Introduction

DR LOVE: Good evening, everyone. I’m Neil Love from Research To Practice, and welcome to “Understanding the Current Paradigm and New Approaches in the Care of Patients with Cancer.” This is the second of our 11-part series here at the ONS Congress. Tonight we’re going to be talking about hormone receptor-positive breast cancer.

We have a great faculty this evening: Ms Jamie Carroll from the Mayo Clinic in Rochester, sitting closest to me here next to me, Mr Ronald Stein from the USC Norris Comprehensive Cancer Center in Los Angeles, Dr Virginia Borges from the nearby University of Colorado Cancer Center in Aurora, and Dr Seth Wander from the Massachusetts General Hospital in Boston.

As in all of these programs, we will be talking about the use of agents that are not approved and regimens that are not approved, so please consult the package inserts for various products for more information.

Please check out our podcast series, Oncology Nursing Update. All you have to do on your phone is go to podcast, hit search, Oncology Nursing Update, and there are a couple of programs there right now, including this one on lymphoma. We’re going to put all 11 of these programs in this podcast series in the next few weeks.

So as you all know, this is the 50^th ONS Congress. We’ve actually been going to ONS for 17 years and always have had the same format. We kind of view what we are doing here as sort of a parallel track to what the ONS meeting is doing. We view this as an integrated experience. This afternoon in our first program, we congratulated ONS in our special way, so we’re going to do it again.

MS SHANNON: Ladies and gentlemen, my name is Sally O’Malley. I’m proud to say I’m 50 years old. I’m not one of those gals who’s afraid to hide her age, unlike some other gals, and I like to kick, stretch and kick. I’m 50, 50 years old, 50 years old, 50, 50.

DR LOVE: I don’t know if I’m a good dad or not, but I sent that to my daughter on her 50^th birthday. I don’t know if I’m a good dad or not.

But anyhow, these are the 11 programs and a variety of topics. But again, we really view this as about oncology nursing in general. In particular, what we’re trying to bring to you is how the clinical research goes into the thinking of the oncologist trying to make a decision about how to treat the patient so you better understand that, can explain it better to patients, and then for a lot of the new therapies to help the patient kind of get through the therapy, including with the toxicity.

This is really an immersion experience. I always loved rounds when I was in training, just to be able to hear people very well-spoken and knowledgeable. We’re bringing 44 people here for you to listen to this week, and it’s really a great experience for all of us.

One of the things we’re going to talk a lot about is this triad that’s so important in oncology, with the oncologist, oncology nurse and the patient and their loved ones and how that goes. Some of the themes that you’ll see this week are, first of all, the idea of personalized oncology, individualizing treatment to the individual patient, taking into account not only tumor factors, and you hear a lot about biomarkers, particularly tonight, but in almost all these programs. When we look inside the tumor, particularly the genetic function and mutations in the tumor, how does that change the way treatment is given. And then also biopsychosocial factors, why is it different to take care of this patient than another patient who’s in the same oncology situation, but it’s a different person, different attitude, social support, et cetera.

We’re going to talk a lot about new agents in oncology. It seems like almost every day another new therapy is approved. It’s very exciting, but also very challenging.

Another theme that you’ll see running through these programs, we’ve always talked about, is what we refer to as the bond that heals, so the idea that beyond any specific antitumor therapy that might be administered to the patient, the relationship that we have with the patient and their family is highly valued by the patients and family and it works both ways. We get a lot out of taking care of patients as well.

So we’re going to get into the issue of hormone receptor-positive breast cancer. We talked a little bit actually about breast cancer this morning when we talked about antibody-drug conjugates. We talked about lung cancer as well. So that kind of gets into, at least in the metastatic situation, the post-hormone therapy. This afternoon we said tonight we’re going to get into the hormone therapy, and it’s going to be a lot to talk about in a couple of hours. This is a deep, deep topic. We’ll start out talking about CDK4/6 inhibitors both in the adjuvant setting as well as metastatic disease. Then we’ll talk about PI3K inhibition and metastatic disease, the use of Akt and PI3 kinase inhibitors, and then finally SERDs, oral selective estrogen receptor down regulators.

Before we get into it, I just want to take a deep breath, Seth, and maybe just go back a little bit and talk about kind of the biology of estrogen receptor and how it works. Seth is kind of my go-to person to try to explain the pathways. So Seth, we’re going to talk a lot about that tonight, but how do you envision what is the estrogen receptor, how is it measured, and why are we trying to target it?

DR WANDER: Yeah, thank you Neil. It’s a pleasure to be with everybody tonight. Thanks for the invitation. And it’s great. These are hugely important topics, and as you mentioned, it seems like every day, every month, we’re getting new drugs, new biomarkers, new opportunities to treat our patients in clinic. Estrogen receptor, the way I think about it is, almost a universal signalling initiator, right? It circulates throughout the body and interacts with a variety of cells and different organs. When we think about it in the cancer, it’s an extracellular signal that comes into the cell, and it turns on regulation of a whole variety of genes that can promote cell survival, cell division, cell growth, cell motility, moving around other areas of the body. And what we’ve learned over the years is not only how important that signal is for the vast majority of breast cancers, about 70%, but also that we have this important synergy with a lot of the other drugs we’re going to look at tonight. We have this 50-year history of targeting estrogen that you and I have talked about before starting with tamoxifen in the 1970s, but now we’re moving forward in these important ways with targeted inhibitors, the cyclin-dependent kinase Akt, PI3K. So we hit estrogen but we’re also hitting some of the other pathways that feed into it and interact with it.

DR LOVE: So Ginger, first of all, I want to thank you. We’re in Miami and I checked the temperature a couple days before ONS, it was 38 degrees here. I got on the plane, I realized I forgot my coat. I was all freaked out but hey, the weather’s great, so awesome. Thanks a lot.

DR BORGES: I organized it just for you Neil.

DR LOVE: Yeah, it’s been a while since I’ve been cold. But anyhow, just picking up a little bit on what Seth was starting to get into. Again, we’re going to get into a lot of these new therapies. Endocrine therapy was kind of stagnant for a while. It seemed like the last frontier of research, and then all of a sudden it completely exploded. We’re going to talk about how some of these new agents work. But in your mind, why is it that the first targeted therapy of cancer, I think, was removal of the ovaries, like more than 100 years ago. Why does removing the ovaries of a woman who’s premenopausal often lead to tumor regression? What’s the mechanism? What’s the mechanism of tamoxifen? You know, we launched our company with a video called Hormonal Therapy for the 1980s. We had these little Pac-Man things that were diagramming how it worked. What’s your vision about how these basic therapies work, like oophorectomy?

DR BORGES: So yeah, surgeons figured out back in the 1800s, when they had no other option, that if they took out the woman’s ovaries the tumors shrunk. And then of course they had to take out the tumor or they would then progress and grow. The reason for that is when estrogen receptor-positive breast cancer first arises, it’s really addicted to the estrogen. It needs it to survive. It is its food source, if you will. In a premenopausal woman, those ovaries are putting out estrogen at a level that, at different times of the month, measures quite high. And so there’s this robust food source floating around in the bloodstream that these cancers can really utilize. And that is why, if you remove the ovaries, you’re taking that estrogen level and dropping it substantially and that is the most targeted therapy that existed back before we even understood drugs. And then when tamoxifen came along, it’s a selective estrogen receptor modulator or a SERM, which is kind of a funny word. But what that means is, depending on what cell in which it encounters the estrogen receptor, it either blocks it and starves that cell of the estrogen or it can actually promote it. And I always like to remind people that tamoxifen was originally studied as an oral contraceptive and it’s actually a fertility drug. And I’m really glad I was not the PI of that study, but it actually can promote fertility when it is hitting the ovaries, but in a breast cancer cell, it does have this opposite effect, where it causes the estrogen receptor to stop functioning, stop being able to signal inside the cell. So now you are starving the cell by basically putting duct tape over its mouth.

DR LOVE: So Ron, in a second we’re going to talk about first adjuvant treatment, the use of hormonal therapy. And there, as we did more and more research, we saw longer and longer therapy. These patients may be on oral therapy, an aromatase inhibitor for 5 years, maybe even 10 years. Any thoughts about sort of the challenge of getting patients through long-term adjuvant endocrine treatment?

MR STEIN: Well, the first thing I point out to patients is the evidence behind the endocrine therapy compared to women who don’t take endocrine therapy, it’s adding somewhere between, we estimate, a 40 and 60, even possibly more greater chance that the disease is not going to recur. So people tend to listen to facts and statistics and the evidence. These drugs have been around for quite some time, tamoxifen since the late 60s, early 70s, and the aromatase inhibitors I believe came out sometime in the 90s. Yes, they can have some untoward side effects, but I try and emphasize that it’s worth it in the end because it’s going to cut down the risk for recurrence, and it’s not the end of the world to get some side effects because possibly we can do something about those side effects and that includes possibly even switching drugs. We definitely have some options. I tell people that those endocrine therapy pills are every bit as important as surgery, radiation, and chemotherapy.

DR LOVE: That’s a great point you made there in terms of the risk of relapse in the adjuvant setting. Hormonal therapy cuts it in half or maybe even more, very profound. We’re trying to cure people in that situation.

Jamie, in the metastatic setting, initially patients a lot of times, even with ER-positive disease, will get chemotherapy if they had very symptomatic disease or extremely ill and people thought that maybe chemotherapy would be more effective or work faster. But more recently we’ve seen that hormonal therapy seems to work just as fast and maybe more effective than chemo in the metastatic setting. Have you seen patients have objective responses to hormonal therapy, tumor shrinkage, feeling better?

MS CARROLL: Absolutely. Patients that have metastatic hormone-positive breast cancer, we know that that’s what’s feeding their tumor. So if we’re able to give them antihormonal therapy and shut that down, that can be more effective than chemotherapy with less toxicity and side effects and better quality of life.

Role of CDK4/6 Inhibitors in Localized and Metastatic Hormone Receptor (HR)-Positive Breast Cancer

DR LOVE: Alright. Let’s get into some of the research. These are 2 clinical scenarios. Really what we’re doing, in all these programs, we’re going to focus on specific clinical scenarios, how the oncologist thinks through what to do and then where the nurse comes in in terms of trying to help the patient understand why they’re getting treatment and to keep them on treatment.

So Ginger in a second, is going to talk about 2 kinds of use of hormonal therapy, 1 in the adjuvant setting, which we were just talking about in an attempt to improve the cure rate, in addition to the classic hormonal therapy, for example, an aromatase inhibitor, to add in another agent, CDK4/6 inhibitor, and then also in the metastatic setting, first-line treatment now. In the past, people got hormonal therapy. Now, almost all patients get hormonal therapy plus a CDK inhibitor.

So Ginger, we want you to kind of go through some of the key clinical research findings that led to how people make decisions.

DR BORGES: So thank you everyone. In 5 minutes, I’m going to invite you into my brain for how we think about the CDK4/6 inhibitors in both early and advanced breast cancer. So a typical day, I do young women’s breast cancer. So a 39-year-old lawyer comes to see me. She is premenopausal. On her exam, she has a 6.5 cm left breast mass. On the imaging it wasn’t quite appreciated to be that big, but the MRI then showed it as well. She also has lymph nodes. On her pathology, it is an invasive ductal carcinoma, Grade 2, ER/PR-positive, HER2-negative. It’s got a pretty high proliferation rate with a Ki-67 of 45 and the lymph node is biopsied and confirmed positive.

