Chapters Transcript Video ASCO 2026 Highlights Panel Discussion Harold Burstein, MD, PhD; Sara Tolaney, MD, MPH; Nancy Lin, MD; Erica Mayer, MD, MPH; and Jennifer Ligibel, MD, discuss important breast cancer research presented at the 2026 ASCO Annual Meeting. Well, good afternoon and welcome to Breast Cancer Breakthroughs, a program from Dana-Farber Cancer Institute's Breast Oncology Center. And today we're going to be discussing some of the most interesting abstracts from the recently concluded ASCO 2026 meeting. We're really delighted you've joined us. We have a fantastic faculty. We're doing this live. This is like Saturday Night Live, except it's uh Tuesday afternoon. Um, but, uh, and they have more screenwriters than we do, but we're really thrilled that you're with us and we hope you, uh, enjoy the program. Uh, I'm pleased to, uh, welcome my faculty, a fantastic group of colleagues, Sarah Delaney, who leads our breast oncology program at Dana-Farber, Nancy Linn, who is, uh, director of our metastatic breast cancer program and associate chief of our division, Erica Mayer, who leads our clinical research program in the Breast Oncology Center. And Jennifer Leabel, who directs our Zacom Center for Integrative Therapies and of course is a breast oncologist as well. So we're going to be talking about some important areas of discovery at the 2026 ASCO meeting. We're going to start with a discussion of endocrine therapy for hormone receptor positive breast cancers, both early and later stage disease. Then we're going to move on to HER2 positive breast cancer, uh, and a bit about, uh, GLP-1 use and some other diet and lifestyle issues that, uh, got some, uh, attention at the ASCO meeting. So to start us off, uh, Doctor Lynn, we're gonna be talking about the Optima trial, and, um, Nancy, can you, uh, tell us a little more about this study? Sure. Uh, so this study was a phase 3 randomized non-inferiority trial. That was looking at test directed chemotherapy versus no chemotherapy in patients with high clinical risk, ER positive, HER2 negative early breast cancer. So here's the study design. So this is quite distinct from the Taylor RX or RX monitor trials where patients were randomized to chemo or no chemo. Instead, here are patients who were over the equals, uh sorry, 40 years or older, who had ER positive and this was defined as at least 10% by IHC. Uh, either node negative or node positive disease, uh, this went up to 9, up to 9 positive nodes, um, were randomized to either receive chemotherapy followed by endocrine therapy in the control arm or test directed therapy where a Prosigna test was performed, and then depending on whether the patient had a high or low score, they either did or did not receive chemotherapy. And the other important point of this study is that for premenopausal patients enrolled in the trial, those patients received ovarian function suppression as part of their endocrine therapy. Next slide. So here are the patient characteristics and just highlighting a few of the key ones, which is that about 37% of the patients were premenopausal and importantly, uh, about 20% of the patients had 4 to 9 positive nodes. Uh, next slide. And so then if we look at the events in the uh protocol population, um, just a couple points to highlight on this slide and then I'll show you the Kaplan-Meier curves. Uh, first of all is that the um overall breast cancer event rates were lower in the control, sorry, in the ROR score less than or equal to 60 groups, which is as we would expect. And then the other thing to note is that most of the breast cancer recurrence events were distant recurrences. Uh, next slide. So now if we look at the total protocol population control comparing the control arm versus test directed arm, this did reach non-inferiority, uh, it, it reached, it was within the non-inferiority limit. There was a 1.5% absolute difference in, uh, uh, absolute difference in five year, uh, outcomes, but favoring chemotherapy, but this was not, uh, this is again within the non-inferiority margin. And then if we look at the specifically those patients with an ROS score less than or equal to 60 and compare the patients who were um randomized to control versus test directed arm, again no difference in outcomes. Uh, next slide. So if we look at the premenopausal patients, I think this was a group that we are all super interested in because now we've taken out the component of ovarian function suppression by chemo because all of these patients are receiving intentional ovarian function suppression. And you can see that in the premenopausal patients, um, there was no clinically meaningful difference in the outcomes. There's a 1.3% absolute delta in a five-year outcomes, and in the postmenopausal women, again, no clinically meaningful difference in outcomes. Again, limited to the low ROR score population. Next slide. And then again looking at the patients with 1 to 3 positive nodes versus those with 4 to 9 positive nodes, focusing on the low ROR score population. For the 1 to 3 positive nodes, the curves really overlap 11.6% absolute delta, but really the hazard ratio is 1.11 with the uh uh confidence intervals crossing 1. If we look at the patients with 4 to 9 positive nodes, there are fewer patients and fewer events in this group, so perhaps less certainty in terms of the outcomes. Uh, interestingly, actually, the curve for the control arm, uh, which is the, the key all. Patients received chemotherapy numerically is a little bit above, but this translated only to a 1.6% absolute difference uh favoring chemotherapy. So I think here again no clear benefit of chemotherapy, although with a little bit of more caveats because of the sample size. Next slide. So Nancy, a great overview here, obviously an important study, adds to the MIND Act, Taylor X, RXponder literature on using genomic tests to figure out who likely does or does not need chemotherapy with ER positive earlier stage breast cancer. Let me just ask you a couple of quick questions. So, is, does this answer the premenopausal issue? You know, we've spent years now discussing with patients whether the modest reduction in risk with the use of chemotherapy in premenopausal women was due to the cytotoxic effects of chemotherapy or just to the ovarian suppression effects of chemotherapy. Does this study resolve that issue? Do we still need to accrue to the offset trial? Is, uh, or is this still an open question in your mind? Uh, to me, I think that it adds, um, Adds data to this assertion that uh we've sort of batted around that the effect of chemotherapy is being mediated through ovarian suppression. Like when you take ovarian suppression out of the equation by giving it to all people equally, we don't see an effective chemotherapy. There are some limitations to the Optimum study. So, first of all, the age cutoff was 40. So, you know, what if you have a 32-year-old woman with 4 positive nodes, I'm not sure that I'm totally ready to use these data to not give chemotherapy to that to that person. You know, Optima has an extension called Optima Young, which is going to enroll a total of over 3000 women from age 35 and up, actually to this same question. Um, and so I think it'll be really interesting to see those results when they come out. And Offset actually starts, I, I