Chapters Transcript Video Case #3: 56 year old woman with ER+ HER2- metastatic breast cancer So we're going to move into now some cases where I, I picked out three different cases in which we're going to try to use some of the abstracts from San Antonio to describe how we might take care of a patient. And this is gonna be an opportunity for all of you to give your thoughts on what you would do for this patient. And then we'll, we'll hear from our panelists. So for this first patient, this is a 55 year old female who presents to the office with a 2.7 centimeter left breast mass. She has a clinically positive node in the left axilla as well. A biopsy of both masses demonstrated an er zero pr zero, her 20 invasive ductal cell carcinoma. And I'd like to give all of you a chance to mark what would you do? I don't know why it's not showing up there. That's OK. I, I read. Wow. Well, it seems pretty clear a lot of you, a lot of, you wanna give a lot of immunotherapy and a lot of chemo anyone want to do anything different. So, all right. Well, I'm gonna turn it over I'm gonna have Hayley over there. So can we go to the case? One slides? OK. So um going off of that with the triple negative breast cancer case, which it looks like 100% responded with the keynote regimen. Um me and Haley are gonna have a discussion about triple negative breast cancer highlighting four of the abstracts that were presented at San Antonio this year. Um These are our disclosures. So I'm gonna start with um the updated EFS results from keynote 522. And so these were presented by Doctor Peter Schmidt. As you all are aware, this is a phase three randomized control trial which added pembrolizumab to neoadjuvant chemotherapy for high risk early stage uh triple negative breast cancer. Um Just a reminder of the study design here, key eligibility criteria. These were newly diagnosed triple negative breast cancer with either A T one C with an N one or N two or T two to T four with N zero to N two. Patients were randomized 2 to 1 to either the chemotherapy backbone carboplatin paclitaxel, DOXOrubicin and cyclophosphamide with pembrolizumab or placebo. All patients then went to surgery and continued adjuvant either in the pembrolizumab arm or the placebo arm for nine cycles. Adjuvant. The primary end point was PC R. Um And as a reminder at the interim analysis, number one, the primary end point demonstrated an increase in PC R by 13.1% favoring the pembrolizumab arm as compared to the placebo arm. So, at San Antonio this year, um they presented the five year up the updated five year event free survival data with a medium follow up of 63 months. And so if you look at the side here, you see, um on the left side, the event free survival at three years with a median survival, I mean, a medium follow up of 39.1 months. And on the right side is the updated EFS at five years with a median follow up of 63.1 months. So at three years, the event free survival was about a difference of 7.7% favoring the Pembrolizumab arm. The hazard ratio was 0.63. And then at five years, the EFS uh difference was 9% favoring the Pembrolizumab arm again with the hazard ratio of 0.63. So very few events occurring between the three and five year mark and the hazard ratio remained um the same at 0.63. So um this slide is looking at the event free survival specific by stage, but also more um specifically by PC R status. And so you can see in the green boxes, these are the two arms in which both um achieved A PC R. The red line being those that just received chemotherapy and the higher teal green line being those that received pembrolizumab with the chemotherapy. And so what they found is that there was about a 4% improvement in event free survival in all patients that had a PC R um if they got pembrolizumab. And so it's interesting because this suggests that the quality of the PC R or the path uh complete response, pathological, complete response can be different if achieved with immunotherapy and chemotherapy versus just chemotherapy alone. And so it suggests that the immune therapy may actually change the tumor biology. Given that this improvement in efs occurred despite both arms receiving a path cr and lastly, I wanted to show this subgroup analysis that was presented as well. And so this is a subgroup analysis looking at just the population of patients that had A T two and zero. This actually made up about 40% of the patients uh included in the keynote study. And what I found is that there was an EFS of 77.9% in the chemotherapy alone arm and 88 7.8% in that, that included pembrolizumab with a hazard ratio of 0.49. So a clinically meaningful and statistically significant improvement in those with T two N zero disease. And so in summary, um the authors concluded that after a medium follow up of five years or over five years, um neoadjuvant pembrolizumab with chemotherapy um continue to show a clinically meaningful improvement in event free survival as compared to chemotherapy alone in patients with high risk early stage triple negative. I think some key points also is that um the improvement of EFS was 9% at five years. And in those that had a PC R, there was still an improvement in the patients who had gotten immunotherapy as compared to those who had not of about