She’s healthy. She has two kids. She doesn’t want any more kids, and her husband has already had a vasectomy, so we have all that taken care of. So in her treatment sequence, at this age she obviously gets genetic testing. She is found to have an early-onset breast cancer-causing mutation, an ATM. She gets up front chemotherapy because of the stage of her disease and she’s on a clinical trial for 6 months. She does bilateral mastectomies with delayed reconstruction because of that gene mutation and then she gets her post-mastectomy radiation because her lymph node was positive. And now she’s coming back to see us in clinic to talk about her adjuvant endocrine therapy. She is an optimal candidate for ovarian function suppression and aromatase inhibitor on the basis of a clinical trial done some years ago called the SOFT study, where that was shown to be better than tamoxifen in a clinical scenario like this. And we also know that we’re going to want to ask her to take bone supportive medication with zoledronic acid. The question is, is should she get anything more?

We have had 4 clinical trials done in the adjuvant space with CDK4/6 inhibitors and they are listed there, PALLAS, monarchE, PENELOPE-B, and NATALEE. PALLAS and PENELOPE-B were with palbociclib, large studies, and they did not show an improvement in invasive disease-free survival, so I won’t be showing you those data. What I will be highlighting is the monarchE and the NATALEE. One was with abemaciclib, the other with ribociclib, both large studies, Phase III randomized, and in high-risk patients. In the monarch study, abemaciclib was given for 2 years, and ribociclib in the NATALEE study for 3 years. Monarch was done first, so we have 42 months of follow-up. NATALEE came later, 28 months of follow-up so far.

And so there’re some key differences in who was able to be enrolled on this clinical trial. In the monarch study, everybody had to have positive lymph nodes. And if their tumor was under 5 cm, they had to have another high-risk feature like high-grade or a high Ki-67. NATALEE went down a little bit lower in stage, allowing for some node-negative high-risk patients if the tumor was big enough and also if they had nodes involved, but smaller tumor sizes. When you look at who comes into our clinic, who would be eligible to get on these drugs on the basis of these trial results, monarchE is at 14.5% of our patients, NATALEE a little over 30%.

And so looking at the data, this is the way the study was set up. It was a randomized study, which means flip of the coin decided if a woman got her standard endocrine therapy alone or the abemaciclib in conjunction with the endocrine therapy. And there were 2 cohorts with high risk defined 2 different ways. And then when we look at the results, this is what are called Kaplan-Meier curves. You want to be on the line that’s not going down as fast. Every time the line goes down, that’s a patient, who has had a recurrence. And so as we look over time, the higher line is winning and the higher line here is the arm that included the abemaciclib. What’s super important about these data is I told you abemaciclib was taken for 2 years, but we now have follow-up out to 60 months or 5 years, where we’re still seeing a very significant difference of a 7.6% gain in our patients not facing a recurrence of invasive disease. The importance of that is, after the therapy stops, you don’t want the benefit to disappear because then you were delaying the recurrence but not actually increasing the cure rate. So that’s why we care about our length of time of follow-up.

The NATALEE trial was similarly designed. It was ribociclib with a nonsteroidal anti-inflammatory drug — I’m sorry, an AI, letrozole or anastrozole. And if they were young, they got goserelin versus the AI alone. And otherwise it was pretty similar except for the inclusion criteria I already showed you. And when we look at the results, the length of follow-up is not quite as long. But so far, at the 48-month mark, there is also a 5% benefit improvement, which was the same as what we saw in the monarchE trial at the same length of time. And so on the basis of this, the ribociclib has also been FDA approved in addition to the abemaciclib in this space.

So in summary, both drugs have shown to improve recurrence risk. Neither drug has yet to show overall survival benefit, and that will be the one that really matters to us in the long run.

Switching over to the metastatic setting, this is a 36-year-old mother of two boys, who comes in with a several-month history of not feeling well. She unfortunately is shown to have widespread metastatic disease, including a lot of liver mets, as you see there. The rest of the history is there for you to read. Our treatment consideration is that we got her off of her OCPs, we got her on highly effective contraception, and we instituted ovarian function suppression. And the bottom line is it doesn’t matter which drug or which schedule you use as long as the ovaries are shut down and both drugs work. We got her on her bone medication, and then what are we going to put her on for first-line therapy, endocrine alone, endocrine with something else, or chemo as you heard Neil ask earlier? We have the CDK4/6 inhibitors all available in the metastatic space. They have all shown progression-free survival, palbo, ribo and abema. These are the 9 studies that got us there. There are some differences in which studies showed overall survival, but in general all of these are fair game in the metastatic setting.

Two studies I’m going to highlight are the SONIA trial and the RIGHT Choice trial. The SONIA trial showed if patients had metastatic breast cancer and got an AI alone versus an AI plus the CDK4/6 inhibitor up front, those who were on the AI alone and then they would get the CDK4/6 inhibitor later, the sequencing didn’t matter. So we now feel more comfortable that there are some patients in whom the endocrine therapy alone up front is fine. We can always add the CDK4/6 inhibitor later.

The RIGHT trial was looking at endocrine therapy versus chemo, and here’s those data. So these patients were very high risk. They had liver metastasis. Some of them were in visceral crisis. They were at very high risk of progressing. And what you see in those Kaplan-Meier curves is that the ribociclib and endocrine therapy arm outperformed combination chemotherapy. So this really proved the point that endocrine therapy combination with ribo, even in very high-risk patients with a concern for progression, is the better choice for our patients.

So here we are with sequencing in the modern era. If they have endocrine-sensitive disease, we can give them endocrine therapy alone. If they have higher risk features, we would still want to consider giving them the CDK4/6 inhibitor in addition. And if their disease is endocrine-resistant, meaning they progressed while on their therapy in the adjuvant setting, we would want to add in the CDK4/6 inhibitor right away and give them fulvestrant instead. Take home message, we really shouldn’t be giving chemotherapy to these patients any longer.

DR LOVE: So before we go on, just to bring up an important concept that again goes through oncology in general, which is patient involvement in the treatment decision. You look at some of the curves that Ginger just showed you. You don’t see that much of a difference between the patient who’s getting treatment for a fairly long period of time. And you could say, well, there’s tolerability issues, cost, et cetera. And one thing that you can always do is bring the patient in. If they’re interested and want to get the information, you can bring them into the discussion as well.

I’m curious too, Ginger, that second patient who presented with metastatic disease had 2 minor children I believe. That’s something we’ve talked a lot about in ONS over the years and we could spend a long time talking about it. But I just wanted to note it and just ask, from your point of view, when you looked at the family constellation there, trying to deal all of a sudden not only with breast cancer, with metastatic breast cancer, what are some of the things you think about to try to support the patient?

DR BORGES: Yeah. So in young women’s breast cancer, this is often what we encounter. Our young mothers who get diagnosed have a higher risk of getting metastatic disease if their children are very young, particularly under 5 or even under 10. So these are our most vulnerable patients. And now they’re facing the potential loss of their life and not being there to continue raising their children. So in the modern era, what is the good thing I get to say to my patients is, I can no longer tell them when they are going to potentially pass away of their disease and at the start of my career 25 years ago I could with fairly good reliability of how long we could keep a woman alive. And so with all of these excellent advances that you just saw and the rest that you’re going to see tonight, we can offer a little bit more hope than we used to. Also, obviously, you want to engage a big team. Someone with children have family and support, others don’t. They’re all going to really need it. So the more you all can lean in on these patients and hear what is their bigger fears, because they’re going to tell you when I leave the room more so than they’re ever going to tell me, and we know that. And also find out what are their supports in terms of who’s working, who holds the insurance, what else are they really afraid of. We have to have insurance to be able to treat patients reliably in this country unless they would otherwise qualify for Medicaid. And so there’re so many constellations of factors it is overwhelming for them. I think it’s super helpful to just compartmentalize it, tackle one topic at a time and bring in the whole team so that each person is kind of their go-to for the fear they want to talk about at that day.

DR LOVE: So Jamie, Ron was commenting a little bit on the issue of getting a patient through adjuvant therapy when we talked about hormonal therapy 5 years or more, but now CDK for the higher risk patients, even some node-negative patients with ribociclib. What are some of the challenges, and we’ll get into this in more depth, but in terms of adherence? I mean, again, that’s a theme that’s going to go through all of these programs, particularly if your patients are getting longer-term therapy, often more of a challenge with oral therapy where they have more responsibility. Any thoughts about the challenge of getting people through these regimens with more than 1 hormonal intervention?

MS CARROLL: Yeah. So as these studies get approved, we add drugs. We don’t usually take them away. And so these patients are looking at sometimes 4 different medications that we’re recommending for them. So I don’t throw it all at them at the same time because that’s too much. I tend to layer things and see them back frequently to make sure that they’re tolerating treatment well. I make sure that they’re having patient family members or friends, whoever is their support system, with them at these visits so that they can hear the same message because we know that our patients only hear 10% of what we tell them. And so, if I tell them, you’re going to be on this drug for 10 years and she shuts down, 30 minutes later I’m still talking and she didn’t hear anything I said. So I think it’s really important that we layer things, make sure that they’re tolerating and then add another medication in.

DR LOVE: So another theme that goes throughout oncology, and you see it here, are multiple agents with similar mechanisms of action approved in the same situation where we have to choose. In this case, in terms of CDK4/6 inhibitor, as Ginger was saying, there are 3 different agents approved. They’re not identical. And usually there’s not much data comparing them. So we have to look at each one separately and indirectly compare them, look at their toxicity profile. And Ron’s going to talk about some of the nursing considerations in patients receiving CDK4/6 inhibitors, both in the adjuvant setting where it’s going to be short-term and in the metastatic setting where it’s going to be usually until they have disease progression or too much toxicity. Ron?

MR STEIN: Thank you. So as Dr Borges just pointed out, why would we recommend a CDK4/6 inhibitor in the metastatic setting? Very often in metastatic patients, this is considered first line. We’re not using as much cytotoxic chemotherapy anymore.

I do have a real case for you of a metastatic patient, a 58-year-old female, diagnosed in 2007, did a bilateral mastectomy, adjuvant chemo, 5 years of tamoxifen, and here we are 14 years later and she has spinal metastasis. We went ahead and started her on — she was post-menopausal, started her on letrozole and palbociclib in April of 2021. And here we are 4 years later and she continues to show stable disease on the scans that we obtain generally every 4 to 5 months. She’s doing very well on this drug. What’s nice is that she just retired. Her husband has also recently retired. They want to do traveling. Being on these drugs enables — she’s not chained to an infusion pump. She’s not stuck coming in for infusions Q 2 or 3 weeks. So for her this is definitely and potentially a better quality of life. And what I explain to patients is that, just like Dr Borges said, we’re hitting these cancer cells in 2 ways. We’re starving those cells by preventing the estrogen from allowing them to proliferate and then we’re also using a CDK4/6 inhibitor.

Also I want to point out that these newer drugs, these CDK4/6 inhibitors, have been studied for about almost 10 years. I remember being, in 2015, I worked in New Orleans at one of the original clinical trial sites for, I believe it was palbociclib, and we were all just seeing these results and amazed. We were trying to get everyone on them.

Why would we put this drug out there in the adjuvant setting? I don’t need to go into detail because Dr Borges already discussed that, but in certain situations this offers maybe not an overall survival benefit but a disease-free recurrent survival.

