Early Stage Hormone Receptor Positive (HR+) Breast Cancer Treatment Algorithm: Dr. Erica Mayer

Hello and welcome back to the oncology brothers podcast. I'm Rahul Gossein here with my brother and co-host Rohit Gossein. Last year we did three discussions around breast cancer treatment algorithms, but given how much data we're seeing and new approvals we continue to see for 2026, we've decided to cover this in four part series. We're splitting hormone receptor positive in two episodes, one focusing on early and locally advanced disease and the other for metastatic disease. We have one dedicated discussion for her to positive and then one for triple negative breast cancer. Right Rahul, this is getting exciting. What we saw was about 40 to 50 drug approvals and indications in 2025. Well, focusing on today is treatment algorithm series. What we are trying to do is reiterate the current standard of care and seeing how these new approvals and indications are changing the field. With focus today will be early stage and locally advanced hormone receptor positive breast cancer. For this we're thrilled to have Dr. Erica mayor, a breast medical oncologist at the Dana Farber Cancer Institute. Erica, thanks so much for joining us. Thanks for having me. Erica, welcome. There's a lot to cover. Let's start with early stage disease and as medical oncologists we're often playing a bigger role in adjuvant settings. We use recurrent risk and genomic assays like onco type or mammoprint to see who needs chemotherapy. In 2024 we saw subgroup analysis for tailorax that a score of 31 and above derived the benefit with anthrocycling based chemotherapy. When we're talking about anthrocycline this is pretty much faced out in her two space. But here in hormone receptor positive early, no negative and no positive disease in your practice who gets anthrocyclines over TC today. Yeah thanks. This is a great topic and is really something that has evolved over the decades of offering chemotherapy to patients with early stage disease. Once upon a time we used to give anthrocycling based chemotherapy to almost every breast cancer patient which while effective can lead to long-term toxicities and other challenges for patients. So it makes sense to be as selective and careful as we can be in making sure that we offer this therapy to the people where we think it's going to be of greatest benefit. As you mentioned we are using anthrocycline less and less for her two positive breast cancer. We still do use anthrocycling for triple negative disease so we want to make sure that we recognize the role of anthrocycline in that setting. But for hormone receptor positive disease there has been a gradual pulling back from anthrocycline was generated around the time that the ABC trials were published which was a pooled analysis comparing anthrocycline based chemotherapy versus more of a TC approach for all subtypes and stages of breast cancer. We learned that anthrocyclines appeared to provide not much substantial benefit for the majority of hormone receptor positive disease in comparison to a taxaing based approach. What we saw at San Antonio in 2024 was a really interesting analysis that Nanchen presented looking at the group of patients in Taylor X who had an archetype score that was greater than 30 so 31 and above looking at what chemotherapy they received and how did they do. Now remember this was not randomized. In the structure of Taylor X if your archetype was more than 30 you automatically were recommended to get chemotherapy of provider choice. So whether people got ACT or TC likely reflected the patient and provider understanding of their disease and preferences. What was shown was that the patients who received the anthrocycline based therapy did better than patients who received the TC chemotherapy which was interesting especially thinking about how we might have offered ACT to a higher risk patient maybe TC to a somewhat lower risk patient and yet the ACT patients did better. I thought this data was compelling and if I have a patient with an archetype score more than 30 we're talking about chemotherapy in that setting if I'm offering chemotherapy I probably do want to optimize what I offer and so I have found myself offering ACT chemotherapy for select patients someone with an archetype of 31 who just made it into that category. Maybe I'm not feeling so passionate about it the most recent person I did this for had an archetype of 54 where I thought that's a pretty high archetype and really wanted to offer what I would consider to be the appropriate therapy in that setting. Indeed tying in that patient shared decision making process and the data at hand and always battling that question about under treatment versus over treatment. Well Eric I'm going from one extreme to the other that score of 16 to 25. We are a bit clear in the postmenopausal group here for N1 disease postmenopausal with low recurrence score based off of RX ponder no added benefit with chemo here. Though what we are looking at is offset trial which is for pre menopausal women with N1 disease but low archetype dexcore that is less than or equal to 25. The choice is OFS plus endocrine therapy versus chemotherapy plus OFS plus endocrine therapy while we are awaiting this data what are you doing in your clinic today outside of clinical trials. You point out of somewhat contentious area in early stage disease nowadays which is how to treat our younger patients with no positive breast cancer. We have a