numbers are sounding a lot like keynote F 522 now. Um and this is the addition of Novum A to chemotherapy in this er positive population. What was even more interesting to me is that when they looked at patients with er, less than 10% 53% of those patients had a complete response when they looked at patients with an er, of less than 80% 41% of those patients had a complete pathological response, still a pretty decent response. And when the er, percentage was greater than 80% that pathological response dropped all the way down to 20%. And so, you know, you know, some suggestion that there is a, you know, we can start to use a little bit of these biomarkers with CPS scores, their, er, percentage points maybe can help us decide which of our ear positive. Her two negative patients might benefit from neoadjuvant um immunotherapy, which uh which I think is, which is really great. Um The keynote fi 756 study looked at similar patients and combining pembrolizumab with chemotherapy in the neoadjuvant setting. This study also looked at patients with uh tumor size of A T one C to T two that were had clinically node positive or T three to T four with node negative or node positive disease. Uh Pembrolizumab was combined uh with paclitaxel for 12 weeks, followed by pembrolizumab with DOXOrubicin and or epiRUBicin with cyclophosphamide. And this was compared to a placebo arm in this study. They did not break down the er percentage points as the checkmate study did, they only looked at er percentage points of 10 and below or 10 and above, but still showed something very similar that in patients with the CPS score greater than one, they were more likely to have a complete response with the addition of pembrolizumab and in those patients that were low er percentage points, those patients were more likely to have a better complete pathological response than those that were higher. Um And as you can see, for those patients with the CPS score of less than one, they were unlikely to respond uh to the study arm. And thinking about the opposite patients that go on and have surgery first followed by um followed by systemic therapy. This is not new in looking at the R expander r expander data. But in thinking about this patient that uh this case number two, that we're talking about, you send off um genomic testing through oncotype. Um And in those patients that uh have a score of 16 to 20 the benefit of adding adjuvant chemotherapy improves their invasive disease free survival five years uh to 91% versus those that do not receive chemotherapy at only 83%. And even those patients with a score of 11 to 15. Um there is a um absolute benefit of 2%. Um and even in those patients with less. And so, and this was independent of, of uh and this was for our node patient uh node positive population as well. And so in thinking about this premenopausal ear positive node positive population currently in what is approved, you know, using knowing what we have with the R Expander data, it does seem that this patient should receive chemotherapy maybe one day. We're gonna get to the point that we add neoadjuvant um immunotherapy as Well, when we think about the soft and text data and looking at these patients that are premenopausal and the addition of ovarian suppression, we know that ovarian suppression in addition to endocrine therapy improves um their disease free survival. But what was really interesting and presented at San Antonio last month is that those patients who received chemotherapy prior to going on um ovarian suppression and endocrine therapy, it does seem that there is a slight benefit to being on Exemestane or an aromatase inhibitor versus going on tamoxifen. And you know, I think we still need to understand a little bit more about why there would be a difference um in this one that, you know, both populations had received chemotherapy and are on ovarian suppression. Um but something for us to think about in terms of their endocrine therapy, uh post surgery and, and lastly, just some quick thoughts on anthracyclines. I think that, you know, this day and age patients come to the clinic, they're very nervous about going on the Red Devil. They, they'll be crying in clinic with you as I'm sure you all know, but I I don't think we're ready to give up on them just yet. Um Clearly, you know, clearly there is still a benefit to anthracyclines, especially in the node positive population. Published last year in Lancet, the early breast cancer trials, collaborative group um published this 100,000 patient meta analysis. Um looking at whether or not looking at this question. Exactly. And there's, there's still a benefit to patients who are ear positive, um node negative or node positive to receiving anthracyclines. But there is more information about what we can do to be more protective about preventing um cardiotoxicity. The use of beta blockers and ace inhibitors can be used. There's newer parameters to monitor for patients at risk for their left ventricular ejection fraction dropping and you looking at the diastolic dysfunction, global longitudinal strain and there's newer biomarkers that are coming out as well. I am going to ask doctor Anderson to come up and talk a little bit about the radiation side of this. Thank you. Just push next. There you go. Thank you. OK, great. So, good evening. Um I'm gonna be discussing the long awaited results. I think of the B 51 excuse me, randomized trial, which was a phase three randomized trial, evaluating local regional radiation in patients with biopsy, proven axillary lymph node involvement at presentation who become pathologically no negative after their new adjuvant chemotherapy. So I think it's important just to give a little bit of background of rationale. We know that for patients who undergo upfront surgery and are found to have pathologic positive axillary lymph nodes, the benefit of adjuvant re regional nodal radiation, which includes