Introduction

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice, and welcome to “What I Tell My Patients.” We’re really thrilled to be back here at the ONS meeting for our 16^th year. We’re going to be using the same basic format we’ve done over the years with 2 nurses and 2 oncologists on our panel. Tonight we’re going to start out talking about hormonal therapy for hormone receptor-positive breast cancer. We have a great faculty here today, Dr Harold Burstein and Dr Komal Jhaveri and Ms Kelly Fischer and Melissa Mikal — Rikal.

So every year we kind of try to do something a little bit different, and this year we have a different approach to what we’re going to do. As always, we’ll be emphasizing new clinical research and what it means in terms of patient care. We will be talking about unapproved agents and the use of agents in unapproved situations so please check out the prescribing information.

For the clinicians here in the room on your iPads you have all of the slides we’re going to look at today, a survey that you can take prior to getting started here just now, and also at the end of the meeting, and finally if you have any questions you can use the iPad to ask questions. For the many people on Zoom here, first of all welcome, and all these same functions are present in the chat room as well. Again, we have a premeeting and postmeeting survey for you to take. If you take that, we have 1 for each one of these meetings that we’re doing here tonight, you’ll get a lot more out of the meeting. We are recording all the meetings we’re doing here at ONS, and we’ll let you know by email when they’re available.

We are doing, this is the first of 10 symposia we’re doing. We do this every year. We’ll be finishing up on Saturday night. But the specific topics that you see here we really want to try to go beyond that because we’re talking about oncology nursing in general, and all the points we’re going to make really apply to people and patients not only with the cancers that we’re talking about but way beyond that. As always, we always get psyched up to play some new music, although we end up playing the same music every year, but this is our playlist. You can check it out on Spotify as well.

So we’re going to talk about hormonal therapy, then tomorrow we’ll be talking about endometrial cancer, antibody-drug conjugates at lunch, so important and happening all over oncology, at night chronic lymphocytic leukemia and bispecific antibodies, Friday morning head and neck cancer, non-small cell lung cancer, ovarian cancer. Saturday we’ll go back to hepatobiliary cancer, myelofibrosis, and we’ll finish out talking about gastroesophageal and colorectal cancers. And just going through this list is a reminder of what a challenge it is to be in oncology. We know many of you are working in outpatient clinics where there’s a general medical oncologist in practice, and so all of these tumors that we’re going to talk about here are relevant, as well as we’re doing a webinar, because we couldn’t really squeeze it in the schedule, in prostate after the program, as well, but with the same format.

We’ve always had a very rounds-like approach to this. Nobody’s going to give a talk for all these 10 meetings. We’re going to talk about taking care of patients and particularly interdisciplinary cooperation as we take care of patients. One of the themes that we have as we hear about some of the patients the faculty’s taking care of is why was it different to take care of this patient than another patient in the same situation oncologically but a different person, different attitude, biopsychosocial factors.

So to try to get into that a little more deeply we tried to do something a little different this year. And so what we’ve done over the last few weeks is I conducted one-on-one interviews with 8 oncology nurses, nurse practitioners, these are all nurses we’ve worked with previously at ONS, and I queried them about some of the themes that we’ve had over the years in ONS. We ended up with an hour and a half of 90-second sound bites. They’re all posted online at the link you see there below. When you go back to your room tonight there’s 85 sound bites, you’re going to see 3 of them tonight in this meeting, going through a number of what we consider critical issues and themes in oncology that we’re going to get into.

So you’ll get a little bit more out of that. And as we go on here are some of the terminology we’re going to use as we talk about clinical trials and how it fits into taking care of patients. We’ll get into this as we go along.

Alright. Well, with that as an introduction we’re going to start out. Here is where we’re heading. We’re going to initially talk about localized ER-positive disease and the use of hormonal therapy in that situation, including the recent use of CDK inhibitors in the adjuvant setting. And then we’ll move on to metastatic disease, which has really been a revolution. So your patients with metastatic breast cancer, for example who are on CDK inhibitors, and then develop a relapse, that’s what we’re going to talk about for the rest, and all the new agents that are coming out for these patients.

So before we dive into this specific content we’re going to just take a minute to just take a deep breath and think about just taking care of patients in general, and we’re going to start out with some thoughts from Ms Glennie about what she thinks about when she goes in to see a patient for the first time. I will let you know that tomorrow night — tomorrow night in this room we’re going to show another video from Ms Glennie where she talks about how she at the age of 22 started working in a bone marrow transplant unit and completely burned out, and tomorrow night she’ll talk about what happened and why she ended up back in oncology. But here’s what her thoughts were, and I’ll be curious, Komal, what your thoughts are about — what you’re thinking when you’re going to see a patient with breast cancer for the first time. Here’s Ms Glennie.

MS GLENNIE: This is a timely question because in the last couple weeks I’ve actually had a couple brand new diagnoses who because of scheduling issues couldn’t get in with one of the physicians, and so they came to see me first.