looked this up, that the eligibility goes from age 18. Uh, so there are going to be like groups of people that I think are, uh, we, we're not necessarily going to all feel comfortable omitting chemotherapy for. That both Optima Young and Offset will, uh, will address. Um, but I do think that for the like 40 to 50 year old Optima eligible patient, you know, maybe not the one with 9 positive nodes, but the one with 1 to 3 positive nodes, I do think that this is pretty convincing evidence, um, that we can use genomic tests to help us make chemotherapy decisions. Let me, uh, open the discussion to my other panelists here and just ask, You know, to me it seems like this at least shifts the question or the burden of proof the other way. So I mean, you know, given the RX bundle, the Taylor X data in the premenopausal women, it always seemed like, well, there might be some benefit. Now it seems like you got to prove to me there is still some benefit. I guess that's what the Optima Young study will do. We've all gotten familiar with oncotype DX. That is our in-house standard assay. We have an automatic process to order it. This is a different test. Do we need to switch tests? Do we need to interpret the lesson here as being that genomic assays work and therefore you can use any of them? Sarah, Erica, what are your takes on The Prosigna test versus the Oncotype test for routine care. That's an excellent question. Um, you know, I think if we're gonna be using the assay in the group of patients, um, where there's been some, you know, confusion for what to do, particularly those node positive premenopausal patients, um, right now I think the data that we have does come from the Prosigna assay, and so I might favor considering that, particularly in the N1 premenopausal, you know, age 40 to 50 type patients. The reason they picked ROR over the recurrent score was. They had done optimum prelim and they did find that there were patients who had low recurrence scores but high ROR scores, and these were the patients who had very high risk of recurrence. And so it's about 25% of these low recurrence scores that will have high ROR and so there is some discordance whether or not we really need to be switching the assay. I think we don't really know, but I would say given this is the data we have, I probably would consider using Procigna in that specific group where we've had an open question. And Erica, let me go to you. Nancy sort of alluded to this, but in a patient who has 7 positive lymph nodes or, you know, pushes the extremes of age, uh, where are you at in terms of thinking about whether this test, uh, answers their treatment question? Well, I think, I think this is a really important and provocative study that was presented at ASCO. Um, I do think the curve that Nancy showed for the multi-node positive patients, it is important to note that there are not that many patients in that portion of the study. It's fairly low events. You can see that 17 versus 20 events. And although the, the numbers are favorable in terms of, uh, remaining non-inferior, um, it's still Perhaps not enough power there to give us great confidence in the multinode positive patients. So, I, I might still be discussing chemotherapy for my multinode positive patients, but I do think the power of this, this presentation was really in helping, um, helping us take a big step forward in how we assess those premenopausal patients, 40 and older, and also helping to confirm the very well-known benefits of ovarian function suppression in younger patients. But I do think that for like, you know, the 70-year-old patient with 5 positive nodes, I, I think this is enough to say I don't want, I, I feel comfortable not giving that patient chemotherapy. Um, I think that when you do the cross of like what about a 40-year-old woman with 9 positive nodes, I personally don't know that I feel not there yet, quite yet, so yeah. Well said and uh common sense always goes a long way here, which is uh important as well. All right, Erica, another, uh, big presentation, another update on Serena 6. You've been involved in this trial. Tell us about the study and, and what we learned, uh, this year, or this, uh, ASCO. Yeah, so, um, Serena 6 is one of the most unique studies we have in the metastatic hormone receptor positive HER2 negative breast cancer space, the advanced to the schema how, um, a study that we first saw results from at ASCO plenary last year, and this year, ASCO 2026, we saw an update from Serena 6 focusing on Some of the secondary endpoints. Just as a reminder, Serena 6 is a two-part study. Step one is a screening step where patients receiving first-line aromatase inhibitor and CDK46 inhibitor have serial cTDNA testing looking for emergence of an ESR1 mutation in the absence of clinical progression. For patients, um, found to have the mutation but no clinical progression, they can move on to step two, which is what you see here, a randomization to switch endocrine therapy from aromatase inhibitor to camazestrant, which is an oral SERD, continuing CDK46 inhibitor and adding a placebo, or, Staying on AI and CDK46 inhibitor and adding a placebo. So it's a placebo-controlled double-blind study and enrolled 315 patients. Um, primary endpoint of the study is PFS. Secondary endpoints include overall survival, PFS 2, quality of life, and a variety of other, uh, clinical endpoints. We go to the next slide, we'll see updated data for the primary endpoint of PFS with now a median follow-up of about 24 months. We can see a maintained improvement in PFS for the patients who've made the switch to Camazestrin from 9 months on aromatase inhibitor to almost 17 months with Camazestrin, where it has a ratio of 0.45. I think this is an interesting curve because if you Look at the kind of 2 to 2.5 year time point, you can see about a third of patients in the Camazestrin arm are remaining without disease progression, which is quite different, but then the control aromatase inhibitor arm. So we see a maintained benefit for the patients who made the switch at time of emergence of the mutation. Next slide. Additionally, there was data presented for secondary endpoint of PFS 2 showing a significant improvement of 6 months, meaning that the benefits seen with the initial switch were carried over, um, until the time of second progression. A caveat here though, and that this was brought up in the session, um, uh, on Tuesday morning at ASCO in a very brilliant discussion from our colleague Meredith Reagan, is that PFS 2 is a bit of a murky endpoint. Um, certainly murky in a traditional randomized study and perhaps even a little bit more complex in the setting of Serena 6, which has a very unique trial design. But another piece of data presented at ASCO was a delayed time to chemotherapy that was significant, about 4 months. This is a more classic clinically oriented endpoint, very clinically meaningful, and perhaps is is somewhat aligned with the benefits we see here in PFS too. And if we go to the next slide, there was some very interesting molecular data presented from Serena 6 looking at total CTDA dynamics. So for a subset of patients on the study, they had serial CTDNA drawn every 4 weeks, and we can see on the left side, the patients who received Camazestrin had a pretty profound decrease in CTDNA 94% at week 4, 99% at week 8, and in contrast in the control aromatase inhibitor arm, we just see it climbing, 16% at week 4, 64. 