variety of tools available including not only chemo therapy but also endocrine and what we might think of as augmented endocrine approaches. In the data from responder looking at the pre menopausal patients was unable to identify a group for whom chemo therapy did not appear to provide benefit but as we know some of the weaknesses with that study is not really capturing the use of ovarian function suppression or chemo therapy induced ovarian function suppression. OFS is an incredibly powerful tool to treat hormone receptor positive disease. We have recently seen 15 year follow up from soft and text which are the seminal ovarian suppression studies demonstrating substantial improvements with the addition of ovarian suppression to either a rheumatase inhibitor or to moxifen versus to moxifen alone. Benefits that mirror what we see with chemo therapy. Furthermore we've seen from Taylor-X and somewhat from responder that patients who are closer to natural menopause either by age or by their AMH level are the ones who appear to be getting greater benefit from chemotherapy but that doesn't biologically make sense unless the chemo is inducing the OFS. There's a lot of circumstantial data that's suggesting to us that the power of chemo in the setting may not be chemotherapy but it may actually impact ovarian suppression or ovarian function. These become very personalized decisions. Today in our tumor board we had two of these cases where we had a really robust conversation about what to offer these patients. We're thinking not only about size and nodes but about the grade, the degree of ER staining, perhaps the KI67 if that's relevant, the patient preferences and what does the patient want to do? And are they a more is more person or are they a less is more person and so you know we have to navigate all of that. I will say in our practice at Dana Farber we do not automatically give chemotherapy to every premenopausal node positive patient. We send onka type on many of these patients. We think this test still has great value and for a number of these patients we are deferring chemotherapy and offering this augmented endocrine plan ovarian function suppression, oeromatase inhibitor and cdk46 inhibitor as many of these patients will be eligible for that. I blood you brought up the offset trial because this is the trial we all need to work together to support and enroll patients on to prospectively answer this question of what is the role of chemotherapy if any in this patient population. At our tumor board today the answer to both of these cases was put them on to offset and help us get closer to that answer. Absolutely we are all eagerly waiting to see the results from offset study here out in the community settings. I'm enrolling these patients. Erica you brought up cdk46 inhibitors as well. This is a good segue. This is going to be relevant when we touch on locally advanced disease as well. So let's pivot to cdk46 inhibitors. In the adjuvant settings along with endocrine therapy today we have ribocyclet based off natally trial and abema cyclib from one archie trial. At asmo 2025 east also saw overall survival data with abema cyclib but we have to keep few things in mind because we're stuck with cross-jaw comparison. Abema is for two years ribocyclet is for three years and we have more mature data and os with abema but the side effects look different. For t2 and 0 high risk disease we have ribocyclet but then for that overlapping disease where abema and ribo are both indicated. Erica can you touch on the data here and how you pick one over the other in your practice? Yeah I think we're in a happy conundrum where we have these two drugs that have both demonstrated very strong data for higher risk patients. Definitely agents that are making a difference in our patients' lives since they were initially approved in the adjuvant setting. As you point out monarchy which is looking at the two years of adjuvant abema cyclib is a bit more of a mature study. We have longer term follow up now at seven years showing not only a consistent and preserved benefit in reducing the risk of invasive disease or improving our invasive disease-free survival but also now for the first time showing an overall survival benefit which is hard to show in the adjuvant setting for hormone receptor positive disease. I think for many of us this helps confirm our confidence in the use of this agent in particular for patients who are very high risk. For example for or more involved lymph nodes that tends to be a place where we really feel a lot of confidence in the use of abema cyclib. Natalie had a much broader eligible including not only node positive patients, but also higher risk, a stage two, node negative patients, which was mostly T2N0. And, you know, we also saw at ESMO this year, five year follow up from Natalie, which shows not only preserved IDFS benefit, but now with more events in the node negative population, we see a significant improvement for node negative patients. I think for that overlap, you know, sort of a, you know, one to two node positive patient population, we might be struggling a little bit to figure out which drug to take a lot of factors come in. The data for both agents is very strong in this setting. So I don't think we can look to the data to to sec down and say that we have superiority or infarct purity of one drug versus another. And that's coming down to toxicity and patient provider preferences, the BAM is cyclops toxicity profile is