For those folks this is like one of the worst weeks of their lives, this is something that’s going to rock their entire world, will rock their family’s world, I try to approach it as honestly but optimistically as I can. And so I will generally start just by asking kind of what they know because when we’re seeing folks for the first time sometimes their primary care has already called and told them they have cancer, they’ve been diagnosed in the ER, and other times they come to us, and they’re like I’m not quite sure why I’m here. And so I always try to kind of set the groundwork with just what do they understand so far about their potential diagnosis.

DR LOVE: So I’m curious, Komal, again, what your thoughts are about this. Interestingly, as I was mentioning to you before, Ms Glennie actually — her focus is AML. But there’s a certain commonality to a new diagnosis of any cancer. Any thoughts, Komal? And also more about the newly diagnosed patient with breast cancer.

DR JHAVERI: It is very overwhelming for patients. I think you have a normal routine, a normal life that you’re leading, maybe with young women with young kids, or anybody in their phase with a normal routine, and all of a sudden they now are being told that they have an abnormal mammogram, they have a biopsy, they have a new diagnosis, they’re figuring out what stage means, what grade means, what does this mean for them, how will they deal with this with their family, how will they deal with this with work because it’s not that just because you have a cancer diagnosis like comes to an end. And there are so many other thoughts that are going on in their minds, including why me. What did I do wrong? I’ve done everything right. I lead a healthy life, I work out, I don’t drink alcohol, I don’t smoke, so why me? And why did this happen?

So there’s a whole lot happening, and I think the first visit, that’s why it’s very, very important that we’re sensitive to the fact about how this all began, what are they thinking about, how would they want to deal with this diagnosis and tell us what they think about. So when we’re doing the history taking I think it’s very, very important to get a sense of what is their understanding, what are their main fears, what are their main questions, and I think addressing those during the first visit is very, very important just so that they can walk out of that consultation with some kind of reassurance or assurance that maybe they will be okay, or they have a team that will care for them, and they’ll be okay. So I think it’s very, very important to get that cross talk between the patient, the nursing team, and the physician, social work if we have to get them involved at the same time.

DR LOVE: So Kelly, as you know, you’ve worked with us many times over the years, one of our themes, we always like to think about people new to oncology, or maybe even people thinking about whether they want to go into oncology. So can you talk a little bit? If you had a student nurse come — I’m sure you have student nurses at your clinic. If you were going to go in with a student nurse to see a patient with breast cancer for the first time what would you be talking to her about what you’re thinking about?

MS FISCHER: Well, I think that it’s important to get a sense of the whole person. It’s very anxiety producing to come into an oncology clinic as a patient, so you really have to kind of read the room and address their concerns and anxieties and sit with them and hear them and offer them support, education. We’re really big on education, patient teaching, and kind of it’s trying to be optimistic and realistic at the same time, so…

DR LOVE: Melissa?

MS RIKAL: I think it’s also just important to remember that the person that you meet at that initial visit is not necessarily the person that they are. They can exhibit a lot of emotions, and sometimes it can be a lot of anger, and that can come out. They have to place that anger somewhere, and it can come out towards you as the nurse or the provider, and so just being as patient as you can with them and continuing to build that relationship over time.

The Utility of Genomic Assays in Treatment Decision-Making for HR-Positive, HER2-Negative Localized Breast Cancer

DR LOVE: So in a way this whole week’s going to be kind of a tasting menu because almost every topic we talk about we could go on and on. And again, if you check out those videos I asked every single one of them the same topic, so there’s more there for you to think about.

But let’s start to get more into the specific content as we talk about interfacing with patients. And Hal, this has really been a great development really over the last 20 years. A lot of women have been able to avoid chemotherapy by these assays that look at the tumor and really have been proven to show whether or not the patients are going to benefit from chemotherapy.

How do you explain to a patient what like an Oncotype is, or one of these assays are, Hal?

DR BURSTEIN: Well, it really is one of the great developments in breast cancer over the past couple of decades, and it was in 1999/2000 when the NCI issued a blanket urgent warning that all women who had cancers 1 cm or greater would warrant chemotherapy because of the data from NSABP-B-20, which in retrospect seems like a catastrophe, but at the time was thought to be very cutting edge. And what we knew then was that there was a small overall benefit for chemotherapy. Undoubtedly there were patients who did not need treatment and were being overtreated but we didn’t have a tool to figure out who those people really were. And that’s where this particular assay, the 21-gene Recurrence Score®, proved so incredibly helpful, both initially in retrospect and now in multiple prospective clinical trials. And it’s allowed us to spare I would guess probably two thirds of women who have ER-positive breast cancer from the need for adjuvant chemotherapy.

So I actually go through the report with them. We print out a copy, we look at the numbers, and then we go to the actual publications in The New England Journal of Medicine, which are actually very clear. You show the Kaplan-Meier type curves, and it makes the point that there’s absolutely no benefit for chemotherapy, particularly in postmenopausal women who have node-negative or limited-stage nodal involvement, no benefit to adding chemotherapy to endocrine treatment. So it’s not like my opinion or my best guess or my substituted judgment for them. It’s like there’s no benefit.