4% at week eight, which makes you think this is progressive disease. And it kind of mirrors what was seen in the quality of life where there was a um substantial delay to deterioration in symptoms of progression in the camazestrin arm that was not seen in the aromatase inhibitor arm where you have this creeping disease. Also, half the patients in the camazestrin arm had complete clearance of CTDNA 51%. Compared to only about 2% in the AI arm. And there was an interesting exploratory analysis where they pooled all the patients together. So this is not by arm, but looking at patients who cleared CTDNA actually had an improved overall survival compared to those who did not. Um, so really provocative, and I think it's very interesting to try to link up the clinical maneuver, like the treatment maneuver, with molecularly what's going on with the disease. So let me ask you a few questions because I continue to struggle with the clinical utility of the study as written. So, a couple of years ago, we had the PO one study, it was fundamentally the same design, that is, Molecular progression and acquisition of ESR-1 mutation, switched to fulvestrant instead of an AI, continued the CDK 46 inhibitor. It improved PFS from 6 months to 12 months. Nobody started doing this. Like that, that did not inform our practice. Now we have it with Cambazestrant. Obviously, uh, I thought the data that you showed here are, are pretty provocative on the CTDNA dynamics. It improves PFS from 9 months to 17 months, about an 8 month change and everybody is suddenly wondering if this is something that we should be jumping on. So can you help me understand what you're doing in practice? Is this an approach that you've started implementing, screening patients for acquisition of ESR-1 mutation and switching over to an oral cert, appreciating that Camazestrant is not commercially yet available, or is this a, you know, a really elegant sort of scientific discussion? But since most patients are going to get the opportunity for an oral cert at radiologic progression, not something that would influence your practice right now. Well, I mean, you're, you're right that this, the trial is quite provocative because Sabrina 6 is unique. We've never had a trial like this before, and it really is trying to bring what has been learned about why cancers develop resistance to endocrine therapy, what's driving that resistance, and trying Use the best possible therapy to target that. PO1 was a very elegant phase 2 kind of preliminary study that showed the proof of concept, but it was using Fulvestrant, which is a SERD, but it's not our best SERD. So Serena 6 was designed to really use a better medication in that. Setting and, and do it in a larger phase 3 fashion. Um, I, I particularly am, um, impressed with the quality of life data to see that patients have a 1.5 year prolongation until they feel bad from their cancer, I think is very clinically relevant and meaningful for patients, and it links up with the delay to chemotherapy. The, um, improvement in PFS is very consistent and, and has, um, held out over time. We await maturity of the overall survival data. Um, I, I don't think this is an approach that we necessarily would, um, uh, roll out for every single patient who perhaps meets criteria for Serena 6. There was an interesting presentation at ESMO Breast this year looking at more the step one, the screening step, showing that most of the positive CTDNA positive ESR1 testing occurred between year 1 and 3 or 1 and 4, so just those first few years. And if you test the patient 5 times and they don't test positive, they're probably not going to test positive. So there's probably a sweet spot where this type of testing is worthwhile to try to find this emergence of ESR1 mutation. And beyond that, the frequency of finding it is going to drop off a bit. So if I have the opportunity to do it, I'm not going to be necessarily offering it to everybody, but probably a select group of patients who, who fit in that sweet spot. Right now in the US we, we don't have approval for the Serena 6, platform. We don't have approval for Camazestrin and CDK46 inhibitor. So I'm not employing ctDNA serial testing because I don't have the action that I'd want to use if I found the positivity. But if this became available for us, I do think it's quite compelling, and I, I would be interested to use this in clinic. That's a great discussion. Um, let me just ask you a related question. We've now seen, and, and maybe Nancy and Sarah wanna weigh in here. We've now seen multiple experiences, Serena 6, Amber 3, the elevate experience with Eliestrian, and to my read here, Avera, don't forget Avera, uh, OK, combination, Gerard Estra and Elius, but that was, uh, first, uh, OK, fair enough. Uh, but I guess the real question I was asking is. You know, to my eyeballs, um, the combination of these oral surges plus ongoing or even switching CDK 4-6 agents looks pretty powerful, median progression-free survival about a year. Is that something we should think of as a pretty standard option yet, or, um, uh, where are you with continuing the CDK 4-6, uh, uh, when you make these surge switches? Well, I'm, I'm a pretty firm believer that the um benefit of using an oral steroid is much greater when we use it in combination with a targeted partner as opposed to using it exclusively as monotherapy. Right now, we only have FDA approvals for monotherapy for LSSran. Um, for immunestrant and for the Protac, uh, veptogestra, but we, we do have an NCCN, um, listing for immunestrant and abamicycllib based on number 3. We await hopefully FDA approval of Gerriestrant and Evrolius based on Avera. And, um, you know, that, and if we have Camazestrin and CDK46 inhibitor approved based on Serena 6, that's another combination. So, I, I think my, my preferred strategy for a patient with an ESR-1 mutant cancer in the second line setting would be to use an oral er combination. I just don't have an FDA approved regimen in my hand yet, but, uh, that, that would be where I would prefer to go. Fair enough. Others want to weigh in, uh, Nancy or Sarah? I mean, I, I agree, and I have used, I've been using a fair amount of immunestrin tabena in the second line setting, um, after, you know, typically an AI ribocyclib in the first line setting. All right, Erica, let's continue on with another targeted study here looking at a phase 3 combination of getatulissa, Fulvestria with or without Palbo versus standard of care in hormone receptor positive PICC 3CA mutated cancer, the Victoria One Study 2. They, these, these names are getting more and more complicated. Uh, so, uh, it's our 3rd talk, Victoria One Study 2. What do we, what do we learn here? Yeah, so, um, the, the Victoria one study is evaluating the new drug gatatolisib, which is what we call a PAM pathway inhibitor, PI3 kinase AKT MTOR. So it's, it's targeting the same targets as some of our other agents, alpellisib, capivosertib, and Navelisib, but in a verilius, but in a more broad fashion. Notably, this is an intravenous drug that is dosed 3 weeks on, 1 week off. Victoria 1 is a complex study. It is a 6-arm study, and it is separated into two parts. We heard part one