a 4% benefit in EFS and specifically for the T two and zero patients. Um there was a sign statistically significant benefit um of about 10% in those patients. And so uh in our tumor board style here, um I'm going to ask Hayley a question in regards to it. So, you know, I think that the T two N zero data is a key subgroup analysis in this um this presentation. And I'm curious how you approach T two N zero in regards to neoadjuvant treatment and whether this data helps support that or changes your decision in any way. Yeah, I think that um you know, thinking back to how we treated patients with triple negative breast cancer five years ago in the new adjuvant setting to the last couple of years where keynote has come out, we are um causing a lot more toxicity um in our patients who are getting the keynote regimen with six months of, you know, four chemotherapeutic agents along with pembrolizumab, um surgery, more medicine after surgery, potentially more chemo and also in the time period that keynote has been out, we're also seeing these path CRS just rolling in left and right, which is so exciting, you know, and so, um you know, I found this regimen um so important use it all the time. Um very toxic, difficult to get patients through it. But you can't ignore the impressive um event free survival here. The T two and zero triple negative patient has been uh it's a common patient and I think in the world of triple negative breast cancer and one that has caused me some pause, you know, really till this data, I mean, you always, you know, you see these patients with 2.1 centimeters tumor that's no negative. And you kind of worry, oh, am I overtreating them by giving them five drugs rather than just dose dense AC T? Um But I mean, this data is really impressive that that event free survival is real. These patients are doing better, they're having more path cr um So I feel really comfortable um you know, giving the keynote regimen in that T two N zero group. Yeah, and they didn't report the the level of T two, right? Is it a is it a 2.1 centimeter or four centimeter mass? And so I think that is interesting too. Um I'm sure that they're not gonna be able to break it down quite that detailed with a statistically significant result. But I agree with you. I think that I'm offering all my T two N zero patients. This regimen with acknowledging that there is a lot of toxicity with it. Um And you know, with those smaller T twos um aid a stronger consideration for risk versus benefit. Great. So I'm gonna move on to our next study that I wanted to review. So this is a poster spotlight but in a theme of triple negative, um this was the clinical impact on timing of systemic therapy in patients with early triple negative breast cancer. This was presented by doctor seats. Um And so the aim of this study was to clarify whether timing of systemic therapy has an impact on survival in early triple negative breast cancer. Um They looked at uh the interval from the date of pathological diagnosis to the date of first neoadjuvant chemotherapy or they looked at the interval from the last surgery that the patient had to the first adjuvant chemotherapy. There were um 515 patients that were available for analysis for 52% of them had received neoadjuvant chemotherapy and about 47% have received adjuvant chemotherapy. So the results are listed here. Um The table at the top shows that the blue line shows those patients who had um more than or equal to 40 sorry. The blue line is 42 days or less um from the time of um diagnosis to treatment. Um And the red line is when that was l longer than 42 days or six weeks. Their medium follow up was thir 3.5 years and so on the left, you can see the timing um in regards to the new Aju chemotherapy and on the right, in regards to the adjuvant chemotherapy, so they found that um on in time in terms of new Aju chemotherapy, if you were able to get to treatment less than or equal to 14 days, those patients were more likely to survive than as compared to if it had been over 56 days. Now, this was not statistically significant and they make the point that it was barely not reached. Um but as you can see the numbers trend um in that in that direction to suggest a benefit. Um And then as far as timing of adjuvant chemotherapy, they did find a statistical benefit in that the 22 to 28 day mark significantly improved um survival as compared to both 29 to 35 days and then also for more than 3043 days. So their summary and conclusions was that there's a critical time interval for initiation of systemic therapy in patients with early triple negative breast cancer and it reduced overall survival if neoadjuvant therapy has started uh more than 42 days after diagnosis or adjuvant therapy has started um no more than 42 days after last surgery. So really that six week mark of diagnosis to neoadjuvant treatment um or surgery to adjuvant treatment was the um timeline that they found. So Haley, do you think this is a reasonable time frame? Like, do you feel like you can get patients reliably into treatment either at that six week mark? We do our best. Um I mean, I think this study is showing us kind of what we already really try to do in practice in patients with triple negative breast cancer. I think we all try