And one of the remarkable things about this assay was it got to the zero point of benefit. So there’s a huge difference when you’re talking to a patient and you say well, there could be a little bit of benefit to treatment, as opposed to looking them in the eye and saying there’s really no benefit to therapy here. And I think most patients will readily understand that difference, and so we use this test all day long every day in our clinics to help patients decide.

DR LOVE: And it’s important also for the patient to realize that because there’s not a benefit of chemotherapy doesn’t mean that they have no chance to have a recurrence. They may recur. It’s just that if that happens you can’t look back and say well chemo would have prevented it because we know it would not have.

And actually, Kelly, Hal told us about a patient, 42-year-old woman, she had a low Oncotype. She actually had a positive lymph node, which usually would get chemotherapy. But again, there’s data suggesting not, and she ended up not taking chemotherapy even though she had a positive node.

Komal, is that something that you see in your patients? Traditionally there’s been a lot of debate about this, about withholding chemo from a patient who got a positive node.

DR JHAVERI: So I think it’s more clear now with the data that has come out from the TAILORx trial and the RxPONDER trial for postmenopausal women, where we know very clearly where we can omit chemotherapy for our patients and recommend not offering them chemotherapy and just endocrine therapy. It’s a little bit of a gray zone in the premenopausal space. Data, at least from the prospective trials, do right now suggest that chemotherapy is beneficial, but there’s always this question about can we get away just with ovarian suppression and endocrine therapy. And the benefits of chemotherapy, are they just coming from the fact that they’re taking away the menstrual — making them amenorrheic and giving them the benefit because of that.

So I think this is where it boils down to who is in front of you, what is their understanding, how is their lifestyle, how are they thinking about all these recommendations, what is their understanding of the risk of recurrence and the benefit from the individual components of these therapies. And so it’s a dialogue that we have with our patients to really try and understand that this is the benefit that you’re going to get as an absolute benefit from chemotherapy versus endocrine therapy plus chemotherapy and try and gauge what they are thinking.

So I’m assuming that this woman really wanted to perhaps not consider chemotherapy or consider that maybe the benefit from chemotherapy is not justifying the risks that come with the chemotherapy and has that understanding and is very comfortable with that decision. So sometimes we just have to depend on that. I think the one thing that I ask my patients is if down the line something were to happen again in terms of recurrence are you somebody who’s going to have that regret factor that I did not do something that I was supposed to do. And if you are that somebody then maybe it’s okay to do and take that risk that comes with that small benefit.

But there are many women who would be very, very comfortable with their decision about what they decide when they make that decision for themselves, and I think it’s okay to be that way. As long as they understand the risk, as long as they understand the implications I think it’s a great patient/physician decision making process here.

DR LOVE: So I want to go on now and talk about some of the traditional approaches to hormonal therapy, and then what we’re really going to get into is so exciting because like this is the most common form of breast cancer, ER-positive, particularly HER2-negative breast cancer, the majority of breast cancer, patients are eligible to receive hormonal therapy, and there’s a lot new.

But first let’s just talk a little bit about how the tools we’ve had in the past, Hal, worked, tamoxifen, ovarian suppression, chemotherapy, these tools that we’ve had in the past that we’ve used in the localized setting. Can you talk about your vision of how they work, and again, how do you explain to a patient why you want to suppress their ovaries, as an example, Hal?

DR BURSTEIN: Oh, sure. So you’re right, because we lean on each of these tools, and historically, by the way, oncologists have been absolutely terrible at estimating the benefits of therapy and the risks of cancer recurrence. There was a famous paper from the Mayo Clinic back in the late 90s where they sent a survey around to doctors around the country, and they said, “Here’s the case. How much benefit would you think there was from this treatment or that treatment?” And the estimates were all over the place.

So one of the great things that’s happened in the modern era is we’ve been able to tease out far more what the actual measurable benefits are. And as Neil alluded to what we’re talking about are marginal improvements. Most women will do well. And what we’re talking about is helping them further lower their risk of recurrence. Many people imagine if they take a therapy then they’re guaranteed to be cured, and if they don’t take a therapy then the cancer’s going to come back. And as we all know it’s something that’s in between those 2 extremes.

So usually in a multidisciplinary conference it starts with a discussion of surgical management, they either have a choice of a mastectomy or a lumpectomy plus radiotherapy for most women, and then we would talk about what comes afterwards. And so if you have lumpectomy you would need radiation therapy to lower the risk of in-breast recurrence and improve long-term outcomes.

And since we’re talking about ER-positive disease essentially all of these women are going to be candidates for one form or another of adjuvant endocrine therapy. These are obviously pills. You’re going to take them for 5 to 10 years. We expand the duration based on the risk, the anatomic risk of how many nodes are involved and things like that.