at ESMO last year, and that was for the PICC 3CA wild type patients looking at a triplet with a CDK46 inhibitor, a doublet with endocrine therapy, or endocrine monotherapy. And this was a positive result from study one. Both the doublet and the triplet were superior to monotherapy. Study two is for PICC 3CA mutant patients. These are patients who've had, um, up to 2 prior lines of endocrine therapy. They all had prior CDK46 inhibitor, no prior chemo, and there was a tight restriction on hemoglobin A1C because of the agents used. The patients are randomized to get triplet, GA, palbociclib, and fulvestrant versus a standard of care doublet, Alpolisib and fulvestrant versus another experimental doublet, GA and fulvestrant. Now the primary endpoint was actually comparing the triplet getta palbo fulvestrant to the standard of care doublet, Alpolissib fulvestrant. The secondary endpoint was comparing the the uh uh doublet of getta fulvestrant to the standard of care Alpolissib fulvestrant. Um, a few important details. First of all, it was mandatory for patients to use a prophylactic steroid containing, uh, mouthwash because of the risks of mucositis with these medications. Um, so that was important. Um, and another important detail is that the use of palbociclovir is very intentional. This is not a study where you can swap out Palbo for some other CDK46 inhibitor. We know that Palbo is the best tolerated and mixes the best into doublets or triplets compared to the other agents. So it's important that this is a Palbo containing regimen. Let's look at the results in the next slide. So on the top you see the primary endpoint of the triplet versus the control. We see 11 months with the triplet versus 5.6 months with the Alpelissa control, and on the bottom is a secondary endpoint of the doublet with Geta versus the Alpelissa control. And again, 11.3 months versus 5.6 months. So a pretty profound doubling in progression free survival using either the triplet or the doublet with Geta compared to a standard of care with Alpelissa. Next, next slide. It is important to just review the tolerability. Um, despite the use of the steroid mouthwash, about 60% of the patients did experience, um, any grade stomatitis, about, um, 10 to 15% with grade 3. There was also incidence of rash, but notably the rate of hyper. Glycemia, which is really a difficult toxicity without Pellisib, is much lower with gatolisib using that low hemoglobin A1C population. Notably, very few patients were reported to stop for treatment-related adverse events. Um, so it did not appear to lead to much in the way of discontinuation, but it is important to note the, the side effect profile. Let's go to your questions. Well, let me go back to this slide first, um, and then just, uh, ask. So, looking at these two things, um, to my eye, I would say the Palbo arm doesn't mean anything, right? I mean, you know, there's no difference here between Palbo plus get a plus full vestriant and get a full vestriant. Is that the correct interpretation? Well, one's a primary endpoint and one's a secondary endpoint, but I agree with you, the numbers look identical. OK, we'll call that, so, so the triplet's not, not a factor here. Is that, that's what I was getting at. So I guess I might just give a caveat though, because there are only about 50 patients in the doublet, and so it was a very small, um, you know, group of patients and it's not powered at all for comparison between triplet and doublet and confidence intervals you can see around the doublet are extraordinarily wide. It was a 3 to 3 to 1 randomization. OK, well, if the primary endpoint is the triplet and the FDA approves the triplet, are you going to give 3 drugs at once or are you just going to give the two drugs? I, I, I would start with this. Given the toxicity that it did add to use the triplet, I would totally agree that I, I would just use to double it. So what's interesting to me about this study is credit to the investigators, but the first time we've actually seen a head to head study of a PICC 3CA versus a previous PICC 3CA or MTOR inhibiting drug. So I thought there was a lot of value to doing it that way. Does that mean that moving forward, like the era of Comparing PICC 3CA targeted drugs against nothing is done, like all the next wave of PICC 3CA targeted therapies should include at least a control arm that has a PICC 3CA targeted therapy. Yeah, so the next wave of drugs is, is really looking at the mutant specific inhibitors. Um, you know, there's two lead agents that are currently in phase 3 trials, and, um, you know, those are the agents that I, I think we all hope will make it onto the scene and be well tolerated and active drugs. But, you know, I, I think this Victoria One data is really, it's, it's pretty impressive. To see that PFS and, um, you know, we as a group have been discussing the data internally and thinking about, you know, that patient who perhaps is progressing into the second line, and they have, uh, you know, visceral disease, symptomatic disease. You really need to give them something pretty robust to, to match the disease. And this is a, a regimen that I think would be appropriate in that setting. So, um, let me, you know, the way I'm seeing hormone therapy for metastatic disease more and more is it's really two columns running in parallel. You have your endocrine therapy, backbone on one side, tamoxifen, an aromatase inhibitor, fulvestrant, and oral serd, and then you have your targeted options. At the moment, that would be, um, you know, a CDK 4-6 inhibitor, of which there are three commercially available, uh, various PICC-3CA, AKT-P10 pathway targeted drugs, intervalisive capive assertive. Alpelisib and perhaps in the future Ga Tissib. You're gonna have to make choices about what you do in the second line. So, if you look at what we just talked about right now, um, Serena 6, 17 months PFS with the second line oral surgeon CDK versus what was, you know, 11 months here, why would you not use a second line CDK 46 inhibitor in general as opposed to switching to a PICC 3CA inhibitor? Well, I mean, if you have PICC 3CA mutant disease, at some point you want to give them an agent to target that mutation. I think the question is at what point in time are you offering it? If you know your patient has a PICC 3CA mutation and they've just recurred, like on or soon after adjuvant endocrine therapy, you're actually going to be giving it first with the Navalisib regimen. But if, It's an endocrine sensitive patient and you're looking for a subsequent line of therapy, um, if they have, let's say, dual mutation with ESR1 and PICC 3CA, then you have a lot of options. And deciding which to pick, you know, involves not only looking at efficacy and, and all, but, you know, tolerability, patient preference, schedule, visits, all of those important details. Fair enough. All right, Nancy, back to you for the IRISA study, an early HER2 positive trial, um, in early stage breast cancer looking at capecitabine and trastuzumab. Uh, tell us about this trial. Yeah, so this is an interesting study. So it's part of a suite of Iris studies, so this is Iris A enrolled 178 patients with um Either hormone receptor negative or or hormone receptor positive HER2 positive breast cancer to receive capecitabine with uh with