So when we look at our second case in the adjuvant setting, we have a 50-year-old woman, ER/PR-positive HER2-negative cancer. She had a mastectomy. You can see, based on her surgical pathology, she had a huge tumor, quite a few lymph nodes involved. Once she completed — and her Genomic Score came out such that chemotherapy was going to be a better fit for her. So we gave her the chemo. She began the anastrozole and abemaciclib. We ultimately reduced the abemaciclib which is a BID drug. She is going to complete 2 years in December of this year, and she’s doing okay. She’s on a low dose, but low dose is better than nothing at all. Mainly her problem was diarrhea. So anyway, she was also diagnosed with a high-grade endometrial cancer, also ER-positive, 4 months ago, 5 months ago. Thankfully, staging exams were negative for any sort of distant disease. She had her surgery and is now on surveillance. Gyn/Onc felt that the chemo we gave her, as well as the anastrozole given for the breast cancer, may have temporized or actually helped her uterine cancer. And theoretically, had she not received these agents, her uterine cancer would likely have been at a higher stage. And, by the way, her genetic testing revealed 2 variants of uncertain significance, not clinically actionable.

So what I tell patients, because just like Jamie pointed out, this can be very overwhelming. They have finished their surgery, they may have finished chemo, neoadjuvant chemo, or adjuvant, they may have done radiation, and they know they got to do this pill. And here we are about to tell them, okay, we’re going to recommend another pill. So I also take a layered approach. I start them on the endocrine therapy initially, and then perhaps after a month or 2 we can discuss it. But I explain how the drug interrupts the growth of the cancer.

Common side effects we see are pancytopenias, abnormal LFTs, fatigue, nausea, vomiting, skin rash, infections, cough, fetal toxicity. Premenopausal women, even if they’re on ovarian suppression, we still recommend a barrier method of contraception. The less common but potentially dangerous side effects that we have seen, liver toxicity, diarrhea leading to dehydration and electrolyte imbalance with ribociclib. We see QT prolongation on EKG. We can see a neutropenic fever. I’ve had a few people go into sepsis, not a whole lot. Interstitial lung disease is a very dangerous side effect, albeit rare, and for all of them we do see an increased incidence of clot formation, whether or not that be a thrombus or a PE.

So real case number 3, we have a BRCA patient, 52-year-old Asian woman, right breast cancer. It was metastatic at diagnosis. We put her, and this is back in 2020, on palbociclib, letrozole, and leuprolide because at that point in time, 5 years ago, she was premenopausal. She did quite well, almost made it 3 years on this combination. She had some disease progression. We put her on the olaparib for the BRCA, PARP inhibitor as a BRCA patient. She did okay for about 10 months or so then she progressed. We went to another oral therapy, exemestane/everolimus. And finally, due to progression, we switched her to fulvestrant in combination with abemaciclib. We thought, okay, it’s been about, a little over a year and a half or so since she had a CDK4/6 inhibitor. Let’s try her on this before jumping into chemo. And sure enough, after 1 week, long story short, she had severe breathing problems, was admitted to the hospital, no PE, but she had a pneumonitis, interstitial lung disease and she was on prednisone and ended up being in the hospital for 6 days. So she’s no longer on that.

Potential toxicities, what do we tell the patients? We’re going to talk to them about what goes wrong, but I can tell you, we go to the bottom of this slide, communication is everything. Some patients are just inherently stoic. They don’t want to bother you. They’re embarrassed. There has to come a point in time where they need to speak up because some of these can be life-threatening. And some of them want to be almost martyrs and stick this therapy out because they know it’s really going to help them and they don’t care if they get side effects. I’m just going to stick it out. Don’t panic if toxicity develops. We can hold and then actually reduce the dose. It doesn’t mean we’re going to take away the drug altogether.

DR LOVE: So — and you can go through the rest of Ron’s slides on the iPad or in the chat room. There’s some great stuff in there, but I want to be able to get some input from the rest of the faculty. And Seth, one of the issues here, we know CDK4 inhibitors really offer a lot of benefit compared to the risk. But a big issue is which one to use, either in the adjuvant setting and the metastatic setting. In the adjuvant setting, we can consider the fact that ribo can be used in a node-negative patient. The ribo is used for 3 years, whereas abema is 2 years. In the metastatic setting, the survival data looks best with the ribociclib, and a lot of docs will go to that. Others think about palbo in an older patient because maybe it’s better tolerated. How do you choose a CDK4/6 inhibitor, Seth?

DR WANDER: I think it’s a great question, and it’s one of the challenges, but also one of the advantages. We have more tools in our toolkit right now, which makes clinical decision-making a little bit more complex. I think the points you just made, Neil, are precisely the factors that I would often think about.

Looking at the data that Virginia just presented to us, I tend to prefer to use the abema for a patient who meets criteria for both because we have more follow-up. We see those curves separating, and now we have several years where everybody on that trial has been off drug and those curves are not coming back together. We see durable benefit from abema. I think the data for the ribo is encouraging, but we don’t have that duration of follow-up where everybody’s off drug. So for my own practice, I think if somebody meets criteria for both, I tend to use abema. I think the data’s more mature, although I think we do run into these problems with diarrhea that can be challenging, that Ron was just telling us about.

And to your point, for the higher risk node-negative, ribo’s the only game in town at the moment, and we see that that really expands the number of patients that may be eligible. In the metastatic setting, it’s exactly what you mentioned. Overall survival really is the gold standard for all of us. If we have a drug that clearly shows a survival benefit, I think we prefer to try to use it. There may be specific situations like we just heard about a patient who has baseline QT prolongation or a patient who can’t tolerate ribo for another reason. Like you said, maybe an older patient with more frailty, the palbo tends to be, I think, the easiest to tolerate, less diarrhea, less medication interactions, less transaminitis and some of the rare but serious things we just saw. So those tend to be the factors that I’m thinking about.

DR LOVE: Jamie, any thoughts, again, from a nursing point of view and trying to prepare a patient to take a CDK inhibitor, what you’re thinking about when you think of each of these 3 agents? The schedule, actually, is different as well. Can you comment on some of the practical issues, Jamie, in each of these three?

MS CARROLL: Yeah, so I think it’s important to look at the whole patient and understand what other comorbidities they may have, what are on their medication list when we’re looking at these medications for them. If the oncologist is recommending abemaciclib, we know that diarrhea is a very high chance that they’re going to get this. So I make sure that patients have that loperamide prescription and that they actually fill it. There’s a big difference between, oh, the oncologist sent it to a pharmacy, but the pharmacy’s only open Monday through Friday, closes at 5. Now it’s Saturday night at 9:00 and you’ve got diarrhea. Now what are you going to do? So I think I try to stress the potential side effects without scaring them, but I want to make sure that they understand what the potentials are so that they have the medications, the tools in their toolbox at home to help them and assist if they need it.

PI3K Inhibition as First-Line Treatment for HR-Positive, HER2-Negative Metastatic Breast Cancer (mBC)

DR LOVE: So we’re going to go on now and talk about our next topic, it’s about PI3K inhibitions. This is another biomarker that’s seen inside of the tumor and we have agents that specifically look at that.

Here’s a typical situation that may occur. A patient has ER-positive, HER2-negative breast cancer. Today we’re talking about ER-positive, but we’re not talking about HER2-positive, ER-positive. That’s kind of another story. So these are HER2-negative patients. So a patient gets metastatic disease, gets adjuvant endocrine therapy, maybe it’s for a post-menopausal woman, an aromatase inhibitor, and soon after starting it, maybe a couple years afterwards, has metastatic disease. And typically in that situation, you’re going to look for genomic markers in the tumor, often in what’s called a liquid biopsy. So you don’t actually need tissue. You draw blood, and there’re circulating DNA fragments there that can be analyzed. And some of these patients have so-called PIK3 mutations, which Seth is going to talk about. And this patient starts on a therapy that just became approved, really in the past year. So you see the CDK inhibitor, palbo, in this patient, fulvestrant, but now you have another agent, inavolisib that quickly became standard of care in this exact situation. So Seth, let’s talk a little bit about what PI3K inhibitors do and what happens in this situation in first-line therapy in metastatic ER-positive disease.

DR WANDER: Great, thanks. We’re going to take a whirlwind tour through this topic and I’ll talk a little bit about the signalling. We’ll touch upon testing, as Neil just mentioned, with solid tumor biopsy and liquid. I’ll go through some data from 2 trials for PI3 kinase inhibitors, and then we’ll talk about some future directions.

Now, PI3 kinase is a signalling pathway within the cell. These are little molecules inside of the cell that sort of trigger a cascade of events and change, again, some of the processes that we were talking about before. So you have these external signals outside of the cell, different growth factors, they interact with proteins at the cell surface, they turn on this PI3 kinase. The PI3 kinase then hits a number of downstream targets, and these are some terms you might run into as you’re hearing about these drugs or looking at some of the test results. Akt, we’re going to hear about a new drug for Akt shortly. And all of these things, again, feed into some of the core pathways that are critical for cancer growth. Cell survival, division, motility, metastasis, there are multiple roles that all of these genes play downstream. What you’re looking at there is a fancy protein structure of PI3 kinase, and the little red and green dots are some of the areas where the key mutations occur that turn this protein on all the time, regardless of the signals outside of the cell. And that causes this constant signal to grow.

Now, tissue biopsies, which we’ve been using for many years, versus liquid biopsy that Neil was just alluding to, which is really exciting new technology over the last 5 to 10 years, they both have advantages and disadvantages. The tissue biopsy is, of course, more invasive, it’s a procedure. The liquid biopsy is just a blood draw, we can do it at any time. The tissue biopsy has the advantage of giving us the estrogen, the progesterone, the HER2, the PD-1 status, whereas we can’t test that yet on a liquid biopsy that we’re working on developing that technology.

The tumor biopsy, the tissue, gives you limited insight into the whole tumor, because it’s just the 1 spot, whereas the liquid biopsy’s reflecting the whole tumor ecosystem, all those DNA fragments around the whole body. The tissue biopsy, you can go back in time and use the old specimens that we have stored in the basement for 10 or 20 years, whereas the liquid biopsy really is being done in real time moving forward.

The point I would make across the board is, these 2 things tend to be pretty similar. About 80 to 90% of the time, you’ll see the same genes pop up, but 10 to 20% of the time, you’ll pick something up on a tumor biopsy that’ll be missed on the liquid, or slightly more often, you might pick something up on the liquid that’s actually missed on the tissue. So there is not overlap in some cases, and we can talk during the discussion about when we might do both.

So truncal versus acquired, here’s a patient of mine. At the time she was diagnosed, just like in the case, she had a PIK3CA mutation. This is a Guardant report. There are many different companies where you can test this. Each color is a different gene that we’re picking up in the blood. And you can see when she was diagnosed, she had PIK3CA and a couple of others. Then I treated her for several years with antiestrogens. When she progressed, you notice there’s more, right, DNA there. It’s fanned out a little bit broader, so there’s more mutations in the blood, and all those new colors are different genetic alterations that were picked up over time. We put pressure on the tumor with the drugs that we give people, and the tumor finds ways around the drugs by acquiring these new mutations. We see here the ESR1 that we’ll talk about in a few minutes. So the PIK3CA tends to be early, which we call truncal. It’s there from the time the breast cancer starts versus ESR1, which is in the estrogen receptor itself that’s acquired. It happens under pressure on the drugs. And the PIK3CA, as Neil was just alluding to, is pretty common. It’s up to about 40% of patients with ER-positive breast cancer will have this.

So this is the SOLAR-1 study. This is the first study looking at a PI3 kinase inhibitor. You can always tell when the oncologists are giving the talk, because we love to put up these diagrams of who goes into what arm on the study. This was in men or postmenopausal women with ER-positive advanced or metastatic breast cancer. This was done a number of years ago, so not everybody had a CDK4/6 inhibitor. There was a PIK3CA wild type, meaning nonmutant. They didn’t have the mutation cohort. And then there was a PIK3CA-mutant cohort. We didn’t know if this drug was going to work in everybody or just in the PIK3CA mutants. They were randomized to get fulvestrant alone, which at the time was the standard of care, or fulvestrant with this PI3 kinase inhibitor, alpelisib.