And then what’s left along the way are discussions in the modern era about is chemotherapy indicated, we use genomic assays to explore that, and then in a very new iteration should we be adding a CDK4/6 inhibitor to higher-risk patients to further help lower the risk of recurrence. And we lay out a roadmap, which talks about each of those decision nodes and the role that each one of those treatments has.

For premenopausal women we’re additionally going to get more granular and talk about whether or not to add ovarian suppression, how much of the treatment benefit from chemotherapy might be due to ovarian suppression, and whether we can go without the chemotherapy and still achieve that benefit. I literally have, and Kelly my nurse and partner here knows, an 8 1/2 x 11 scratch sheet, and we literally work through a piece of paper, it keeps me from talking too fast when I lay it out for the patient, and then they take it home. And they’ve sent me pictures because they often like will take a magnet and put it on their refrigerator at home because that shows them what the next 6 months of their treatment plan is going to look like and helps orient them.

DR LOVE: So Komal, any thoughts? And maybe you can talk a little bit about it sort of makes sense that you want to either take the ovaries out or suppress them because it makes sense, estrogen is going to stimulate the cancer, but then it gets a lot more complicated.

Incidentally, I showed a 1-minute clip of you at a meeting explaining how — the hormonal program we did, and I showed people how you use your hands to explain. So can you explain how these drugs work?

DR JHAVERI: Yeah. Absolutely. I love using my hands, yes. Good observation, Neil.

So I’ll make 1 comment, and then I’ll talk about the mechanism of drugs as well. I think the 1 analogy that I sometimes think resonates with patients when you’re really trying to explain this complicated ways of yes, the chemotherapy might benefit, does it really individually benefit a patient, I think is a very complicated concept. We try and simplify as much as we can in that 1 hour we spend with that patient for the first time who’s going through so much.

But the 1 analogy that I’ve felt like resonates with them is that when you go to a dentist your dentist always tells you, right, if you do fluoride treatment you can avoid cavities, and that’s why we all do fluoride treatments. But if he were to see a hundred people in a room and say I gave you all fluoride, can he pinpoint and say he will definitively be able to avoid a cavity in 1 particular person of the hundred people he treated? He did not. But together when you give fluoride we know we prevent cavities. I think that’s 1 concept for getting benefit from chemotherapy that kind of resonates a little bit in a lay language if you would try and explain to the patient.

So that’s about chemotherapy risk. And I think one other thing that we want to do, we had done a patient survey to see how do they think about what was explained to them as a risk of recurrence. And about 16% of these patients really walked out not realizing that the risk of recurrence was even discussed with them. You say so many things to them, there’s so much going on in their minds. Maybe they’re listening to things. Maybe some of the things they’re not understanding. I think it’s very important, again, to go back at the end of the conversation and ask them what they understood and do they understand what the risk of recurrence is and what benefit is happening.

So those are the 2 things I feel like sometimes helps me get them to where they need to be just to get started and then reinforce more and more each time. Take one step at a time. Talk about chemo first, then radiation first, and then we go into the mechanism of actions of all the drugs.

So when we think about tamoxifen — it’s tamoxifen, aromatase inhibitors, ovarian suppression, all they try to do it take away the estrogen, but they’re to do that in very different ways. So one is trying to shut down the production of estrogen in the body, which is aromatase inhibitors in postmenopausal women. You have androgen that’s converting into estrogen, and you have an enzyme called aromatase that does that conversion, and you’re trying to take that away. And that’s how that works. But the idea for all of these drugs is to take that estrogen away because estrogen is what is driving their tumor.

DR LOVE: And Kelly, of course in all of these therapies that we’re going to talk about this week and more obviously a big issue is tolerability and toxicity. What are some of the things you mention to patients who are going to go through ovarian suppression or ablation? You could look at it as an acute menopause that a lot of people go through, although they’re not maybe in the same life situation. How do you approach describing what’s going to happen?

MS FISCHER: So —

DR LOVE: I’m sorry. I meant Melissa.

MS RIKAL: You were looking at me.

DR LOVE: I was looking at her, calling you Kelly. I’m just getting warmed up here.

MS RIKAL: Well, with the aromatase inhibitors and ovarian suppression we’re mainly looking for potentially arthralgias. We can see that in about 30% of patients, and oftentimes that seems to be the most cumbersome or debilitating side effect that drives them to sometimes want to switch endocrine therapies. Hot flashes of course. Vaginal dryness can be an issue. Hair thinning.

And then with tamoxifen we can see a little bit different side-effect profile. We actually can see a little bit of increased of endometrial cancer, so the patients need to go for screenings annually with their GYN, assuming they still have a uterus. We also can see increased risk of blood clots. We kind of usually describe that to patients as similar to the blood clot risk that you see when you’re on birth control pills. You know tons of women on birth control pills, but we don’t actually see them getting clots every day. So I try to explain it in that way, that it is an increased risk, something to note. You go to an emergency room with a swollen leg, but you’re still minimal risk.