trastuzumab, followed by trastuzumab maintenance. Uh, next slide. So I think one of the key points of this presentation is just to look very carefully at the patient population. Uh, if we look at the patient population, 56% of patients had T1-Mic disease, 24% had T1A disease, 4 4% T1B, and 15% T1C. So if you just combine the T1B T1C, what we're typically thinking about offering standard chemotherapy transfused mad-based regimens, um, in the adjuvant setting, that only represented 20% of the patient population, uh, and then 87% of the patients were hormone receptor negative. Next slide. Uh, the outcomes that you might expect from this patient population alone, uh, not to mention the chemotherapy that was given, were excellent. So the five year IDFS was 97.8%, the five year RFS was 98.9%. Uh, they did see a signal of what it's worth, uh, favoring, uh, the hormone receptor positive patients having a somewhat, somewhat better outcomes, although all patients did have very good outcomes. Next slide. So, yeah, you know, the practical question here, and I take your points that this was a very small, a, a cohort of very small tumors, um, uh, but you know, the practical question here is there were no metastatic recurrences, and so let's, let's ask the obvious, is the Tolani regimen dead? Are, are we done with Paclitaxel trastuzumab? It has had its moment. It's like melphalan chemotherapy for early breast cancer. Are we moving on? I do not think the Salandy regimen is dead. I, I really, you know, I mean, if you look at the APT trial, just to look at the patient population. 30% had T1B cancers, 41% had T1C cancers, 9% had cancers between 2 to 3 centimeters. And so it's like a totally different patient population than this study. And at 10 year follow-up, there are only 6 distant recurrences in over 400 patients. I mean, I think that that data are very solid, and I don't think that these data really make me feel comfortable in the average patient replacing Cape Sodaby Trustes meb for uh paclitaxel Trustes meb. I do think that there are patients who can't tolerate Paclitaxel, who may not want neuropathy, you know, maybe their, their profession depends on, on, on their hands. I mean, there, there, you know, we can think of different reasons why we might want to substitute, and I think it says that for those patients, it's probably a reasonable substitute, but I, I don't think. I don't think it provides a level of evidence that the ABT trial did just because of the risk level of the population. So to recap, you are reserving this regimen for women with 2 millimeter cancers who are either neurosurgeons or professional viol. Well, I think the other point is I don't think those patients with T1 mic cancers. should be getting chemotherapy. And I actually saw a recent, there's a recent publication of Andrew Seidman at Memorial, and they looked at like over 200 patients with HER2 positive T1MCN0 cancers. They found that, you know, specific niche population. 16% of the patients got chemotherapy, so the majority did not get chemotherapy. There were two distant events. So I, I just, you know, I, I think we gotta be careful not to overtreat. I would not use these data to say that we need to give everybody with T1 mic cancers trust use methcapecitabine. All right, well, as the Tolini regimen persists, we'll ask Sarah to discuss DBO9's update on the duration of clinical outcomes by response for TDXD and pertuzumab. Sarah, take it away. Oh, thanks, Hal. So, I think, uh, as people know, the Destiny Presto 9 study was really looking at the First line treatment approach for patients with metastatic HER2 positive breast cancer, and we've previously seen the data from the trial which had demonstrated that TDXD plus pertuzumab did better than the Cleopatra regimen THP with a near doubling of progression-free survival favoring TDXD and pertuzumab. And the data for the THC monotherapy arm has not yet been presented because it did not meet the criteria that were set at the time of the interim analysis for success, so we'll have to wait till the primary PFS data. But at this time at ASCA, what we saw was an interesting analysis where they were trying to understand the relationship between depth of response and efficacy. And so what they did is they looked at um how many people got a CR, so had a complete response by resist, and then they looked at something that isn't a real standard uh endpoint, but it's something they termed having a deep PR. So if you had more than 80% reduction in your tumor that didn't quite meet a CR, so between 80 and 99%, that was considered a deep PR, whereas if you had a partial response that didn't meet that threshold, it was just called other PR. And then they looked at that relationship with progression-free survival. And so if you go to the next slide, what you can see is that the people who achieved a complete response, which was about 15% of the trial, had very good long-term outcomes in terms of PFS. But what's interesting is that people who had a deep PR, which was about 37% of patients in the study, also did very similarly. So you can see those lines are pretty close together in terms of progression-free survival. Uh, so I think the take home in my mind was getting a deep PR is pretty similar to getting a CR in terms of your long term outcomes, whereas if you had an other PR you didn't quite meet that 80% threshold, but you still had over a 30% reduction. It's actually quite different, right? You see that 64% um PFS rate at 24 months, and then the stable diseases at the bottom, and this was actually a different relationship than what was seen with the Cleopatra regimen. So they looked at these data also with THP. And the people who had DPR didn't do as well as the people who had a CRT. So it does seem like that relationship is just slightly different. And then if you go to the next slide, I think the other take home here is that it does take time to get a really good response to TDHD and pertuzumab. So The time to get to a CR was a little over 8 months. The time to get to a deep PR was about 9.5 months. So it wasn't that that happened instantaneously, and they found that about 80% of people had maximal tumor reduction by 2 years. So again, just like this is just to give a sense of how long it takes to get to that response and then what the relationship of response is with long term outcomes. So something I really like about this is, you know, for a long time we've kind of dichotomized response like you either have a response or you don't have a response, and most of the time there is CR, I suppose that's relatively uncommon, but you know, I think it's important to think about the depth of response in all seriousness, you know, there's clearly You're seeing more sensitivity to the drugs, you're seeing things and probably does kick out the ultimate PFS. I, I guess the commercial corollary here as we look at these analyses is, you know, does this mean in first line HER2 positive metastatic disease, one should be treating, You know, towards 24 months with a TDXDP regimen as opposed to giving, say, 6 to 12 months of induction therapy and then switching to a maintenance approach which has been talked about in the wake of the Patina study and other sort of, you know, practical considerations about this trial. Oh, I think that's a big