different than ribocyclib where it's more GI toxicity prominent with diarrhea being something of patients might experience. Whereas ribocyclib, LFT abnormalities have become an issue with about one in 10 patients having more significant LFT abnormalities, making it sometimes hard to take the drug. And all differences such as the need for EKGs with ribocyclib differences in duration a lot to it that when I speak to colleagues around the country, both in academic and community settings. Sometimes people feel that they're using one drug or the other drug more frequently in the metastatic setting and they understand how to prevent or manage toxicity. So it feels more comfortable to use that drug in the adjuvant setting. I think there's value in that as well. It really comes down to speaking to a patient and understanding what their goals are going through the toxicity and talking about how to manage that and see where we end up. I will add, which I think we're going to chat about is I've been very interested in this question of how to mitigate toxicity with novel cancer therapies and in particular with the BAM is cyclop, we know that that early diarrhea that can happen, at least in monarchy, did lead to a number of patients discontinuing therapy early, not finishing the two years of the day. And a number of those patients discontinued without even trying dose reductions, which we know now does not impact the efficacy of the drug. So I was interested to study whether starting low and escalating and kind of getting the patient used to it might be helpful. We ran a investigator initiated single arm phase two study called the trade study where we enrolled about 90 patients who are starting a BAM cyclop for regular clinical indications. We started low 50 milligrams twice a day for two weeks, then escalated to 100 milligrams twice a day for two weeks. And then at the beginning of the second month tried to get to the target 150 milligrams twice a day onward for the plan two year course. We designed a study with a composite endpoint that was looking at inability to reach 150 inability to maintain 150 or having to discontinue the drug early. And we measured that at 12 weeks, so three months into treatment. And what we showed was statistically significant reduction in that composite endpoint compared to what we calculated from monarchy. In particular, what we saw was a very low rate of discontinuation was like 6% of patients had discontinued by 12 weeks, which is definitely lower than monarchy like 94% of your patients are still on drug three months in is really reassuring. As we followed the data over time, I think we find that patients settle out at different doses and some people end up needing to be at 100 and some people end up needing to be at 50 using dose reductions. But if they have to be at that dose, I think it's okay, as long as we can try to get them to the finish line. There are a number of people for whom the drug is just hard to take and maybe they need to discontinue and think about a different agent, but for the majority of patients on trade, they've been able to successfully stay on drug and hopefully get the full benefit. Wow, thank you so much for summarizing all that Erica. There's quite a bit to unpack here. I'll continue on with the CDK 46 and a bit of story tying in first full ribosyclip in adjuvant setting the dose here is 400 milligrams versus 600 milligrams, which is in metastatic space. And as you mentioned, Erica, the treatment here is for three years when comparing to a BEMA cyclid, which is two years. I do want to bring up the Ki 67, which was part of the inclusion criteria for a BEMA initially was taken away. So I saw what you were talking about the overall survival data and Erica, you reiterated that what we saw at Esmo was seven years with the BEMA cyclip 87% versus 85% with hazard ratio of 0.84 looking at just this number that seems small, but again, it's early on during the disease and seeing these curves getting wider is very reassuring. Recently at Esmo, what we saw with the data published by Dr. Sarah Tullaney, which was rather a real world outcome of high risk and one disease is rather in line with early triple negative breast cancer. This is very different than what we are seeing with non high risk features where the outcomes are excellent. What we also saw was the 60% of these patients qualified for a BEMA cyclip as per monarchy, but did not get a BEMA cyclip. And now the data that we have at hand is overall survival at seven years. And also what you mentioned, ribocyclip at five years as well. These are reassuring to utilize in our clinical practice. Erica, we talked about the side effect profile. If we are to decrease the dose of whether ribocyclip or a BEMA cyclip, are we compromising any efficacy? And if you could tie in some clinical pearls and managing these side effects. Yeah, I think transaminitis in the diarrhea are the two side effects of this class of agents that can be most challenging regarding ribocyclip. And if as majority of people do not have any trouble with LFT abnormalities, so this just is really a fraction of people. But when we start ribocyclip, it's very important to be checking LFTs regularly. We check it baseline in every two weeks for the first eight weeks of treatment to look for LFT abnormalities. When they happen, it's important to recognize this if they reach a certain threshold to hold drug. And take a long time for the LFTs to resolve after this hepatic inflammation initiates