DR LOVE: So Kelly, what I was going to ask you about, your 27-year-old lady. That’s pretty young to have your ovaries suppressed. And then on top of that push the estrogen level even lower with an AI, anastrozole. So again, how did you prepare her and kind of what happened? How did she do?

MS FISCHER: She’s doing great. So she’s very young, like you said, 27. She’s a nurse, so she’s a med surg nurse, so very well educated, very smart. So I educated her about potential side effects, discussed hot flashes, vaginal dryness, hair thinning. With the leuprolide she was having — we were having issues with getting her ovarian function adequately suppressed, so she was having episodes of breakthrough vaginal bleeding.

So we usually check estradiol levels periodically when patients like her, 27, are on leuprolide. Her levels were actually not adequately suppressed at the dosing that we were giving her monthly. So we kind of had to do a little back and forth. We had to switch her over to tamoxifen because you have to technically be postmenopausal to be taking an aromatase inhibitor. And eventually we were able to suppress her ovarian function actually with an increased dose of leuprolide every 3 weeks, which is a bit nontraditional, but that’s what got her ovarian function suppressed. So now she’s on anastrozole and leuprolide, and she’s doing very well.

DR LOVE: And here’s, we won’t go through it in detail, but you can take a look at it later, the mechanism of action of how GnRH analogs work.

But also we want to get into more of the clinical side of this and also get into some different aspects of this that relate to younger patients. You mentioned that this woman is a nurse. Hal, is she your patient also?

DR BURSTEIN: Yeah.

DR LOVE: Any comments about her as a person and what it’s like to take care of somebody in the medical field? And anything you want to say about this patient that made it different to take care of her?

DR BURSTEIN: Well, all of us who work in major medical centers take care of a lot of physicians and nurses, and it is both a challenge and a joy. It’s really a joy because to share colleagues and know them as patients in that way is immensely gratifying, and I think we all take a lot of pleasure in doing that. But they’re very informed, and in my experience physicians and nurses are much more worried about side effects than the average patient would be. They’ve seen it all. If you’ve given someone chemotherapy, and you say oh, there’s a small chance you’ll be hospitalized. Well the nurses all know oh, my God, I just discharged somebody who had febrile neutropenia or had colitis from some drugs or things like that. And so they’ve seen it all, and they are appropriately cautious about taking many of these therapies.

And they also don’t like medicines. So the other irony about physicians and nurses in general is medicines are good for other people, that’s what I give my patients, but frankly I do not want to be taking as many medicines as you’re prescribing me. So we often have to say I know that you don’t like taking these medicines but for the moment I would like you to try them and see how it goes. So that’s — as I said, it’s a little bit of a different dynamic.

Most of these people get it, like they get it perhaps all too well. And again, they’ve seen a lot, they’ve dealt with a lot, they know a lot of these issues. And many of them will move very quickly to discussing side effect management and interventions that can help that are reasonable and what to do when there are problems. And they’re all very scripted. The teachers have the best preparation, but the nurses have the second best preparation. Teachers come with a 3-ring binder with colored tabs, and everything’s all very organized and laid out. But the nurses are always very informed.

And I forget what the question here was really, but —

DR LOVE: I can’t remember either.

DR BURSTEIN: I think that the key point is that they’re going to have some side effects. So I think the biggest difference in taking care of a patient like the one Kelly’s alluding to is just really making sure they understand the side effects well because they’re going to know them, they’re going to look for them, and knowing how to anticipate them is very important for that particular cohort of patients.

DR LOVE: So any time you hear about a premenopausal woman with breast cancer in the adjuvant situation, Kelly, the thing I’m going to want to ask you is what was her social situation and her thoughts about future childbearing?

MS FISCHER: She underwent neoadjuvant AC-T prior to all of her adjuvant therapy, so she did meet with our reproductive medicine specialist.

DR LOVE: No kids?

MS FISCHER: No kids. No.

DR LOVE: No life partner?

MS FISCHER: No. She was single. So she actually lived with roommates. She just got a dog when she started chemotherapy, and that actually was a great source of stress relief. She was able to walk the dog every day and exercise.

So she did all of her reproductive stuff prior, before chemotherapy.

DR LOVE: So that leads us to our next topic, which is really fascinating, involving just over the last couple years, a trial, and now we’re doing clinical research on getting pregnant after the diagnosis of breast cancer. And Melissa has an incredible case of an example of that. I guess it’s only been a year and a half. Is it a year and a half since POSITIVE was presented? It seems like 10 years, but it’s a year and a half since these data came out. What happened with your lady, Melissa?