question, right? It's because in DBO9 everyone was treated until either toxicity or until time of progression. So you're getting TDXDP for a long time, right? The median PFS was about 41 months, and to be honest, that's at an interim time point. It could be longer at the time of the primary PFS analysis. It's a long time to be on therapy, so I think our. Is, does this help inform how long you should give that upfront therapy? And I would say, not really, in a sense that I think it shows that getting to a deep response is important, but these people continued on cytotoxic therapy. So what we've just shown is that getting to that deep response correlated with outcome in people who continued to get treatment. And so I still think we need to address the question, which is how long do you need to be on upfront therapy to get these really good outcomes? Do you need to just treat until you hit CRDPR and then you could go to maintenance and you'd still do really, really well as if you were continuing on TDXDP? And we don't know the answer to that. There are ongoing studies trying to address that question. So the Demether trial, which actually completed accrual now, did a shorter course. They just did 6 cycles of TDXD and then moved on to HP maintenance. And then there's a new planned trial called Destiny Breast Guide which will give 18 to 24 cycles that was designed based on this data from Destiny Breast 09 trying to give you about a year of upfront TDXDP and then. Go on to give HP plus endocrine therapy and palbociclib, so kind of merging the Patina regimen with Destiny Breast 09 in ER positive HER2 positive patients. It is a single arm study though, so it's not going to be definitive, but I think it will help us understand what the outcomes are if you. Do take this kind of upfront approach followed by maintenance. Just a reminder to the audience though, in the DBO9 trial, if you were in the THP arm, they peeled off the chemotherapy after a finite amount of time. I forget exactly how many cycles, but the point is, if you, you know, you, one of the reasons that the deep response analysis may not be as complete here is by intention they stopped the taxane chemotherapy. Is that fair to say? Yeah, the way it was written is that you're supposed to get a minimum of 6 cycles of taxane or treat until toxicity, so there wasn't a stopping point. It was per investigator discretion. In fact, there were some people who got 51 cycles of taxane, which boggled my mind, but the average duration was about 5 to 6 cycles in the THPR. So you're right, they got. Upfront therapy mostly followed by a maintenance approach very different than the TDXDP arm and I think it's also interesting that that relationship was different for CR and DPR and the THP arm. I think my guess is because they're not continuing cytotoxic therapy and so that relationship of DPR to PFS may not be the same in that situation. All right, well, we're gonna move away from some of the newer drugs that were profiled and talk about some of the lifestyle issues that were discussed actually quite widely uh at the meeting and to lead us through this is Doctor Jennifer Ligael. Jennifer, thank you for talking about GLP agonists and breast cancer risk here. Absolutely. So lots and lots of talk about GLP ones at this meeting. If you go to the next slide, please. So this was one of the abstracts that looked at the relationship between GLP-1 use and cancer risk. There has been a lot of attention to this question with many recent publications, looking at large databases, a lot of the large prescription databases, showing some connections between GLP-1 use and breast cancer risk. Uh, this abstract actually kind of looked at this in a different way, so, Um, you know, the rationale here, as it has been for many of these studies, is that obesity is a risk factor for breast cancer and many other cancers. In breast cancer, this risk is really seen in women after menopause. Um, there are some data from bariatric surgery. Studies, not randomized trials, but looking at individuals who undergo bariatric surgery versus people who are matched that don't undergo bariatric surgery that have really suggested that bariatric surgery may significantly lower the risk of developing not just breast cancer, but many other cancers. Um, you know, we are definitely in the era of GLP-1s. There are estimations that somewhere between 13 and 20% of US adults are using or have used a GLP-1, so I think a lot of exposure and kind of a natural experiment that's happening. So we don't really know yet how these drugs impact either the risk of developing cancer or cancer outcomes, but there's a lot of interest in studying this. So if you go to the next slide, please. So, this study was a little bit different, uh, than a lot of the things that have been published so far, which again have kind of looked across populations and looked at who takes these drugs versus who doesn't. This study started with a screening population, so it looked at individuals who had undergone breast imaging. And then identified a population of individuals who were taking GLP-1s. They first started by removing individuals who did not have at least overweight, so they were, they had a body mass index, all of the individuals in this analysis of at least 25 kg per meter squared. So you can see there are about 50,000 women that weren't in that category. Um, also important to recognize this is a screening population, so it's a little bit older, the median age of the patients that were included in this cohort were 61 years old. And first they looked at this kind of whole cohort, looked at individuals who had been treated with GLP-1s versus those who didn't, and then they did some propensity score matching, because they found, not surprisingly, that the women who were treated with GLP-1s tended to have higher levels of adipocity, really a very large shift toward obesity, had more comorbidities, so then they did some propensity score matching, and they looked kind of at these two different analys. first at all of the women and then at this propensity score matched group. And here you see on the left, uh, the analysis that looked across all of the women, whether or not they were matched, and you see that the individuals who were treated with GLP-1s had about a 1.62% risk of developing breast cancer compared to 2.6% in the patients who were not treated with GLP-1s. Um, Some differences obviously in this population that the patients treated with GLP ones, a little bit more diabetes and things, but really in this kind of all comers, they found this reduced risk of Breast cancer in people treated with GLP-1s. If you go over to the right side of the slide, then you see the matched analysis, uh, where they kind of lined up these factors. They, uh, tried to match people for their comorbidities, their breast density, other known risk factors. And you can see here that the differences are a little bit attenuated. But still quite significant. The risk of breast cancer in the GLP-1 users 1.62%, whereas the non-GLP was a 2.31%. So in both of these analysis really showing a very statistically significant reduction in the risk of breast cancer. Of around 30% in the matched analysis in the individuals who are using GLP-1s versus not. If you want to keep going, we will keep talking