with ribocyclip, sometimes even months for it all to subside. And depending on the severity of what we see, it may be helpful to involve a liver specialist like a hepatologist or gastroenterology consult to weigh in and see if we need more assistance. For example, does a patient need steroids or a liver biopsy or some other more kind of advanced workup and management regarding the diarrhea. This tends to be early onset with a Bema cyclob. This is why the trade study was focused on the initiation of the drug. For many people, their body seems to adjust to it. And once they get over the initial experience of diarrhea, it settles out for the rest of the course. What dose a patient settles on so they can not experience any ongoing diarrhea might vary person to person, but we do have substantial data telling us that patients who use a lower dose intensity of a Bema cyclob during the two year course have a essentially identical outcome compared to patients who have a higher dose intensity. The idea is that we want to use a dose reduction if necessary and we want to get the patient to the two year finish line if we can. And if we need to use a dose reduction or a dose hold or use other strategies to manage toxicity, that's fine. We just want to try to avoid early discontinuation if we can. I think it's very reassuring on our and for the patients that we're not compromising that efficacy, but I know you want to move on. But before I let go to CDK 4 6 topic, timings of all this, especially in relationship with radiation, Erica, how soon are you starting CDK 4 6 inhibitors and adjuvant settings. I like to do one thing at a time. I think patients like that. I have my patient finish radiation. I'll usually start adjuvant endocrine therapy a couple weeks later. And maybe a month after that will start with CDK 4 6. I also give adjuvant zoldronic acid to a number of patients with stage 2 and 3 disease. I might get to that a few months later. I really want to make sure they're stable on endocrine and CDK before I add anything else. I try to avoid doing too many things at once. Finally moving along into locally advanced Erica with guards to locally advanced disease where we have a lapper approved for Braka positive patient population. What we are seeing out of Olympia trial is overall survival data that is 87.5% versus 83% with hazard ratio of 0.72. And the presence of CDK 4 6 inhibitors. How are you combining for that rare patient population with Braka positive, a lapper rib initially and then sequencing that CDK 4 6 post that. This is not the most common patient we encounter, but it is definitely someone where we need to think hard. So if someone with hormon receptor positive disease qualifies for adjuvant, a lapper rib, we know they have high risk disease because they would have multi node positive disease or a lot of disease present after preoperative chemotherapy. So we are thinking their high risk in these patients because of the overall survival benefit with a lapper that was seen pretty soon into the Olympia study. We've always prioritized use of the one year of a lapper. But we also know that CDK 4 6 inhibitors have a role in this setting. We do know from monarchy and Natalie that the window to initiate this adjuvant CDK 4 6 was about a year after initial treatment. One can stitch together a plan where the patient does the year of a lapper and then transitions to initiate CDK 4 6 inhibitor for an additional 2 to 3 years. Now that's a lot of therapy and is a bit of a marathon. I have done this successfully in patients though, but I think it really requires a lot of preparation and education. The patient I'm doing this to knows they're going to do it the first day I meet them like I'm already talking about it and I'm already kind of laying it all out for them. So when we get to that point after surgery when we're making the plan, I hope I'm not surprising them by saying we need to do this. That way they know the whole time. in their head what the plan will be. So far so good that it has helped I have had a number of patients reach the finish line with this but I do think it would be a lot for a patient to receive news about this degree of therapy without prior preparation. I think the communication is really important. You know as we were talking about adjven alapreb in my practice anytime there's a patient that might qualify for this I have to go back to the trial to look at that inclusion criteria because this is different for triple negative and for hormone receptor positive disease. You have to have deverisageal disease you have to have hypes with features there's a score where you're keeping that clinical stage pathological stage grade and estrogen receptor status in mind. Also with alapreb we have to keep side effects like site opinion fatigue on our radar. I know we've covered a lot here but before we wrap up Erica I would love to hear your thoughts on the recent data around juridestrant from SABCS 2025. Yeah I think the presentation of the adjuvant Lidera study was probably our top abstract at San Antonio 2025 was sort of a surprise I guess. We weren't necessarily expecting it but wow what a great abstract to summarize Lidera is studying the oral surgery juridestrant a drug that recently we've seen positive data for in the metastatic setting as part of the avera trial. Lidera is one of the very large adjuvant oral surge trials that have been ongoing. A key details about this design of Lidera is that it is one of the trials that