And here are the curves. Now, if you look, we got a great lesson about these curves a few minutes ago. If you look on the top in the patients with no PIK3CA mutation, the curves really don’t separate very much. It’s a kind of 1 to 2-month difference, nothing statistically significant. On the bottom, in the patients who have the PIK3CA mutation, you see a nice separation between the curves. In blue, the people who get the PI3K inhibitor do better. And that was about a 6 month benefit almost.

These drugs do have some toxicities. They’re not chemo, but they do cause some problems. Hyperglycemia in these early studies was one of the key, key issues. And you can see here, Grade 3 to 4, really significant numbers of hyperglycemia. GI, nausea, diarrhea, mucositis, rash, these are some of the most important things we run into, and we’ll talk about how we manage that momentarily.

This is the INAVO120 study that we were just learning about. This is in that high-risk group of patients who are actually on endocrine therapy. And while they’re on treatment or shortly thereafter they have progression, they were randomized to fulvestrant plus palbo, or fulvestrant plus palbo plus a newer PI3 kinase inhibitor, inavolisib. And this data just came out last year and you see on the top a really nice separation in progression-free survival, almost a doubling, or more than a doubling of median progression-free survival from 7 to 15 months. And on the bottom, you see also improvement in overall survival with a significant p-value there. So this drug really was a slam dunk, and as you mentioned, rapidly changed standard of care. And I have given this to a few patients. The approval just came a couple of months ago, so I’ve had maybe 3 to 4 patients in my clinic, and we can talk about those patients and sort of real-world experience.

Toxicity here was also a bit lower. We see hyperglycemia, GI, mucositis, but if you look at the rates of Grade 3 to 4 toxicity, it was not quite as bad as what we saw with some of the earlier generation PI3 kinase inhibitors, and we’re moving in that direction across the board now.

And here’s a table that, we’ll hear about the CAPItello-291. That’s the Akt inhibitor, same pathway. And what I highlighted here for you in blue, were the areas that had the lowest rates of toxicity for some of the key issues. So for hyperglycemia, the capivasertib that we’ll hear about in a moment had the lowest rate. For diarrhea, the inavolisib had the lowest rate, for mucositis, the capiva, for rash, the inavo. So we’re fighting between these 2 drugs as to which is probably the most tolerable. The first generation alpelisib, didn’t win in any of these categories, unfortunately.

So the PI3K pathway, very frequently activated in these types of cancer. It’s an early truncal event. You can find it in tissue or liquid. Alpelisib can be used in the second-line setting with fulvestrant, the triplet of inavolisib, palbo, and fulvestrant in the first-line setting, endocrine resistant. We talked about the toxicities. We have really exciting new drugs coming. They’re mutant-specific, much, much lower rates of toxicity, much lower rates of hyperglycemia, and we’re working on combining them with some of the newer antiestrogens that we’re going to talk about momentarily.

DR LOVE: So I’m just going to bring up a quick point before we get into more depth about this. You showed this slide before, and this kind of relates to everything we’re talking about this week, trying to look at clinical research studies. And what I want to point out to you in this study here, the top line there on the left are people who got the inavolisib added to the endocrine therapy. The line underneath it are people who didn’t. I want to point out 1 number there, it says HR 0.43. That’s called the hazard rate. You always see that when you see these kinds of curves. And sometimes it’s hard to figure out how effective something is by how it looks. But if you look at that number, what that is is, if you take that number, 0.43, and subtract from 100, that’s 57. That means at any given point in time, a patient who got this treatment is 57% more likely to be not progressing. So more than half of the patients are doing better. And you see down on the right, the hazard rate for survival is 0.64, which means at any given point, regardless of how the thing looks, is 36% more likely to be alive than patients who don’t get the treatment.

Also another thing that you see in oncology all the time is that we talk about ONS being 50 years old. Well, the big breast cancer meeting’s every December, the San Antonio Breast Cancer Symposium. We always go to that. We do meetings. And at San Antonio, the year before, I always see, is when a trial’s positive, the first thing that happens is there’s a press release, because the company who makes the drug is obligated to let the public know, hey, there’s a positive trial. You know, maybe it’s going to be approved. It puts everybody on alert. Well, this press release just came out the day before San Antonio was going to happen and we were working with these docs, and somehow they managed to get the thing presented by Friday of that week, and then it accelerated the whole movement by quite a few months. So it was kind of a fun situation.

I guess the other thing I was just kind of curious about, Jamie, and we’re going to ask you to talk about this in a second, a big issue not only with PIK3 inhibitors such as alpelisib and inavolisib, but as Seth was saying, also capivasertib, is glucose control. And it’s interesting now in prostate cancer, capivasertib has a positive trial. And maybe you’re going to see it being used in men with prostate cancer. And urologists have no experience with this and all the issues that come up. I know you’re going to get into that in a second, but just sort of overview of how sort of glucose control and management of diabetics ties into using these drugs.

MS CARROLL: Yeah, so patients that went on any 1 of those 3 studies had to have hemoglobin A1c less than 6, 6.4. One study was less than 8. So they could not be patients that had type 2 diabetes to go on any of these studies. So I think anytime you have a patient that does have type 2 diabetes and is already on some sort of agent like metformin, you really need to be careful and consider whether these drugs are the right ones for these patients. But I think we’ve learned a lot since SOLAR-1 with alpelisib in putting patients on, and now we’re giving glucose monitors to all of our patients when we’re prescribing therapies, because we know the hyperglycemia can happen within the first 7 days. So 7 days to median onset of hyperglycemia. So you have to really have a close watch on your patients. You can’t just prescribe a drug and say I’ll see you in a month, because they’re going to be in DKA before you know it. So it’s really close monitoring of our patients.

DR LOVE: So Ron, anything you want to add to that? You know, picking up on what Seth said that, with time, it seems like we’re finding agents in the same class that maybe aren’t as toxic. Alpelisib was very difficult to give to patients. Now we have inavolisib, seems a lot more tolerable. Any thoughts about that?

MR STEIN: I agree with Jamie in that we need to be very, very diligent in who we give the drug to. As Dr Wander pointed out, the capivasertib didn’t have as much hyperglycemia associated with it. I haven’t encountered too many problems with that one, but I’m very, very quick to making a referral to endocrinology if necessary. You’ve really got to watch certain people. You’ve got to watch not only based on the drugs that they’re on or if they have a personal history of diabetes, but you also want to look at ethnicity, because certain ethnicities are more prone to diabetes. In Los Angeles, where I’m from, we have a huge Hispanic population, and many of them are very prone to it. The other thing we look at is body habitus, BMI. We know that a higher BMI is associated with greater insulin resistance, right? So it’s a double-edged sword. These drugs are great when they work, they prolong life, but we also, like Jamie said, we don’t want anyone going into DKA and losing her life over that.

DR LOVE: And so we kind of joke around now, with all these new agents you see, now you’re seeing a lot of tolerability issues we never saw before. We’ve been joking that we’re going to do a diabetology 101 course, because after you’re in oncology for a while, you don’t hear about all the things that are going on.

Tomorrow night we’re going talk about chronic lymphocytic leukemia. We talk about doing cardiology 101, because there the Bruton tyrosine kinase inhibitors cause arrhythmias and other cardiac problems. We’re actually about to do a program on ophthalmic issues in oncology. We’re talking about ADCs this morning. You see problems in the eyes. So you really have a lot of general medical issues to deal with in oncology.

So Jamie, let’s talk a little bit about a patient who’s going to get triple endocrine treatment.

MS CARROLL: Alright, so this is a 65-year-old woman who presented with a screen detected abnormality in her breast. So diagnostic workup ensued with the mammogram, ultrasound, MRI, moved on to biopsy. She had an invasive ductal cancer. It was Grade 2, ER/PR-positive, and HER2 is 1+. She went and received 6 months of neoadjuvant endocrine therapy, proceeded to bilateral mastectomy. So pathology revealed a 2 cm tumor, Grade 2, and then the tumor cellularity was 30%. So it was a T1cN0 cancer.

So we talk about our medications and how they cause a lot of side effects. This woman really struggled with the arthralgias and myalgias with aromatase inhibitors. So you can see over the 5-year course, she received all 3, anastrozole, letrozole, and exemestane, and struggled with side effects on both of them, but she was determined. Jamie, you told me this medication was going to help, so I’m going to keep taking it.

But unfortunately, just in March, she presented to her local Urgent Center with flank pain. She thought she had a urinary tract infection and, unfortunately, they did a CT scan, which showed bony lesions most prominent in L1 and L2. So the Urgent Care provider called me and said I’m not sure what to do and I said, I got it. So I saw her back in clinic, explained what we need to do, next steps. Obviously, they only did a CT of her abdomen and pelvis, so I needed to complete her workup. And then additionally, I needed to get a biopsy. So the biopsy was positive for malignancy, consistent with breast primary, and her receptors were similar from her prior cancer, but this time, the HER2 was 2+, but was FISH negative.

So then I got Tempus testing on this patient. This is her actual report. And so you can see at the top here that she has a PIK3CA mutation. So then I started her on inavolisib, fulvestrant and palbociclib. So you can see here that each one of these medications is taken with a different schedule. So inavolisib is a 9 mg tablet taken daily, days 1 through 28, whereas palbociclib, the starting dose is 125 mg, and it’s taken days 1 through 21 and then you have 7 days off to complete your 28-day cycle. And then fulvestrant is given 500 mg, days 1 and 15, so you get a loading dose the first cycle, and then every 28 days after that.

So as we’ve talked about before, the safety data from the INAVO120 study, but what I highlighted here is this patient’s specific side effects that she has, so that’s the arrows here. So she developed neutropenia, and we know that both inavolisib and palbociclib cause neutropenia. So then you say, well, what drug’s causing it? She had stomatitis, she had hyperglycemia, diarrhea, and nausea.

And so my next slide here is what we did. So with the neutropenia, we held until she recovered and then we dose reduced her palbociclib to 100 mg. That was my first pick and I was right. Her neutropenia did not resolve, but it improved with the dose reduction of the palbociclib. For stomatitis, we like to use dexamethasone mouth rinses, so it’s 0.5 mg/mL, it’s a small dose, but they need to do it 4 times a day, and it’s really to prevent stomatitis. Four times a day is really challenging for a patient especially if they’re working, but I really try to encourage them to do that prophylactically and then if they don’t develop mouth sores, then they could decrease the frequency of the dose. But I would rather prevent than try to catch up if they get mouth sores.

And then she developed hyperglycemia, so we provided a glucose monitor up front, but then we ended up having to put her on metformin. Diarrhea, so I think everyone knows loperamide 2 mg dose, but I think a lot of patients are afraid to take loperamide and they’re afraid to maximize the dosing. So I think it’s really important that we have these conversations with our patients and talk through, okay, so you’re calling in, you’re saying you have diarrhea, tell me what you’re doing for it. Tell me what dose you’re taking of loperamide, because I think a lot of patients worry that they’re going to flip themselves into constipation, so then they struggle with the diarrhea. So I think it’s important. And for every patient, I don’t have a standard what I do, I kind of go based on how much diarrhea they’re having. For some patients, I say, take 1 capsule in the morning, and then 1 after each stool. If they’re having a lot of stools, sometimes I say, take 2 in the morning and 1 after each stool. I really encourage them to get tablets versus capsules, because for patients that are really worried about constipation they can break them in half, whereas a capsule you can’t. So it helps me titrate a little bit more nimbly if it’s a tablet. And then, with nausea, we prescribe ondansetron 8 mg, prochlorperazine 25, and then I’ve been using a lot more olanzapine recently, which helps with that nighttime nausea for patients on top of the ondansetron and the prochlorperazine.