MS RIKAL: So when my patient was diagnosed we actually didn’t have any data. So either way, with data or not, this is a very difficult conversation to have because I mean honestly for some of these women the drive to bear children is even stronger than the drive to treat their cancer. And so it’s a conversation that we usually have very much initially when they’re diagnosed with an ER-positive breast cancer. Whether they need chemotherapy or not factors in. If they do need chemotherapy we’re talking about considering fertility treatment, potentially an egg retrieval, because we know it can throw them into menopause or affect their fertility. If they don’t need chemotherapy then we’re still talking about potentially 5 to 10 years on an endocrine therapy, and obviously you cannot become pregnant if your estrogen is suppressed.

DR LOVE: What was this woman’s social situation and her issue — interest in having children?

MS RIKAL: She was 34 years old, and she was married but had not had any children yet.

DR LOVE: And she wanted to have children.

MS RIKAL: And certainly wanted to have children.

So she was fortunate in the sense that they had the financial means to go ahead and pursue fertility treatment. Because she was 34 the concern was she needed to be on tamoxifen for 2 years prior to considering a break to try to get pregnant, which is what we normally recommend to patients, really try to stick it out for 2 years, and then you can potentially take a break and try to conceive. That would have put her at age 36, and as we all know the higher the maternal age the less chance of fertility.

So she did pursue fertility treatment. She took 2 years of tamoxifen. She was actually a little bit higher risk. Her Oncotype was fortunately low, but she had a micrometastasis in one of her lymph nodes. She had a fairly decent size tumor at 2 cm, but obviously felt very strongly that she wanted to have children. This is a quality-of-life discussion for these patients. If they have these goals, I mean, that is something that is very important to them, so we always try to support them in that decision.

She actually did take her tamoxifen religiously for 2 years, took a break, very quickly got pregnant since she had frozen embryos and was able to do IVF, breastfed for a few months, and then went ahead and aborted that and went back on her tamoxifen for a year and a half, then took another break, had another baby. So she successfully had 2 pregnancies, and she is planning on restarting her tamoxifen soon. Her last baby was just born this past January, so…

The recommendation we usually give is to pause endocrine therapy for 2 years, give it a few months to wash out of the system, and then they can try to conceive.

DR LOVE: And this was based on a trial presented by Ann Partridge from Dana-Farber, where Hal and Kelly are, where they did this. It wasn’t a controlled study, but they took lower-risk people, stopped their hormonal therapy, allowed them to get pregnant. 75% of them got pregnant, went back on their treatment. I guess the key issues here, Hal, are A) even beyond this does pregnancy itself have an adverse effect on breast cancer is 1 question. And I guess the other issue here by looking for low-risk people one of the issues is going to be if you have a patient with breast cancer get pregnant she may develop metastatic disease, and now a child has a mother with metastatic disease. Very complicated ethical and personal situation.

But Hal, basically everybody has to understand what we know about this and how it applies. Any other thoughts about it? I don’t think any of the — anybody else on the faculty has seen a woman get — do this twice. But any thoughts about how this played out, Hal?

DR BURSTEIN: Well, the first thing to say is the single hardest discussion in breast oncology is the care of a woman who is pregnant and is diagnosed with breast cancer and needs treatment. And the second hardest conversation is a woman who’s a young woman who wants to preserve fertility, anticipate fertility, but still needs chemotherapy or hormonal treatment. And as Melissa said, there are big challenges, going to the high-risk OB service, lining things up if IVF is an option. For very young women they will often retain sufficient fertility. We know that ovarian suppression during chemotherapy can already reduce the risk of infertility afterwards, so that’s a very important thing.

The study, the POSITIVE study, was led by Ann Partridge in the US and Olivia Pagani worldwide. It was a very important prospective study which obviously was not a randomized trial but looked at the outcomes for women who took 2 years of tamoxifen or other endocrine therapy, consciously interrupted that treatment, attempted to conceive and then bear a child, and as Neil said the vast majority were successful, and then were scheduled to resume endocrine therapy.

And the question you might be asking is well how do you know what their outcome is, what do you benchmark that against? And what they were able to benchmark it against were the outcomes in the SOFT trial, which was a really important study that looked at using endocrine therapy in premenopausal women either with or without ovarian suppression, and they were able to use that as a matched cohort. And they showed that there was no excess risk from stopping the tamoxifen, carrying the pregnancy.

So I think there are just 3 things you have to remind yourself and patients of. The first, as Neil just alluded to, was that doesn’t mean there’s zero risk of the cancer coming back. In fact, in that study in women who had Stage III breast cancer, which was a small subset, 20% had recurrent breast cancer within 3 to 4 years. So it’s not that you escape the risk of breast cancer, it’s just that there’s no excess risk.

The second is that for most patients it looks reasonably safe in the short term, that is to say you can interrupt the treatment and then resume later on. And parenthetic footnote, we’ve spent a lot of time thinking about adherence and compliance with medications, but it turns out you can stop hormonal therapy for like 2 years and there isn’t really a major detriment. So once I learned that I stopped worrying so much about whether people were taking their tamoxifen every single day or not because you can miss a lot of pills and it really doesn’t change things all that much. And I think this has been really remarkable, powerful data for women.