enrolls patients at time of initiation of adjuvant endocrine therapy. So patients who are starting their endocrine therapy and the eligible patients were stage two and three breast cancer and higher risk stage one breast cancer. They were randomized to receive geridestrant or provider choice endocrine treatment. There was no adjuvant CDK46 inhibitor used in the study that's a very important detail. What we saw in the DERA was that at this interim analysis there was a 30% reduction in the risk of disease recurrence in the patients who received the geridestrant compared to those who received standard of care endocrine. An important detail is when the data was shown in the Kaplan Myer plot was shown there was a magnification of the beginning of the Kaplan Myer plot and we could see that the separation between the curves began very early on. This wasn't something that was delayed but this was an immediate effect that was being seen. This corresponded to about a two and a half percent difference between the two arms. Overall geridestrant was very well tolerated. There did not appear to be any substantial toxicity differences compared to standard of care endocrine therapy. It was noted though that looking at treatment discontinuations for toxicity, the discontinuations for our througes was much lower in patients receiving geridestrant compared to patients receiving standard of care endocrine therapy. Overall, very interesting, very provocative data that has potential applicability to a very broad spectrum of our breast cancer patients. The abstract was discussed by our colleague Lee Secari who did a masterful job putting this into context. One of my favorite figures from her slides was looking at the series of major trials for early stage ER positive breast cancer over the past 10 years, noting that the early reports of studies including Natalie and Monargue at this early time point showed essentially the same difference. The same has a ratio, the same absolute difference between the curves as is shown in Lidera where instead of adding a CDK46 inhibitor or another targeted therapy, we're just switching endocrine treatment. So I thought that was really provocative. There are many questions about all of this. I mean, of course, we need longer term follow up and see more stability of the data. Much of the narrative around oral serds has been around using these drugs for patients with ESR1 mutations, which are resistance mutations that we don't pick up on until we are in the setting of pre-treated metastatic disease. And the estimated prevalence of ESR1 mutations in a newly diagnosed patient is thought to be quite low. So again, it's wondering how is this working better than endocrine therapy if that mutation is limited. And of course, if this drug gets approved, it's going to be an expensive drug. And how is that going to work in our practices and with insurance coverage and all of that? Indeed, impressive results, but we do need long term data and tying in the financial toxicity. It's all going to come down to that patient shared decision making as well. But given overall survival data in hand from CDK46 inhibitor, they're not going away. They're certainly part of our treatment paradigm. Erica, thank you so much for sharing your thoughts on your current treatment paradigm with regards to early stage hormone receptive positive breast cancer. Rahul, let's go over a quick recap from today's discussion. In today's episode with Dr. Erica Merer, we walk through the treatment algorithm for early and locally advanced hormone receptor positive breast cancer. Rohe, we touched on quite a bit here. Your tea takeaways. Right, Rahul. We talked about in early stage setting utilizing Onkotive DX score. We have a clear understanding in postmenopausal patient where we are using Onkotive DX score 25 and below. There is no added benefit from chemotherapy. However, that tricky population is that premenopausal patient population that is low onkotive DX score and node one disease. Here we are awaiting results from offset trial. I do bring up OFS plus AI versus chemo plus OFS plus AI. But in that right patient, I am considering OFS plus AI. Then we also touched on adjuvant abemocyclet and ribocyclet. A abemocyclet is for two years. While ribocyclet is for three years, three weeks on one week off at dose of 400 milligrams, which is different than what we use 600 milligrams in metastatic space. And also some key side effects with abemocyclet, one has to tackle diarrhea with ribocyclet, QTC prolongation and transseminitis. Rahul, what did I miss? More recently at Asmo 2025 with abemma, we also saw that update of overall survival. So at seven year mark, abemocyclet is showing improved overall survival. The other thing to keep in mind that you brought up side effects when we're decreasing that dose to mitigate some of these side effects, thankfully the data supports that we're not compromising efficacy. So that's important. Talking through locally advanced disease, another adjuvant topic that we have to keep on our radar ends up being parpinabitters. So germline testing for that right patient is important. Here, a laparb is improved, but also, again, overall survival with a laparb we have to monitor for cytopenia's and fatigue. Thank you so much for joining us. Be sure to check out our upcoming episodes on metastatic hormone receptor positive breast cancer, plus our other discussions on algorithms, approvals, and conference highlights. We are the oncology brothers.