DR LOVE: So just a couple of points. One, another sort of theme that you’ll see throughout oncology is, these new regimens, new drugs that we’re talking about, are used in very specific situations. So this triplet was not used in every patient with PIK3 mutation metastatic disease. They pick patients who are “endocrine-resistant”. So they’d gotten endocrine therapy, usually adjuvant treatment, and either they developed recurrence while they were on the endocrine therapy, for example on AI, which obviously is resistant, but also within a year of having finished it. For a patient who presents with metastatic breast cancer, PIK3, they weren’t in the trial. And generally oncologists just use these new regimens, at least in the beginning, just in patients that would’ve gone into the trial. So we don’t know, it might work in some of these other patients but we’re not going to be able to use it until it’s actually studied.

One other thing I want to just bring up in general, and again I think it’s a theme, big theme in breast cancer, but many other cancers Jamie, is the issue of patients who go through adjuvant therapy but end up having metastatic disease anyhow. This lady really struggled. She tried 3 different agents. She really did her best and went through a lot in the adjuvant setting. I can imagine that the day she was diagnosed with mets that you describe … it must be very difficult, as it is for all people in that situation. Any comments on how you support a patient who’s been through adjuvant therapy and now is dealing with metastatic disease?

MS CARROLL: Yeah, it’s really tough, because you have patients that did everything you asked them to do and then they still get metastatic breast cancer.

For this particular patient, she is the primary caregiver of a young grandson. And so stopping aromatase inhibitors and switching her to fulvestrant as the endocrine therapy backbone made the arthralgias better. So she was able to get on the floor and play with her grandson. We did not want her to get metastatic disease, but she was tolerating the endocrine therapy better now that the arthralgias went away.

Clinical Utility of AKT and PI3K Inhibitors in Progressive HR-Positive mBC

DR LOVE: Alright, so we’re going to move on and talk about another new therapy, capivasertib. And I was mentioning, it’s really interesting. We’re going in a couple weeks to the annual urology meeting and we’re going to be talking about this, because this may become — we’re going to talk about prostate cancer tomorrow. We’ll mention it tomorrow. Nobody knows. This is one of these situations where there’s a press release saying the trial’s positive in prostate cancer. We haven’t seen the data yet. It’ll probably be presented in the next couple of months. And it’s going to be really interesting, Ginger, too, because there they gave it not alone, but they’re giving it with abiraterone and a corticosteroid that you use. So the diabetic issue, we’re really curious to see how that’s going to play out. We have enough trouble as it is without having steroids onboard. But these men got a little steroids. We’ll see how that works out.

But let’s talk about the use of capivasertib in patients with breast cancer.

DR BORGES: Thank you, Neil, and yeah, I hope they have their endocrinologist on speed dial.

So back to me, in the inside of my brain, going a little bit further down the treatment pathway than where we were before. You’ve heard it alluded to by everyone on the panel tonight, about what we had and when. And so you can see, tamoxifen was eons ago. The aromatase inhibitors came out in the ’90s, all 3 in a blush. And fulvestrant was the only SERD that we had for an incredibly long time. And as you guys know better than we do, 2 very large shots in the you know what once a month. So there was a big push to try and find a better option. Then we started being able to understand these other targets and we had the mTOR inhibitor everolimus, the CDK4/6 inhibitors we’ve talked about and the PI3 kinase, Akt, PTEN pathways all coming about sort of in the same time, plus the second SERD, a pill, elacestrant you’ll hear in a moment.

Stay tuned, because if that has seemed overwhelming, what is about to hit, and who will get that next key line there is going to be an explosion based on all the clinical trials ongoing.

So our case now, is a 35-year-old with initially a locally advanced breast cancer, HR-positive HER2-negative. Got the usual up-front chemo and whatnot for that disease. And then, unfortunately in 2001, comes back to us with metastatic disease, same markers, pretty extensive. We immediately sent that tumor off for the genomic testing and found that there was a PI3 kinase mutation. She was estrogen receptor mutation wild type, BRCA wild type, and ERBB2 wild type. So those were not things we were going to be able to use to target. She was asymptomatic so she got back on her OFS, her AI, her ribo, and her zoledronic acid. She opted to take her ovaries out, 2022 all’s good, 2024 new PET scan, we’ve got progression. What are we going to do now? Well, we did send off one of those liquid assays that Seth walked you through, because the ESR1 mutation develops in the face of treatment. So we wanted to figure out if she had that or not. She didn’t. So now we’re thinking about what to do after a CDK4/6 inhibitor in the second line space.

And so you heard about the PI3 kinase mutation. And if you take a look at all the subtypes of breast cancer, which is the graph down there, it shows you how frequently we see it. And so in hormone receptor-positive, HER2-negative breast cancer it is just below the 40^th percentile. When you look at the types of mutations that make up that, it is mostly PI3 kinase mutations. A smaller number will be the Akt, and a smaller number will be in the PTEN. But we can use them now all to our advantage.

The signalling cascade pathways are super important, because you can think of it as a string of dominos. And the cancer is constantly trying to develop a way to out-sneak the drugs. So depending on where you hit it in these cascade pathways, these other pathways can come in and take over how it’s allowing the cell to survive and that’s why patients progress and that’s why they get resistance. So it’s super important we have a multiple number of options even though it’s the same pathway.

And so the CAPItello clinical trial, which has resulted and got the drug capivasertib approved, was a similar design to what you’ve seen with all the others. These were patients with hormone receptor-positive MBC. They had to have recurred or progressed either on or within less than 12 months for the end of their adjuvant AI or progression on an AI in the advanced setting. So this would be considered aromatase inhibitor-resistant, or endocrine-resistant. They couldn’t have been too heavily pretreated and at least half of them had to have previously seen a CDK4/6 inhibitor. Again with capi, a little bit more liberality with the hemoglobin A1c, had to be less than 8%. And so randomized fulvestrant with or without a pill, half of which got capi, half of which got a placebo. And when we look at the results, again it’s very important we see that separation in the curve. And I’m only showing you the results of those patients on the trial who did have the mutation in the Akt pathway, one of those ones I just showed you. The overall study does not look this good, and this is where the drug is currently approved. And you want to see that separation in the curve for the progression-free survival, so we know we are really giving our patients benefit, it’s 4 months. We don’t yet have survival outcomes yet. It’s a relatively immature trial in terms of its follow-up and it takes time for overall survival to potentially become significant. So there’s no stats for that B chart you’re seeing, but there’s a signal that those curves are starting to separate, and we are excited about that and look forward to updates in the data.

In terms of the efficacy of the 3 drugs, everolimus, alpelisib, capivasertib, because now we’re in the second-line space. So Inova was for up front. We can’t really compare across trials. So we can’t really say which one would be better than the other if we knew head-to-head. We do know that capi is the only one so far with Phase III data in patients, many of whom had a prior CDK4/6 inhibitor. They look about the same when you look across the studies. The response rates are a little bit higher for the ones that are hitting the Akt PI3 kinase pathway, than everolimus, which hits the mTOR.

In terms of the side effect profile, there are differences, and this little schematic shows you. In terms of the stomatitis, much higher with the everolimus. Nausea is fairly equal, a little bit worth with the alpelisib. Diarrhea, we’ve already talked about. Rash, we’ve already talked about. Capi is favored in those. Everolimus is also less. And the hyperglycemia, you’ve heard about some significant differences there.

So now, this is how complicated our second-line therapy decision-making is. If they’ve only had a single agent endocrine therapy, we can now give them the CDK4/6 inhibitor. If they had the CDK4/6 inhibitor plus the AI, we want to figure out do they have one of these mutations? If the answer is yes, we have the data for the alpelisib or the capivasertib with fulvestrant. I think you’ll see more capi being used because of the favored side effect profile. Also it allows expansion of the different mutations. If they don’t have one of those mutations, then we have the data to give them abemaciclib/fulvestrant, which you’ll hear about, and also our old choice of everolimus and endocrine therapy. Now on to another case. Oh no, back to the same case. This patient does get started on the fulvestrant and the capi and so far has an enduring benefit, has a little bit almost a year later.

DR LOVE: So very interesting. Also when you think about it, I guess this patient was diagnosed with metastatic PIK3-positive disease in 2022, before the Inova data came out. She might have been a candidate for that. It just shows you how fast things are changing in oncology in breast cancer.

Quick question, just as a follow-up, Ginger. You mentioned the hemoglobin A1c limits in the trial and the use of these agents. I’ve heard people talk about using GLP drugs like semaglutide to bring down the hemoglobin A1c so the patients might be eligible for this therapy. Do you ever do that?

DR BORGES: I have had patients with type 2 diabetes who are extremely well controlled. They are exercising. They are watching their diet. They are on their medication, which might be one of those, might be metformin, might be any of the other of variety of diabetic control medications, and they have this mutation. I have an amazing team who supports me, my nurses, my APPs and my PharmDs, so I can be a little brave and we will follow this patient very closely. So I have used it in that case. I have not tried to alter somebody’s uncontrolled diabetes into the controlled range and then take that risk, though if it was a bad enough cancer situation I might.

DR LOVE: So we’re going to go on in a second, and Ron’s going to go through nursing consideration, but just coming back to you Seth, 1 thing that’s interesting about capi is there’s a different schedule. A patient can take it for 4 days then they’re off for 3 days. I’m curious why that was done and whether you see people, when they’re off therapy, feeling different, different glucose control, et cetera.

DR WANDER: Yeah. It’s a great question. I’m not totally sure what the derivation, whether it was a preclinical or sort of early phase data, but certainly in our experience, having given a lot of this drug now, I think patients like it. And you saw from that table, when you line them up together, capi’s winning the battle with many of these toxicities. Part of it, to your point, we’re getting better drugs, we’re developing better drugs with a wider therapeutic index between effectiveness for the tumor and reducing toxicity, and I think part of it may be dosing. Part of it may be that we, as a community, know what to look for. It sort of reminds me of — I know you talked about the ADCs this morning, but when trastuzumab deruxtecan came out in the Phase II we had a lot of pneumonitis and some deaths with that. And then as it moved into Phase III and into practice, we don’t see nearly as much high-grade pneumonitis or fatal pneumonitis because we know to look for it, we catch it. It’s the same, I think, with hyperglycemia and with the GI toxicity. I think the intermittent dosing is interesting too. From the tumor biology we haven’t fully figured out what that does. Is that a good thing or a bad thing, by sort of putting the brakes on and off. It’s similar to what we do with palbo and ribo. That’s due to the cytopenia. We can’t just give it continuously 4 weeks across. And I think here we’re minimizing the hyperglycemia and the GI toxicity, but there’s more for us to learn about what’s happening to the genetic makeup of that tumor with the on/off, on/off, on/off, if anything.

DR LOVE: Interesting too to kind of survey breast cancer investigators in terms of what their practices are. We have these practice guidelines out there that people look at. That’s often based on evidence. What we do as a group, and we actually had a poster at the San Antonio meeting, where we just talk to 20 people, like our faculty here, and said what do you usually use in a patient who has a PIK3 mutation in a situation we’re describing. And when capi came out, we saw people switch from alpelisib. Like everybody switched. And it wasn’t because it was better necessarily efficacy-wise. It was much better tolerated. And the investigators saw this. They started doing it, and the docs in practice in the community did it as well.

So Ron, can you talk a little bit about some of the things you think about when a patient is about to begin capivasertib?

MR STEIN: Sure, thank you. Again, why are we recommending it, because these patients, they’re metastatic, they’re ER-positive, HER2-negative. They’ve had multiple therapies in the metastatic setting. And as Dr Borges and Dr Wander have already delineated, progression-free survival benefit is there when compared to fulvestrant therapy alone.