about this topic in kind of different ways that people have looked at the use of these agents and cancer risk and outcomes. So, this was a study, if you go to the next slide, um, that got a lot of press at the uh ASCO meeting because it was one of the first studies that didn't just look at how the use of GLPs related to the risk of developing cancer, but this was one of the first analyses that looked at People who'd already been diagnosed with cancer and how GLP use was related to cancer recurrence and mortality, the development of stage 4 disease. Uh, so this study, a little bit more of a traditional design, kind of as there have now been a couple dozen of these studies that look at these large pharmacy databases. This used the Trinex database to identify a very large group, 150 million patients from. 106 health organizations, and so they identified people that had taken a GLP-1 after diagnosis of several common cancers. So they looked at non-small cell lung cancer, breast cancer, colorectal cancer, uh, they looked at liver cancer, prostate, renal and pancreatic cancers. Now, notably, some of these cancers have been linked to obesity before, but some, such as non-small cell lung cancer, are not really thought to be as obesity-related. Now one of the things about this study was that, you know, they needed a comparative group, and in this situation, they chose individuals who were treated with DPP-4 inhibitors, uh, which are drugs that are used to treat diabetes. So just one caveat here, we know now that the GLP-1s are used to treat a lot of conditions, obesity, they're used to treat cardiac disease, they're used in some types of renal disease. So there's a broader usage. So these two groups, one of them, the DPP-4, only included individuals with diabetes, whereas the group with the GLP-1s had a mixture of people with diabetes, people with just obesity or other medical concerns. The propensity score matched them for the type of cancer, and then they looked at which individuals progressed to developing metastatic disease. So if you go to the next slide, what they found, um, and again, reduction is kind of a, we don't, we don't know that this was a reduction, but there were lower risks of recurrence, um, in non-small cell lung cancer, which was very interesting, um, you do work. A little bit about bias there because of, you know, people are very sick with non-small cell lung cancer, they're probably not being treated with GLP ones, they've got other medical conditions. But the obesity-related cancers, breast cancer, colon cancer, liver cancer, you see, That these individuals who were treated with these drugs after cancer diagnosis had a lower risk of recurrence compared to this matched group of individuals with diabetes treated with the DPP-4 inhibitors. Not statistically significant, but numerically favorable for prostate and pancreatic cancers, um, and then renal cell kind of not really much of a signal there. Interesting, renal cell is a one malignancy where some studies have suggested on the risk side that people who use GLP ones may have a higher risk of renal cell cancer, so that's sort of not sorted out yet. If you go to the next slide, just kind of seeing here what these uh curves look like, and again you can see these are kind of landmarked from 6 months after the uh index date, but you can see the separation of these curves with this lower risk of the uh progression to metastatic disease in these cancers. So, you know, I think these are really provocative studies, and there now are quite a few of them showing these associations between GLP-1 use and lower cancer risk, now seeing for the first time some evidence that GLP-1 use after diagnosis is associated with lower risk of metastatic disease, um, you know, and the question we get asked all the time is, you know, are we, oh, I'm asking, sorry, how you're supposed to ask questions. No, no, this is exactly the question. Um, you know, should we be prescribing these? Like, do we have enough evidence that these should be cancer drugs at this point? Um, I have my opinions here. Um, this is the perfect time to share them, I would say. You know, I think this, these data are really, really provocative, and I think that there is no doubt that these drugs have completely revolutionized the weight loss landscape. There have been so many benefits of these agents. If I were somebody that had a patient in front of me that had been diagnosed with breast cancer and I needed to pick a drug for her diabetes, I 100% would pick a GLP-1 at this point. I think that in individuals with diabetes, there's pretty clear evidence that use of these drugs versus other drugs does seem to be linked to better outcomes. It is true that You choose different drugs for people who have diabetes of different severity, and you know, I think there's there's some concern here that, you know, we know diabetes is a risk factor for developing breast cancer. We know individuals that have higher levels of insulin and higher levels of glucose have a higher risk of recurrence. So there's some murkiness here when we think. About the diabetic population. I don't think that we're ready to be prescribing these drugs to people without diabetes for the purpose of lowering their risk of developing cancer or developing recurrence. But, you know, this is really an area where we need strong data from randomized trials. I, I will just Remind people that a number of years ago we were incredibly excited about the drug metformin, where we had very similar data in individuals with diabetes where you compared metformin versus insulin and showing lower risk of breast cancer, lower risk of cancer recurrence and mortality, and then when that was, you know, tested. In a randomized trial in individuals without diabetes, the drug didn't have any benefit. So I think we have to be a little bit careful about extrapolating these findings to our non-diabetic patients and making the assumption that there's going to be a benefit here in terms of cancer reduction or outcomes. Great discussion. Um, so, Uh, as in the World Cup, you know, when they finish one of those halves, then the referee holds up a card that says the extra minutes time. So we have about 6 minutes of extra minutes here. Uh, I will use a few seconds of that time to remind our dedicated listeners online that on Saturday, July 18th, we are doing a full day update on breast cancer. Our New Horizons and Current Controversies course, which for the first time is going to be one day and is going to be hybrid. We would be delighted to welcome you to our campus at Dana-Farber Cancer Institute here in downtown Boston at 450 Brookline Ave. if you wanna join us in person, uh, or you can join online. And, uh, we are very much looking forward to catching up to many of you at that event. For my panel, let's move to our lightning round, as it were, and I just want to remind everyone to keep the answers succinct, uh, as we move forward. Jennifer, I'm gonna go back to you. We have an interesting question. Do you think, uh, this was posted ahead of the meeting when people registered, but do you have concerns about the GLP-1 agonists affecting absorption of drugs for cancer, you know, like, do you think they might affect the absorption of a CDK46 inhibitor or some other drug that would in