to rush to get them to treatment as quickly as possible because we know that this is an aggressive phenotype. Um I, you know, being in a place where there's all these academic centers in one location, we struggle with the 2nd, 3rd, 4th opinions um in the neoadjuvant setting. Um and also in the adjuvant setting, sometimes there's, you know, surgical complications, reconstruction, things like that, that might delay things a little bit. But I think this is a nice benchmark, you know, that we all like to shoot for in thinking about getting this chemotherapy started as quickly as clinically possible. You know, I feel like uh historically, it was always, how quickly can you get the echocardiogram before you start neo Adrine ac T. But with keynote, you have a little bit of wiggle room too if you don't want to get that right away and you can get your Carbotaxol pen started. So um that's not such a rate limiting step quite, quite anymore. Just the port. Yeah, I get that port scheduled MRI guided biopsies for the Yeah, what else do we deal with? Um OK, so moving on in um uh to our next poster spotlight, this was looking at systemic therapy in geriatric patients with triple negative breast cancer. And it was a National Cancer Database analysis. And so this was presented by Doctor Anna uh Sandoval Leong. And so this was a retrospective analysis from the National Cancer Database. It was from 2004 to 2019. It included patients 65 years or older with uh early stage triple negative breast cancer except treated the patients out into three groups. So no chemotherapy chemotherapy or those that receive chemotherapy plus immunotherapy and using the L rank P value, they basically use that to find the age cut off over which survival rates were not statistically different between the two treatment groups being no treatment versus treatment. Um And the treatment group included both chemotherapy or that with com combined with immunotherapy. And so the main outcome in this study was all cause mortality. So the cut off that they found using log rank P value show that above 81 years old, there is no survival benefit between no treatment versus treatment and IO and here I show you the one in three year survival rates by treatment um by treatment and age categories. And so, um for those, if you're looking at the three year survival in this, in those that were 65 to 80 there's about a 5% benefit um for survival for those that favor treatment over not treatment. But in the 81 for those 81 years and older, even though there was a trend towards um improvement in survival. For those who receive systemic therapy, it was not statistically significant. And looking a little further into that are the Kaplan Meier curves demonstrating this and so on the left, you can see those patients who are 65 to 80 there was a statistically significant difference, favoring uh systemic therapy, which is shown in the blue. And then those 81 years and older, there was a trend towards improvement in survival, but this was not statistically significant. Oops, sorry. And I think this uh study, you know, well, first of all, a major limitation of the study is that there were a low proportion of patients who were over 81 that had received chemotherapy or chemotherapy IO So did that um affect the ability for them to actually find a statistical uh difference possibly? Um But I do also think that, you know, this highlights the importance of needing additional studies looking at our geriatric population. Um the uh life insect life expectancy in the in the US continues to rise. Um And for triple negative breast cancers, especially we're using m mostly chemotherapy. And so I think it's really important for us to look into how much benefit are we giving these patients. And also not under treating these patients at the same time. Um vice versa. So, oh sorry Haley, I didn't even ask you a question for this one and I had one. So I'm just curious how you for triple negative breast cancers specific in patients who are um geriatric. Um specifically those over 80. I'm just curious how you approach them in your, in your clinic. Yeah. Um you know, thinking back even over the last couple of years, it's pretty uncommon to see an 80 plus year old with triple negative breast cancer. We see this so often in these really young patients. So it's not a real common situation that we're coming on. But I think this just really emphasizes patient selection is really important. You have to think about who's sitting in front of you. What are their medical problems? Um I definitely have treated with um neoadjuvant chemotherapy patients who are elderly um not without its risk and a lot of worry on my part. Um I have done a sort of almost like a deescalated keynote, the carbotaxol pembrolizumab without the ac portion. Um and had luck um thinking of one woman who I did, she did great with the first half of keynote, went to surgery, had a complete response. Um So, you know, I think, you know, this data really makes you pause when you, when you see someone that's elderly and how are we gonna try our best to help this person? And also not, not hurt them in the process. Yeah. And I think your point about the keynote data and two because we know that pem um pembrolizumab can be really well