So briefly, we have a case of a 67-year-old Asian female, originally diagnosed in 2018. She went through all the surgeries, adjuvant chemo, radiation, AI. Three years later she presented with a spinal cord compression. Long story short, she has seen a lot of therapies since her metastatic disease developed, including the abemaciclib with fulvestrant. She couldn’t tolerate it very well. She also received sacituzumab. She received trastuzumab deruxtecan, did the everolimus, progressed, was on weekly paclitaxel and doing very well, but just couldn’t handle neuropathy. And so we’re kind of on, I don’t want to say a last-ditch effort because there’s many cytotoxic chemos we haven’t had, but we went ahead and ran a liquid biopsy on her and it showed pathogenic variants, PIK3CA and PTEN. We started her on capi with the fulvestrant in late January. Again, we explained to her that it’s hitting the cancer in 2 ways. We explained how it works, why we got the liquid biopsy, that she happens to have one of these mutations, which is a good thing because it makes her eligible to receive this drug. We went through all the different side effects and, again, communication is everything. Once again, we said please call us if you have any problems. It’s given twice a day with or without food. You take it 4 days in a row then 3 days off. They have special nuances if someone vomits the drug or if it’s missed in greater than 4 hours you skip that dose.

The common side effects, which we’ve discussed already, hyperglycemia, skin rash, diarrhea, stomatitis, leukopenia, fetal toxicity. Occasionally you’ll see hypocalcemia and hypokalemia. It can cause some fatigue. When I’m seeing this patient, I go beyond the package insert, especially during those first 2 months of therapy. I am taking a very, very, very close look at the patient especially in terms of cutaneous skin reactions, diarrhea and of course hyperglycemia, asking hey, are you having any of these symptoms of hyperglycemia, the diabetes symptoms, excessive thirst, urination, confusion? Hemoglobin A1c prior to initiating therapy is incredibly important.

In this case, she began taking it in January. She did okay for the first week. No complaints at all. She came back into clinic with a severe rash generalized to her entire body but especially prevalent on the upper extremities, anterior/posterior torso, labial vaginal area. My attending and I determined this to be a Grade 2 to 3. Again, this is a very stoic patient. She was walking around suffering from this tense itching for days and didn’t want to tell us. How we managed it — she tried taking 25 of diphenhydramine, obtained very little relief, she wasn’t anaphylactic, so we ended up giving — we stopped the drug for a couple of days, giving the diphenhydramine, famotidine and put her on triamcinolone cream. And finally we ended up contacting the pharma MSL who recommended starting cetirizine 10. Normally you take that just once a day. They said take it twice a day. I was like a little bit nervous about it because we’re going to dry somebody out with this antihistamine. But I looked it up on UpToDate. It’s perfectly okay to do. And so literally her rash resolved within 2 days, brought it down ultimately to a Grade 0 and we started her up at the original dose and she’s taking cetirizine 10 mg once a day.

We also had, this lady, after the skin problems, she developed severe diarrhea. She’s tiny. BMI is 18 and here she is losing 5 pounds in 2 weeks. Again, she didn’t tell us. And so we have to really, really emphasize the importance of good communication with our patients, that it’s okay to call. She was eating a couple large meals a day. She was taking loperamide 1 pill, 1 in the daytime, 1 in the evening. Obviously, as Jamie mentioned before, it’s not going to cut it. This lady was afraid of getting constipated. So we had a really long talk, did a lot of nursing education about that, gave her some IV fluids and electrolyte replacement. She is being more liberal in her use of loperamide and is doing much better.

We’ve got to watch for hyperglycemia. This was not a problem with this lady at all but don’t take it lightly. There’ve been case reports of diabetic ketoacidosis. And as Dr Borges pointed out, if someone is a well-controlled diabetic, to me that is not an absolute contraindication if this drug can be of potential benefit to them. This lady is doing very well. Her tumor markers have been coming down and she is having restaging scans next week.

DR LOVE: So another kind of theme I want to mention here, Jamie, and this goes throughout oncology but I think particularly important in breast cancer, and I think you see it in some of these cases, in patients who are having toxicity issues, is the question of dose reduction. And this is something a lot of times you bring up to a patient and they don’t like the idea of having a dose reduction. And we need to point out to them, when we look at this, many times patients who have their doses reduced seem to do just as well. How do you deal with patients who are having tolerability issues, you mentioned your patient earlier, particularly in terms of the issue of dose reduction?

MS CARROLL: Yeah. So I talk to my patients about safety. Number 1, we have to do this in a safe manner. And then, if you’re having side effects, I would much rather dose reduce and keep you on a therapy if it’s working, than have to stop the drug because of side effects, and either you can’t restart it or you’re off more than you’re on. So usually when I try to explain it that way, that we would rather have you at a dose reduction rather than off or go to the next thing, in terms of lines of therapy, then they come around to the idea of a dose reduction. Sometimes I will say, how about if we dose reduce and see how you feel, and then we can have conversations down the road about increasing, knowing that that likely will not happen, that they will feel much better on the dose reduction and be happier.

DR LOVE: Ginger, anything you want to add to that? How do you think through patients who are struggling on a therapy? As Jamie says, you have the alternative potential. You go to the next line of therapy but you kind of don’t want to do that prematurely. What about dose reduction?

DR BORGES: Well, I like humor in my interaction with patients because cancer is grim but sometimes we can have some levity. I tell them how imperfect the drug development system is for how we got to that starting dose in the first place in a few short sentences. And I remind my patients, we are all individuals and not 2 of us will tolerate the same thing the same way. And these drugs are not based on height nor weight. They are a scripted dose, and we all have these biologic pathways and some of us metabolize it faster, some of us slower. Some of us will have no side effects. Some of us will have every side effect known to man. I reassure my patients that I don’t tolerate a thing, and I am allergic to paper tape, so I get it. But it is very important that we give these targeted therapies the best chance because they are the smartest drugs that we have. They are the most effective. They are giving us these very significant progression-free survivals, which we haven’t shown you guys any of the really old data where we felt great if we saw like a 6-week difference, and that’s what got some of our older drugs approved, and the chemos. Chemos are terrible for hormone receptor-positive breast cancer. And so we really want to lean in on that which we know best.

Other point, there’s a lot of discussion in the patient community about being warriors. There is war language in the treatment of breast cancer. I’m not fond of it. I remind them that their needing a dose reduction is not a failure of anything on their part. They don’t get to control the enzymes they inherited from their parents of how they metabolize drugs, so just relax into what we need to do.

DR LOVE: So Ron, any thoughts? Do you find that there’re patients who actually are reluctant to even tell you about toxicities because they’re afraid they’re going to be taken off the drug?

MR STEIN: Yeah, unfortunately. I don’t see that a whole lot, but I chose this case in particular because it was that way with the loperamide and not notifying us about the rash. This particular patient is such a fighter and is so afraid of being taken off. I also like to show, not that I’m showing the patient the package insert, but I explain there’s a science behind this, I’m not making these dose reductions up. We need to take a look at the grade of toxicity they’re experiencing and let’s revisit this. And we can potentially add back. In this particular case, with the cutaneous reaction, skin reaction, we were able to restart it at the original dose because within a week she went down to a Grade 0 and she was just thrilled.

Current and Future Role of Oral Selective Estrogen Receptor Degraders in HR-Positive mBC

DR LOVE: So we’re going to finish out talking about oral selective receptor degraders. My team got a big laugh earlier when I said estrogen receptor downregulators. I have some problem in my brain that I can’t seem to remember the word degraders for some reason. But anyhow, they are degraders, and we’ll get into how they work and when they’re used.

And we’re going to look at a situation of a patient with ER-positive, we should say HER2-negative breast cancer, who has disease progression on first line treatment for metastatic disease, which is we said, almost every patient means they’re going to have had a CDK4/6 inhibitor and now they’re getting second line therapy. Usually we try to keep endocrine therapy going as long as possible before moving into antibody-drug conjugates like we were talking about this morning, or actual chemotherapy, trying to preserve quality of life. And one of the things we always do in this situation is to do a liquid biopsy, regardless of what the original breast cancer biopsy is, because a liquid biopsy, which can be very helpful, is done and you see what’s going on. Sometimes mutations show up. And this particular mutation, you don’t generally see it at the beginning of hormonal therapy in metastatic disease. But once they become resistant to it, some of these patients have a new mutation in the estrogen receptor and that’s where these estrogen receptor down regulators — down degraders. Can’t do it. I need to get a big sign here. But anyhow, that’s the situation where these agents are used, really similar to fulvestrant, which has been out there forever, but this is oral as opposed to IM, and allows you to increase the dose and looks like it’s maybe more effective. So Seth, let’s talk about SERDs.

DR WANDER: Great, thanks. And you know, Neil, I would do an hour with you on this. We’re going to do a whirlwind tour of a very intense topic here that’s very active for our research right now. We’ll talk a little bit about ESR1 mutations, what they are, how we test for them. I’ll show you data from 2 of the key trials. There are many of these drugs in development, the EMERALD and the EMBER-3 trial, and then I’ll end with some future directions and a press release that’s relevant for the next couple of months.

So ESR1, as we’ve been talking a little bit about and Neil was just alluding to, if you look at the primary tumor, or a tumor that was just recently diagnosed metastatic disease, very often will be negative. They’re very rare mutations in untreated tumors, less than 5%. But as the patients get treated with particularly the aromatase inhibitors, like anastrozole and letrozole, again the tumor under pressure from those drugs develops these mutations. And this is a picture of the gene on the bottom, the ESR1 gene. This is the gene that makes the estrogen receptor. All those little dots with the black nomenclature there at the bottom, that’s the area where the mutations cluster. They all cluster in the same spot. And what they do is they turn the estrogen receptor on without estrogen. So if you use a drug like letrozole that drops the estrogen level, it doesn’t matter because the receptor’s able to just turn on and constitutively activate itself. So it’s a really sort of devious and clever way around these drugs that we’ve developed. And I tell patients we developed tamoxifen in the 70s, we developed the aromatase inhibitors in the 90s, we’re due. It’s been about 20 to 30 years for a new class of antiestrogens, and they are here. They are very much here.

And I showed you this patient before. She had the PIK3CA mutation. She did really well for a couple of years on anti-estrogen therapy. When we retested her blood she had all of these new mutations, including the ESR1 in green there, that popped up under pressure. And if you test these patients more and more, second line, third line, fourth line, as you might expect, you see increasing rates of ESR1, upwards of 40-ish percent, 25, 35, 45%. So they become more and more common as we use more and more antiestrogen and targeted therapies in this patient population.

Now I’m just going to show this. Again, we could spend 15 minutes going through this. This is a really nice paper, and I think you guys have this in your handout. This is a schema of all the different anti-estrogen drugs that have been around for the last 50 years, and all of the ones that we are developing right now, and it’s a little diagram of how they work. On the far left there you see the aromatase inhibitors. They drop the amount of estrogen. Then we see the SERM, tamoxifen. We heard about that earlier. That interacts at the receptor. It sort of blocks the receptor.

Then in the middle you see the SERDs and these newer drugs called PROTACs. They actually degrade the estrogen. So they put a tag on it and tell the cell to chew it up and get rid of it. So it’s almost like targeting for taking it out with the trash almost. And then you have the CERANS and the SERCAs. These are newer versions of drugs that bind to the estrogen receptor and turn it off. So we have all these ways to turn off estrogen. We can get rid of estrogen itself. We can bind to and block the receptor. We can tag the receptor and chew it up and get rid of it. And we’re going to focus on that mechanism, the SERD, the selective estrogen receptor degrader here.