The final caveat is we don’t really have long, long-term follow up. So these data were presented with about 3 to 4 years of follow up, and while it’s all very encouraging, and it’s a great story, and when Ann gives this presentation she has pictures of patients with babies, and you can’t top that when you’re giving a talk. But it’s a remarkable effort that they put into doing this study, and it’s just been brilliant. But the other small caveat is we don’t really know what the long, long-term consequences of interrupting the endocrine treatment will be.

So it’s a nuanced conversation. It is not a 12-minute get the patient in and out conversation. But I think it makes a lot of women feel much better about conceiving if they want that as part of their life goal.

DR LOVE: So I want to move on now and talk about CDK inhibitors in localized disease in the adjuvant setting. But I will say that we have a nurse practitioner on Zoom. Thanks for tuning in and sending in. She says she has a personal history of bilateral IDC, adjuvant chemo, bilateral mastectomy, reconstruction at 42. “I know work in a surgical oncology office. So you think it’s good for me to share my personal story with my patients?” Just something to think about. We’re not going to talk about it right now.

I think it’s a very interesting question.

The Role of CDK4/6 Inhibitors in Therapy for HR-Positive Breast Cancer

DR LOVE: But let’s talk about CDK inhibitors in the adjuvant setting. And just starting out with you, Melissa, I’m kind of curious how you explain to patients what a CDK inhibitor is and why we’re thinking about it or why you’re proposing it in a localized disease setting. Adjuvant.

MS RIKAL: Yeah. So a CDK inhibitor essentially pauses the cell cycle and its DNA replication. I think that’s an important conversation to have, particularly with patients in the metastatic setting that are on maybe palbociclib or ribociclib, which can cause neutropenia, simply because when we’re explaining the neutropenia we explain that although they’ll have neutropenia it comes with actually a very low infection risk. And that is actually because it is pausing those neutrophils in their replication and actually destroying the cells like it would with say chemotherapy.

Abemaciclib is actually the treatment that is approved in the adjuvant setting, and that one actually causes more diarrhea. So that is certainly a conversation we have to have very early on when we’re starting this because sometimes these are very young patients, many times they are working, and the diarrhea is in about I think 80% to 90% of patients, so it’s seen almost across the board. This can really affect their quality of life, their ability to continue working, caring for their children. And so we like to educate them very early on to have loperamide on hand, start that at the first sign of diarrhea, and how to take that with each episode of diarrhea and max that out and call quickly if needed and be very quick to dose reduce if needed.

DR LOVE: So I’m curious, Komal, how you discuss the potential use, and also how you bring in clinical research that’s been done and try to explain it. Here’s the most recent paper that came out on what we were just talking about. We know there are 3 CDK inhibitors, as mentioned. Abema is the one right now because it has the data from this trial. And while this may not look that impressive, in fact it was a pretty substantial improvement in the chance of relapse. And also, as was just mentioned, we see a lot of tolerability issues, or some tolerability issues, particularly in terms of GI issues. So how would you take that scientific data and explain that to a patient?

DR JHAVERI: Yeah. So I think the very first part that we do is talk about how they work and what did they show in trials in when we studied them, right? I think the very fact that they add on to what we already have — so endocrine therapy provides benefit, prevents risk of recurrence, has an impact on mortality. What does this bring to the table? I think that’s the very first conversation that we try and have. This is how they work, this is what they showed, not only that they improved the disease-free survival, so the very first time they had an event, they actually had an absolute benefit in distant recurrence-free survival. So any spot that can happen outside the breast in a distant site, that survival was also improved, and the absolute benefit was 7%. So I think that’s the first conversation we want to have.

Certainly when you’re adding a therapy you’re adding more toxicity and more side effects to the regimen. And so then the second conversation then shifts gears and talks about what does that mean on a daily basis. How do you take the pills? Do you take it twice a day? So abemaciclib is taken twice a day. You want to talk about that. And then you want to talk about what do they expect. What do they expect them in the first 2 weeks. What do they expect overall. How should they be feeling about it so that they can prepare themselves for what’s to come and more importantly communicate that back to us as a team.

So I think it’s very, very important that we educate our fellows who take the calls, our nurses who are the first line of defense who actually talk to the patients first and really get all the information from them, and then more importantly our patients so that they actually pick up the call or send a portal message to us and say hey listen, this is what’s happening. What should I do?

So preparing them for the diarrhea is the first thing I do. Tell them about what supportive management they can take, what kind of antidiarrhea medications they should be taking. And I think one interesting analysis that was recently presented was actually in patients 65 and older, and what was really interesting to me that really stuck with me was about a third of these patients discontinued abemaciclib in the first 6 months. And these were patients who did not even do any dose reduction or dose interruption. They started the drug, and a third of them discontinued the drug due to side effects.