some way affect your treatment outcome, or are you very comfortable? prescribing them in almost any breast cancer situation that would warrant the drug, if you see what I'm asking. I think that is a fabulous question and something that really, really, really is screaming for a trial to evaluate because there is almost no information about the Use of these agents in individuals who are treated with sort of modern, you know, we're treating our patients with CDK 46 inhibitors, with endocrine therapy, and there is very little information about the toxicity patterns, uh, the potential impact on absorption or drug levels. I think that's a really important question, and I am not aware of a whole lot of information at this point to guide that. Um, so I think that, you know, there certainly now are data about women taking endocrine therapy at the same time, and some data from, and you said short, and I'm not doing a good job, um, but there's some data from Yale and Memorial that suggests that people on endocrine therapy. May not lose as much weight with these drugs as people that are not on endocrine therapy, but I think we just don't have a whole lot of information about toxicity or drug absorption. Nancy, I'm going to go to you here. A provocative question also posed to the head of the meeting. If we know that the recurrence score or the optimum prosigma method is low, let's say 50 or less, do we need to do any sensitive lymph node surgery now that we can treat people up to multiple positive lymph nodes? Well, it sort of depends on what the value of the lymph node surgery is. I mean, I, I wouldn't leave, you know, if I thought somebody really had 9 positive nodes, I personally would not feel comfortable leaving macro, you know, macrometastatic disease behind. I do think that it, it You know, shifts the pendulum as it has already been shifting towards omission of sentinel node biopsy in a larger and larger proportion of patients where we feel like we can, we, we actually can get the information we need to make systemic therapy recommendations based on the biology of the tumor and the clinical staging and the and the nodal information to be gained by sentinel node biopsy is less important. Erica, uh, to you for a question about CTDNA testing. Um, are you, not, not just in the context specifically of Serena 6, but are you using CTDNA more for sort of just gauging metastatic cancer burden? You showed those data on the reduction in CTDNA with the switch to the er. Is this, you know, some patients are getting semi-quantitative Signaara test readouts or things like that as a surrogate for response. Is that something you're using regularly in practice? Yeah, I, I don't think we know that doing that type of testing, which is, you know, in some ways like a surrogate of, of, uh, clinical staging is going to help patients do better or get more out of their medications. So, um, you know, I, I don't necessarily see a role for that. However, I will say that that doing CT DNA to interrogate the genomics of the cancer is why we want to do it and, you know, You are the author of the ASCO guidelines that recommend that we for the time being do the CTDNA at time of disease progression and, you know, if we adopt Serena 6, we might be doing it more frequently. So I, I think we want to be using sensitive assays that are looking at um evolving genomic um uh changes and actual biomarkers, but looking for just burden of disease. I, I don't think that's a tremendous value. Can I add one thing? I mean, in Serena 6, you know, I think even though there's not a survival advantage as of yet demonstrated or may or may not ever be demonstrated, there was a quality of life difference demonstrated, and I think that's ultimately where the debate comes in is, you know, what do we do with this drug that doesn't have so much toxicity and has this quality of life. But what was so interesting is that the patients who turned positive, they still had 9 more months of median PFS, and they didn't get a survival advantage, so I don't think we can extrapolate Serena 6 to say that we should be monitoring cTDNA levels in all patients and changing their therapy as soon as the cTDNA level goes up. I think we could cause harm by doing that, and I would not recommend it. Sarah, let me give you the final word here. We didn't talk about um some of the newer ADCs that are coming along. There was discussion of the so-called ISA-ren molecule, which is a bi-specific um EGFR and HER3 directed ADC. Um, there was a lot of talk about these newer ADCs and how quickly they're proliferating and Where, where do you think we're gonna be, say, in 5 years with all of these, uh, newer ADCs that are coming along, and how does that relate to the ones we have already in the way of detapotumab, trastuzumab, rustican, uh, cestuzumab, govetecan, and, and others close in the pipeline? Yeah, I mean, I wish I could predict the future. I will say that I think that it's exciting to see so many new ADCs arising. It's hard to know how much better they will be compared to one another, you know. I think we've seen these TOA 1 payload ADCs are all having excellent outcome, but for example, you know, with the by specific type ADC, is that better than Um, the Trope 2 ADC, I, I think we'll have to see, uh, what happens as those, uh, get developed. I think what we've been longing for though is an ADC with a different payload, uh, and so we are starting to see some of these emerge with, you know, MMAE, MMAF, etc. and so I, I hope that this will change the landscape so that we can start sequencing ADCs one after the other. And you know now these ADCs are also getting studied in the early disease space and it will be interesting to see how they evolve, how we'll be substituting chemo with ADCs, what combos we'll be using, so I think a lot more to come. Well, with that, we invite you to join us again in just over a month for our comprehensive multidisciplinary program on breast cancer care called New Horizons and Current Controversies. There is the option of either an in-person event if you wanna see us live and, and have a Dana-Farber baked doughnut and a few other things like that, or uh joining us virtually. We are looking forward to A great crowd and it'll include both multidisciplinary management of early stage disease surgery, radiation oncology, reconstructive surgery, and a variety of other topics, of course, in hereditary breast cancer and advances in treatment of early and late stage breast cancer with systemic therapies. And with that, uh, I want to thank you all for joining us. Um, we are interested in your feedback. And if you have a moment, you will see at the end of this presentation, uh, the opportunity to, uh, give us, uh, your impressions of the series of talks we've been putting together, uh, in a virtual format, uh, with a live webinar. We hope you've enjoyed it and we look forward to hearing from you. On behalf of my colleagues, thank you very much and have a good afternoon. Published August 22, 2026 Created by Related Presenters Harold Burstein, MD, PhD Medical Oncology View Full Profile Sara Tolaney, MD, MPH Medical Oncology View full profile Nancy Lin, MD Medical Oncology View full profile Erica Mayer, MD, MPH Medical Oncology View full profile Jennifer Ligibel, MD Medical Oncology View full profile