So this is the EMERALD trial. This is a Phase III trial, was published a few years ago. Now these patients were pretty heavily pretreated. They were allowed to have had prior chemo, they had 1 to 2 prior lines of endocrine therapy, 100% of them had a CDK4/6 inhibitor. And they were treated with either endocrine therapy of clinician choice. Most clinicians chose fulvestrant or this new version of an oral selective estrogen receptor degrader, elacestrant. And we were talking about how much of a pain it is for patients literally to get these fulvestrant shots every month. This is an oral formulation. It took them more than a decade to develop this. And here are the curves. You see there is a steep drop off. It's a theme for all of these trials. There’s a steep drop off in both arms telling you, this population of patients, they’re really not sensitive to estrogen blockade. We’re developing strategies to use the genetics to figure out who those people are so we’re not sort of wasting time and toxicity putting them on drugs that aren’t going to work. We’re developing new strategies for those people. But you can see, once those people progress, the curves split. And if you look on the right-hand side, the ones with the ESR1 mutation, the curve splits even further. That blue line moves up a little bit better, meaning, as we talked about before, the patients are doing better. As Neil taught us, the hazard ratio is dropping even further in that ESR1 mutant group.

And then here, they did an interesting analysis where they said, okay, let’s look at the ESR1 mutants and let’s say, how long were you on the CDK inhibitor? Did you do 6 months, 12 months, 18 months? And as you looked at patients who had a longer time on the first treatment, they did better on this treatment, on the second treatment. It makes sense. The patients who did longer on the first anti-estrogen blocker with the CDK inhibitor, did better when you did elacestrant. If you look at that middle curve and the right curve, we’re now talking about differences from about 2 months to almost 9 months. So that’s a 6-plus–month difference, that all of us would say I think is clinically relevant, with a nice hazard ratio below 0.5.

These drugs are very well tolerated, but they do have some toxicities. I would say they have more GI toxicity compared to the traditional antiestrogens, nausea, a little bit of diarrhea, but less arthralgia, perhaps less hot flashes. Many of the things that we heard about earlier can be really limiting for patients on an aromatase inhibitor.

This is the EMBER-3 study, just recently presented a few months ago at San Antonio and published in the New England Journal, a similar study, except these patients were not allowed to have prior chemo. They were only allowed to have 1 prior anti-estrogen. And some of them never had a CDK inhibitor. So this is a little bit less heavily pretreated. They got imlunestrant, another oral SERD, or standard estrogen blocker, fulvestrant typically, or imlunestrant plus abemaciclib. So this was the first combination with a CDK4/6. And you see these curves have similar patterns. On the top, just like in EMERALD, if the patients were ESR1 wild type or kind of all population. There wasn’t really a significant difference. But on the bottom, if you look at that ESR1 mutant population, the patients who really retain that estrogen sensitivity, the curves pull apart further and the hazard ratio drops. And if you add the abemaciclib to it it gets even more impressive. Now you’re going from 3 to 4 months up to 9 plus months. Again, many of us who are treating a lot of patients in clinic, and all of you would agree for the patients that you’re seeing, that’s, I think, getting to be a really meaningful clinical benefit of 6 plus months there.

And again, these drugs are very well tolerated. There were not many Grade 3 toxicities. If you combine it with the abema on the right you see diarrhea, you see cytopenia. You see all the things we talked about. But if you look on the left for the SERD, very few Grade 3 toxicity, some GI toxicity, very similar to elacestrant.

So let me end and just show you some future directions. ESR1 mutations are rare in untreated tumors, but they are acquired on treatment typically with an aromatase inhibitor, and they’re really best identified with the liquid biopsy as we’ve been talking about. These new oral SERDs are very well tolerated, and they have some activity even as a single agent particularly in patients with ESR1. We have many, many, many trials going on with all kinds of different new SERDs and new antiestrogens, and we are developing them in combination with lots of drugs, the PI3 kinase inhibitors, the Akt inhibitors, the CDK4/6 inhibitors, and we’re really working hard to understand the molecular and the genetic changes in the tumor that helps us pick the right patient for the right drug, who’s going to get the most benefit, who’s going to get toxicity without a lot of benefit.

And this is a table I put together for your notes. You can take a look later. These are some of the key trials over the last year or two. A couple of them are still pending. We’ve had a couple of negative studies where it didn’t seem to be much better than fulvestrant. We’ve had a few of the positive studies that we’ve already looked at tonight.

And then this is the SERENA-2 study. I’m introducing this to you because camizestrant, they all end with t-r-a-n-t, is another oral SERD. You see a similar pattern, a drop, but a little bit of a benefit for the SERD here compared to fulvestrant. This was true, again, particularly in the ESR1 mutant population. And I mention it because, again, very well-tolerated drug, not a lot of significant toxicity.

But check out this trial. This is a very cool trial that I want to end with. This is the SERENA-6 study. These are patients on an aromatase inhibitor and a CDK inhibitor, like we heard about. They are being tested every 2 months with a liquid biopsy, every 2 to 3 months. If the patient develops ESR1 but does not have progression, no clinical progression, no change on the scan, but we detect it in their blood, in a highly personalized way, half the patients stay on their treatment, half the patients switch their aromatase inhibitor to this new oral SERD. So this is really the dawn of personalized medicine. We switch the drug before there’s anything on the scan, before there’s any progression.

And there was a press release, as Neil mentioned. We haven’t seen the data yet. But the press release suggested this study is positive. So we’re going to see that data soon in the next couple of months. And I really do believe that this will usher in an entirely new era for clinical trial design. We’re really going to be putting sort of radiology out of business here, because we’re going to be using the liquid biopsy to find the right moment for the right patient to deploy these drugs. I think it’s very exciting.

DR LOVE: So now we are in that situation where there’s a press release out there. All we know is the trial is positive. It may be just a little bit positive, or it might be something everybody gets super excited about. So we’re all ready to, once we see these press releases, we’re ready to see it. Hopefully we’re going to see this at the upcoming ASCO meeting. But if it looks encouraging enough to be practice changing, what it means is these people who’re on CDK inhibitors are now going to be getting liquid biopsies maybe every few months looking for the ESR1 mutation, and if they get it they maybe are going to be switching to this other SERD.

And I’m curious too, Ginger, this is from a slide that was presented at the San Antonio meeting by Dr Burstein from Dana-Farber, trying to compare, again indirectly, because we don’t have trials comparing 1 SERD to another. Again, another situation in oncology, multiple agents in the same class. In this situation only 1 approved at this point but we know there’s great data with imlunestrant and camizestrant. It seems like very possible, if not likely they’re going to get approved. There’s another agent out there. But any comments, Ginger, in terms of your clinical experience, sometimes it’s hard to look at trials and figure out what really happens. Jamie’s going to get into a little bit, particularly some kind of things you don’t hear too much about in oncology, bradycardia and photopsia. Any comments?

DR BORGES: Yes. So sadly I feel we might re-enter the similar times of back in the ’90s when we had 3 AIs, they all worked the same, they have almost overlapping side effect profiles, and it became kind of AI wars for a while and then everybody just voted with their feet and picked their favorite drug. There are some differences here. You mentioned you’re starting all of these new sessions on these different toxicities that we have historically never dealt with.

In the bradycardia space I find it interesting. It really doesn’t tend to be symptomatic bradycardia. It’s because we all wear one of these devices that the patients are aware of it, and they get concerned about it. But occasionally someone will have a big enough change that it matters. Photopsia is a change to their vision. That’s very concerning for patients. We now also have ophthalmologists on speed dial.

You know, I think in time as we have more drugs available, because we will, it’ll be sort of talking to our patient and understanding what bothers them the most. Are they the patient whose GI tract revolts at every drug you try to give them so maybe you would go with the one that has less GI side effects? Do they have a high hemoglobin A1c or tendency to diabetes. You might want to avoid that. It gets to start to be very nuanced. Having worked with a number of these drugs in clinical trial, I say I definitely have my favorites but I’m not going to tell you which ones they are until you see the results of the studies, and I’m sure you do too.

DR WANDER: I like the AI wars. I’ve been saying the SERD wars, which is sort of what this is going to look like here.

DR BORGES: It’s like Star Wars. We’re on to the middle episode.

DR WANDER: That’s right.

DR LOVE: So remind us what photopsia is and what the patients tell you.

DR BORGES: It’s blurry vision and also floaters is what I’ve heard mostly them describe. It’s not really loss of vision. If you hear anyone telling you they feel like they’re seeing black spots or losing vision, that could have nothing to do with this drug and we worry about their retina in that case. The photopsia usually does not result in anything that is not reversible when you take away these meds. And a lot of the newer ADCs do this too, including the datopotamab that’s been recently approved. So we’re all going to get better at our eye exams.

DR LOVE: Yeah, we talked about that this morning.

So Jamie, let’s hear your thoughts about some of the nursing considerations in patients starting on these agents.

MS CARROLL: Alright. So I’m going to go back to another case study. So this is a 37-year-old who presented with a self-detected right breast mass, right, because she’s under the age of 40 and was not having screening mammography yet. Biopsy showed she had invasive ductal carcinoma, Grade 2, ER/PR strongly positive, HER2 is 2+, and then FISH negative. She had a clinical T1cN1. She had wide local excision or a lumpectomy, radiation, and then she had an Oncotype done, which was a 23. But she was like, I’m good, I had surgery, I had radiation, I don’t want any systemic therapy. And so I think in that situation you educate, you inform, but ultimately it’s the patient’s decision what they want to do, right?

Well, unfortunately, 2 years later, she presented with bony pain. PET scan showed that she had osseous metastatic disease. We confirmed that with a biopsy of her right iliac bone, same receptors as before. She was young so we started her on ovarian function suppression, so we gave her monthly injections to shut down her ovaries. And then at that time we started her on palbociclib and letrozole. She had stable disease for 5 years on that therapy. So you think about that, in terms of some patients have really aggressive disease, and other patients have more indolent disease or disease that slowly grows. And so when you have a patient that’s gotten 5 years on their first line of therapy you tend to think maybe they have more indolent disease.

So mid 2023 she had progression of her bony disease. Thankfully it’s still only in her bones. She doesn’t have any visceral disease. So we radiated a few painful areas and then ordered liquid biopsy or Guardant360. So this is her result of the Guardant 360. She had an ESR1 mutation. And so, if you’ve never seen these reports before, they kind of walk you down, okay you have this mutation, what can you give them? What is FDA approved drug? And so that’s your second column there. So we can give her the new oral SERD that got approved in 2023.

So here’s your safety data. This was discussed earlier but all grades, musculoskeletal pain, and then mostly GI symptoms, which is obviously different than the profile for fulvestrant with an IM injection.

I do want to talk about the warnings from the package insert. So there is the potential for dyslipidemia. So they do recommend baseline lipid monitoring and then periodically thereafter. And there isn’t guidance on how often you should be checking, so at baseline and then when patients have future blood draws will work fine. And then it can cause fetal harm, so you want to make sure that patients are using effective contraception.

Also important is your dose modifications. So the dose for elacestrant is 345 mg tablets. And then if you have to dose reduce they turn to 86 mg tablets. So it’s 1 pill as your full dose. But then if you need to do a dose reduction then they go up to 3 pills, and then a further dose reduction is 2. So for some patients, number of pills does matter. And then here is your CTCAE for dose reduction of the elacestrant. If somebody has a Grade 1 toxicity you can continue at the same dose. If they have a Grade 2, you need to consider interruption until they resolve to a Grade 1. And then you can resume at the same level. If it’s a Grade 3, stop, and then resume once they’ve returned to baseline. But at this Grade 3 you do need to dose reduce.