tolerated in this patient population. And I myself have also also done like a deescalated cheno regimen um for older patients um who may not tolerate doublet or triple chemotherapy and they've done quite well. So um definitely, definitely an option. OK. And so our final um study that we're gonna go through today um is shifting a little bit to um uh the metastatic disease. And so this is the final study I will present it's a phase two attractive study. Um It was a um a study that reported the efficacy and safety of first line teum bevacizumab paclitaxel in patients with triple negative breast cancer. And this was a phase two trial. Um This was pres presented by Doctor Guillaume. And so here is the design of the trial um including the key eligibility criteria. Uh patients had to be untreated or um and have to have un resected locally advanced or metastatic triple negative breast cancer. Um regardless of PDL one status um did not matter, they could enroll PDO one positive or po one negative those who had received neoadjuvant or adjuvant um treatment utilizing, attacking in the curative setting had to be had to have a disease free interval of 12 months before they could enroll in this trial. Um 100 patients uh were enrolled, they were um given a Talab on day one and day 15 along with Bevacizumab on day one and day 15 and paclitaxel at 90 mg per meter squared on day 18 and 15, the primary end point was investigator assess PFS. Um And the key characteristics is that 97.6% of patients were PDL one negative in this trial. Um and those who had a prior early breast cancer um were made up 71% and of those 86% had had a prior taxing. So this is majority of patients who are PDL one negative who had received um a prior taxing. Uh the median follow up was 16.7 months. And so here are the results that they presented. So the median progression free survival was 11 months they received. Oh, sorry was 11 months. Um And the overall survival was not reached um but they reported an estimated 18 month overall survival of 69.4%. The confirmed overall response rate was 55% with 13% of patients having complete responses and their clinical benefit rate that they reported was 77%. Um So when you combine chemotherapy, bevacizumab and immunotherapy, I'm really interested to see what the adverse events would be. Um And so not unexpected, the grade three or four treatment related adverse events were 47%. Uh peripheral neuropathy was actually the most common grade three or four event made up um a significant portion of it and 40% of those had to discontinue paclitaxel because of that. Um the others uh pertinent uh side grade three or four, side effects were fatigue, hypertension and neutropenia. And then as far as the immune related adverse events, um the grade three or four made up about 5%. Um and it was hepatitis and nephritis were the only two that were reported. So let the author's conclusions. Um were that a Teal Liza Bevis and Paclitaxel demonstrated robust anti tumor activity in the first line setting for advanced triple negative breast cancer. And the majority of which were PDL one negative. So I think key points here are, you know, the median PFS was 11 months um for first line triple negative treatment in a PDL one negative population. Um and the confirmed overall response rate was 55%. So, you know, um I trained in the non Bevacizumab uh breast cancer era. And so, um it's interesting to see this being brought back into um treatment regimens. And I'm curious what you think about this or where it could possibly be inserted in the future. So this study is pretty interesting. I mean, although we don't always like to do cross trial comparisons when you think about impassion. Um 131 the these numbers were a lot better. The um complete response rate on this study was almost double that from impassion 131 and the overall response rate was significantly higher as well. So, you know, when two out of the three drugs are the same in these two trials, you know, that third drug bevacizumab looks like it's doing something here. However, this is a single arm study. You know, there's no comparison and it was just 100 patients. So to me, um this is not practice changing, but I'm intrigued, um, you know, willing to definitely interested in, willing, you know, to see where this goes in the future. Um I feel like my memory with Bevis is a is in like lung cancer clinic in my fellowship at Fox Chase and it's been a while and that was scary. Exactly. People would end up with strokes and wounds and you know, so, um you know, not super excited to get bevacizumab, you know, something that we use a lot. But hey, I mean, in these um PDO and negative patients, it's nice to have more options. Yeah, I think that's a key point too that there were majority, almost all of them were PDL one negative and so a potential effective option given that media over all survival. So definitely would be interested to see further studies of this and with that we are done. Mm. Created by Related Presenters Melissa McShane, MD Department of Hematology/Oncology Assistant ProfessorAssociate Program Director, Hematology/Oncology Fellowship Training Program View full profile Hayley Knollman, MD Assistant Professor of Clinical Medicine(Hematology-Oncology)Penn Medicine