chest wall radiation after mastectomy with the regional nodes or when added to whole breast radiation. After lumpectomy is well established, we all know that but we also know that patients who present with ax and lymph node involvement who receive new adjuvant chemo are found to be pathologically none at surgery have a lower local regional recurrence compared to those who remain pathologically node positive. So in this phase three randomized trial, the authors were trying to evaluate whether chest wall and regional nodal radiation after mastectomy or whole breast radiation and regional nodal radiation. After lumpectomy significantly improved invasive breast cancer recurrence free interval in the clinically and lymph node, positive patients who were found to be YPN zero, meaning pathologically node negative after new adjuvant chemotherapy. So the study included clinically T one to T three N one patients. Ok. Sorry. It's the print small. I apologize. Um They had to be documented pathologically positive in the axilla by an FN A or core needle biopsy. They did not allow a removal of a lymph node and they underwent standard neoadjuvant chemotherapy and then they proceeded with definitive surgery. And what was great about this trial is you could have a lumpectomy breast conservation or a mastectomy and apologize. And the patients were randomized. And this is where it gets a little confusing maybe for our non college colleagues, the randomization was to no read regional nodal radiation or regional nodal radiation and they were grouped based on their definitive surgery. So if someone had lumpectomy, then the randomization was relation to the breast versus radiation to the breast and lymph nodes. And if they had mastectomy. Then the randomization was no radiation at all or radiation to the chest wall and regional lymph nodes that's just redundancy. Um So I don't want to confuse people. And the study schema again, clinical T one to T three node N one positive by pathologic biopsy, axillary lymph node had to be either FN A or coral biopsied standard new adjuvant chemotherapy. And then they were randomized like I said to no regional nodal radiation versus regional nodal radiation. And the objectives or multiple. The primary objective of this study was to evaluate whether again chest wall radiation with regional nodal after mastectomy or whole rest with radiation to the lymph nodes after lumpectomy, significantly improved invasive breast cancer recurrent free interval. So that's a long word for saying the local regional recurrence in breast cancer. They want to know if there was, if there was a difference when people were found to be pathologically, no negative. OK. The secondary objectives were multiple. They had local regional recurrence free interval. They looked at distant recurrence free interval, disease, free survival, overall survival and as well as toxicity. So again, the eligibility we went through already patient population over a span of seven years, they randomized over 1600 patients. But um there was a small subset where there was no clinical follow up. So they were excluded. So there was a total of 1556 patients. They're actually analyzed for the disease related end points and it's pretty well divided. You see who got no regional note of radiation versus the regional node of radiation. And the median follow it was about six years and the patient and tumor characteristics were very well balanced between the two groups and the median age was a little younger than I thought it was gonna be 52 years of age. And here the results, the primary end point for the invasive breast cancer recurrence interval was essentially, you can see the two curves essentially overlap. So no stati statistically significant difference in the P values for the five year estimate for ipsilateral breast tumor recurrence. The secondary endpoints of isolated local regional recurrence free interval also nonsignificant essentially the same. The number of isolated regional um local regional occurrences were actually very small. They divided by location. Um You can see it's a little over 1% for no regional no radiation versus just less than about 0.5% for patients that did receive regional nodal radiation, distant recurrence free survival. Again, essentially identical. The curves overlap and for disease ress survival again and it's kind of boring here. Um dizzy overlap, no sign, no sign, statistically significance between those and overall survival. Again, no difference between the two groups. In terms of toxicity. There were no study related deaths and no unexpected toxicities. The most common toxicity was of course, what we see all the time grade three toxicity being radiation dermatitis a low rate in both arms. So in conclusion of the patients who present with biopsy, proven axillary node involvement who convert their axillary nodes to YP and zero after new adjuvant chemotherapy chest wall and regional radiation after mastectomy or whole breast and regional nodal radiation after the lumpectomy did not improve any of the five year end points that were examined. And and these findings suggest that downs staging the involved axillary nodes with new adjuvant chemotherapy can optimize adjuvant radiotherapy without adversely affecting oncologic outcomes. And of course, this, you know, they have to say follow up remains to keep, it's only been five year follow up. I think we need more. But I think that it really, in summary, we don't get many potential, you know, practice changing uh studies in our field of racial ecology. Uh We don't compared to you guys, but I think this might be one of them um just in terms of how to approach people and how to approach patients who are no positive upfront. Um And I just think it was a long way to trial, of course, it's only five year follow up and I think there's more to come. So, thank you.
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