Before I go to my next slide, I have a question for everybody. How many of you, in your purse, have pills in a box, like your acetaminophen and your calcium carbonate and your ibuprofen? You keep them all together? Many of you. Okay. So if you’re on elacestrant don’t put it in your pill box because it looks identical to naproxen. So your 345-mg strength looks the same. Your 86, also the same. So you don’t want your patient to think that they’re popping 3 naproxen and, oops, they took 3 elacestrant instead of 1. So this is one thing that we really want to make sure, when we’re doing the education with our patients, that you really should keep this separate and don’t just throw them in, even though you’re going to take this pill every single day.

And then this has already been talked about, approved in emerging oral SERDs. There’s many in development. I like the term SERD wars. I like that a lot. So more to come. Maybe next year the talk will only be on oral SERDs, we’ll find out.

And then obviously adherence. So our patients, when you’re prescribing these oral therapies, it’s a lot different, obviously, than your IV medications. You know if your patient missed their appointment for cycle 2 when they’re on an IV drug. But if the patient is at home and they’re not taking their medications, you’re not necessarily going to know it. So I think it’s really important that we engage our entire care team, that we’re checking in with our patients day 7, we’re checking in with them day 14. If you have a clinical pharmacist, they’re amazing resources in calling patients and ensuring that they’re, number 1 getting their drug, right? Because if we prescribed it and we don’t know if the patients get the drug in hand because they’re having insurance issues or they need to apply for a grant but they don’t know how, it’s really important that we make sure that this drug gets to our patient, and then when it does how they’re tolerating it so that the adherence is 100%, their persistence is 100%, so just making sure that we’re having good communication with our entire care team and with our patients.

DR LOVE: So I want to switch to a final topic here, not directly related to hormonal therapy. But Ginger, I know you have a great interest, and a lot of your patients are younger. And actually we had a conference for oncologists recently, which Ginger participated in, and there was a case there that really I’ve been thinking about ever since it was presented. It brings up another issue, which is fertility. And this is more of an issue in the adjuvant setting, in metastatic disease not so much. But I wonder if you could talk a little bit about how you think through the issue of a premenopausal woman who would like to conceive at some point, who is going to be getting adjuvant therapy. We know that there was a study out there, a positive trial, where patients we talked before about, in the adjuvant setting, that these patients may be on hormonal therapy for 5 or 10 years, and while they’re on hormonal therapy they really cannot conceive. And so what they did in this study was actually have these women stop their hormonal therapy and attempt to conceive. And in fact, quite a few, I think three quarters of them in the study actually were able to. And then they go back on treatment.

The case that was presented at the conference was really an issue because that’s what the patient did and then the patient conceived, had a child and then was diagnosed with metastatic disease, so a very, very difficult situation for her, for her future child. And I wonder if you could just comment on the positive strategy, and in general the issue of breast cancer in younger women, Ginger.

DR BORGES: Sure. So I have an algorithm I follow for all of my young women and it’s how I talk to them when I’m in clinic. The first thing we think about is why did they get that breast cancer. There are 9 genes that predispose them to it. We want to make sure they do or they do not have that, because we then have to add a list of cancers to the homework assignment for later down in their treatment.

The second thing I ask them is where are they on this topic in life, because I have some women who come to me, and they know they do not want to have children and then we’re good. I need to make sure they have effective contraception if their partner is someone who could get them pregnant, and then we move on. If they have not completed their childbearing, then we want to make sure they see our oncofertility specialist before we get going. If they are very young it might not be that pressing of an issue, particularly if they are not going to need chemotherapy for their treatment. And when I say very young, I mean in their 20s and early 30s. Mother Nature starts taking away our natural fertility around 35.

So if I have a patient who is 39 and not yet done with her childbearing, she needs to get into the hands of the oncofertility folks quickly if she wants to have banked material that will increase the likelihood of for-sure success of her having a child that is biologically half hers. And I use that language very specifically because she can have a child. There are many ways to have one. Adoption is a fantastic strategy for some, not all. But if she’s caring about it being biologically half her, we want to get her either egg-banked if she does not have a partner, embryo-banked if she has a partner, and I’ve had some couples who do both eggs and embryos. The male partner looks at me and says, well what if I kick off, I don’t want her stuck with my kid, because we can make babies out of eggs that are frozen, sperm comes along later. Embryos have a slightly better success rate. So if we have the sperm of choice, we like to use it. In terms of then how do we feel about that, there really is no subset of breast cancer for which this would not be an okay thing to think about unless they already have metastatic disease. It becomes pretty hard to conceive of how someone would be able to off-treatment for 40 weeks to safely carry a pregnancy and not have their cancer progress to the point where it would threaten them and their child. And we only have a handful of drugs that we can safely give a woman who is pregnant, and we tend to use those as our chemo drugs up front. So once we’ve burned those, we don’t have a lot of options should she be pregnant at the time of the metastatic cancer showing up.

But if all goes well, she undergoes her treatment. And if she is going to get chemotherapy we want to offer that woman one of the ovarian suppressing drugs at the time of the treatment, because that’s been shown in a number of clinical trials that it preserves the woman’s fertility for later being able to successfully have a child. We don’t know exactly how, but all the studies show that it does it. It doesn’t matter which of the drugs that are out there to supress the ovaries that you use. I tend to use the 3-month schedule when they’re on chemo because our chemo cycles tend to be every 3 weeks, depending on what you’re giving them, and that’s just convenient, but you could do it either way.

On the back side, I talk to them up front about this topic. So it’s not that they’re going to stop their endocrine therapy. It’s they are going to pause their endocrine therapy. They have to come back and get back on it or they will not continue to receive the benefit that we have quoted them at the beginning. And I build into that topic up front, the concept of lactation. If they are going to have a breast that is not treated at the time that they would have this pregnancy, that breast will work just fine. They’ll be a lot of asymmetry, but women unilactate very successfully all the time. The treated breast, if it was breast conservation, doesn’t perform very well. And if the woman has had a mastectomy or bilateral mastectomies, obviously they can’t make milk.

But I also talk to them about the fact that they cannot lactate for as long as they would like. In Colorado women lactate for many years quite commonly and that’s not going to be okay. So I talk to them up front that they can have, depending on how long it takes them to get pregnant, they can have a few months, but then they have to come back and get on their treatment because the most important thing for them and their child is that they remain well and are there to raise that baby.

The POSITIVE trial is based on reams of evidence of retrospective data that women can do this, and they do not have an increased risk of recurrence. That does not say they don’t have a risk of recurrence. It says that the subsequent pregnancy is neutral to the risk, provided they eventually complete the recommended length of time on treatment. The POSITIVE trial was specifically looking at women between 18 and 36 months because of this issue of naturally declining fertility. We can’t tell a 39-year-old to wait 5 to 10 years and expect her to be able to have a child unless there’s a lot of science involved. And so from 18 to 36 months they pause their endocrine therapy, they had 2 years to conceive and get pregnant and they could do it any way, the natural way, banked material, IVF at that time if they didn’t have the opportunity to bank before they wanted to do this. And now we’ve been following them longitudinally. It’s 500 women from around the globe, all different stages, and we are not seeing a difference in the rate of recurrences so far when we compare these outcomes to the SOFT trial, which was the contemporary trial that was the randomized one with patients on therapy. Because you can’t really randomize to have a baby or not.

So that is where the study currently stands. Again, retrospective evidence, particularly from Europe, already told us this was probably going to be an okay thing to do. And you realize there, the doctors who take care of breast cancer are OB-GYNs who are now gyn oncs, and breast is in that group. In the US we are internal medicine doctors who become oncologists who do breast. So they’ve always been ahead of us on this topic because they deliver the babies. That’s kind of the synopsis.

DR LOVE: So Jamie, just curious if you’ve had any patients who’ve tried the POSITIVE strategy as in the case that we had at this conference. I think this woman did nurse for quite a while — the issue of then having to deal with metastatic disease and a newborn child. I’ve got a 1-year-old grandson. I think about what’s involved in his care and imagining also having to deal with metastatic breast cancer at the same time. Any thoughts?

MS CARROLL: Yeah, I actually share a patient with somebody in the audience who was diagnosed, got her chemotherapy, had surgery, started on her tamoxifen with plans to take it for the 18 to 30 months before pausing and attempting pregnancy. She had 4 miscarriages prior to getting pregnant, did get pregnant, carried a successful baby, had a little girl, and then didn’t want to revisit her tamoxifen. We ideally want them to get back on their tamoxifen or their endocrine therapy within 2 years, but she wanted another baby. So she got pregnant again, carried it full term and had a little boy.

DR LOVE: Awesome. Seth, any comments about how you deal with fertility issues at MGH?

DR WANDER: Yeah, these are all great insights. We do a similar approach. Definitely you want to engage with this topic right away, because if you have a patient where you’re thinking about egg banking, that can add delays and we’re trying to get going with chemotherapy and things like that. So that’s typically the first call I’ll make after the multiclinic when we see them. This is one of the ones, now with our endocrinologists, ophthalmologists, right? I have my fertility doctor on speed dial. I think the positive data has helped all of us have these discussions with patients, but I completely agree with the points we just made about really emphasizing it’s a pause, it’s not a stop. And we want to get people back on for risk-reducing therapy as soon as safely possible to maximize their longer-term outcomes. But I think it’s a very patient-centered decision. I’ve, in my own experience, been through every angle of this, with patients who wanted to adopt and patients who wanted to do egg banking, patients who didn’t want to go 2 years and just wanted to go straight to pregnancy. This is all risk/benefit. This is all patient-centered decision-making, family-centered decision-making, and it's all about having good kind of multidisciplinary discussions.

DR LOVE: And Ron, it also brings in the issue of involving patients in treatment decisions and their families as well. I’m curious how you go about doing that. I mean there’re some patients who don’t want to be involved. They just want to be told what’s the best therapy and others who want to get very involved. You may have a patient who is a physician or a nurse, even in oncology, who wants to know a lot about it. How do you approach the issue of involving patients in treatment, difficult treatment decisions like this one?

MR STEIN: Yeah. It can be very, very difficult, especially when we’re talking going back to the fertility. We want to get that patient involved, family members involved, partners involved, potential parents involved, and we want to do it as soon as possible and as quickly as possible. But here we are in a multidisciplinary clinic setting, when the patient’s been diagnosed. And the first thing on their mind, most of their minds, is I want to get rid of this cancer. They don’t necessarily want to be talking about fertility. They think this is — I got to live, okay? This has just been my personal and anecdotal experience. So the more people the better. You don’t want to overwhelm the patient, but you still want to put out that possibility and at the same time have that patient and his or her loved ones hear you and know that we have a plan for the cancer but we also want you to be thinking about these other issues as well. The first question I’m going to get is, how much does that cost? Does insurance cover it? Very often it doesn’t and that’s going to be, unfortunately, guiding the decision-making process, whether or not that patient wants to eventually bear children.

So it can become very, very complex. I think we need to just be there. I think as nurses, talking nurse to nurse here, we need to listen and really hear that patient and be as nonjudgmental as possible, but at the same time provide the information that’s out there and certainly serve as a conduit for access to specialists, such as fertility specialists.

DR LOVE: So I want to thank the faculty for a terrific job tonight.

We’ve been talking a lot about targeted treatment of cancer. Tomorrow morning, 6:00 AM, we’ll be talking about the first maybe targeted therapy that was really successful, even today, one of the most fascinating corners of oncology, chronic myeloid leukemia. Come on back here, same time, same place, 6:00 AM tomorrow. Have a great evening. Thanks so much to the faculty.