So this is an opportunity for us to really educate our patients, make sure that they understand this is what they expect, how we can deal with them, and there are dose reductions available. So not every patient can tolerate the same dose, and some patients might require a lower dose, and that’s okay. What has been shown in these trials is even with a lower dose the efficacy is not compromised, and I think that’s very important for us to convey so that we can actually help our patients understand this. They can communicate back to us. We hold therapy. We dose reduce when we have to. So I think this is something that we really want to discuss.

DR LOVE: So we’ll talk more about the 3 available CDK inhibitors when we get into metastatic disease, but — particularly in terms of the tolerability issues. But another thing about adjuvant therapy, Kelly, that’s very kind of tricky I think, is to try to explain the benefit because when you have metastatic disease, and people have symptoms, and you talk about survival, you can see the effect of the treatment.

But in the adjuvant situation they don’t have disease that you can measure, so it’s really the risk of recurrence, that we know has as the analogy that was just made, you have a hundred people, and fluoride is a perfect analogy. We don’t even know who benefits at the end of the day. We just know as a group they benefit more. They still might relapse. And keep in mind that some of these people, even if they have high-risk tumors, may survive fine without any therapy whatsoever, right, because there’s always some, even the highest-risk people, who somehow have an immune system that prevents them.

So when you have a therapy that has not only physical toxicity but financial issues that come in. And really that is where patient, I think, involvement gets in.

Let’s just talk about — you have, actually, Kelly, you and Hal have a patient together, a 66-year-old woman who got adjuvant abema but interestingly on the TRADE trial, which I think — and this is something we’re going to talk about the whole time, all 8 of these nurses on the web are talking about the same thing, adherence and keeping people on therapy and dose reduction if you need to in order to do it. Any thoughts, Kelly, again?

MS FISCHER: Yeah. So we have a 66-year-old female. She has a high-risk hormone-positive breast cancer, and part of her adjuvant therapy is use of abemaciclib, and she’s also on letrozole. So we have the TRADE trial at Dana-Farber, and it’s looking at dose escalation of abemaciclib just to see if we can make this a little bit more tolerable for patients.

So what they do is they start at the lowest dose of 50 mg BID for 2 weeks and then they move up to 100 mg BID for 2 weeks. And then the goal is by 12 weeks we can get them up to 150 mg BID.

So this woman, she did great at the lowest dose. No issues at all. No diarrhea and no other side effects. We moved her up to 100 mg twice daily, and then she started to have a little bit of diarrhea, a couple bouts of diarrhea, mild nausea, but it was well controlled with loperamide. And then once we got up to that 150 mg twice daily dose we started to have a lot of diarrhea. Daily diarrhea, taking loperamide several times a day. She was actually having quite a bit of nausea and a few episodes of vomiting as well. So it got to the point where that dose was not tolerable for her, but we had the option of going back down to 100, and she did just fine and continues to do fine.

So I think that we have to always remind our patients that we have multiple doses. Just because you’re at a lower dose it doesn’t actually mean that it’s less effective. It’s still effective. It’s just going to be better tolerated for you as an individual person.

DR LOVE: And, actually, the FDA is putting more and more pressure on trials to try to get the right dose before we even start using therapy. This is throughout oncology you see this dose escalation strategy. It’s used in breast cancer with the post-adjuvant neratinib in HER2-positive disease as well. So it’s an important strategy.

I want to move on now and talk about metastatic disease because there’s so many new things there. I mean, the adjuvant CDK thing is still, I think, fairly new and really important. And incidentally, this woman had 6 out of 6 positive nodes, a seriously high-risk patient.

But I wanted to talk first, before we dive into the biology and all these new drugs, a little bit about just taking a breath and thinking about coming into clinic to see a patient who’s gone through adjuvant therapy, that we just talked about, maybe adjuvant chemo, maybe hormonal therapy, and now in spite of that has metastatic disease, and you’re going to walk in and discuss the plan. Here’s Mr Stein talking about what he thinks about at that point when he sees a patient like that.

MR STEIN: These are cancer survivors that we’re dealing with, and once they feel that they’re cancer-free, they’ve made it through everything, they reached that light at the end of the tunnel, and whether it’s a month or a year or 10 years from reaching that light it can happen any time.

I think it’s very, very important to let the patient express those emotions, whether or not that’s anger, sadness, crying. I think just being present after you’ve said what you need to say. Let them take some time to process.

And instead of jumping right into “now listen, everything’s going to be okay, we have a plan for you,” and all that, kind of let them process this, this news. This is devastation.

Their life sometimes goes flashing before their eyes. Many have children. Many have grandchildren. Many have entered into new marriages, new partnerships, new jobs.

I like to have a plan ahead of time, and I work with fabulous oncologists, and we know going in there what we’re going to offer or recommend to that patient because they will want to hear some sort of plan. So I want to be prepared.

DR LOVE: So Melissa, I saw you nodding your head several times apparently in agreement. Any thoughts?

MS RIKAL: I just think with our patients they’re so well informed, and the more you can give them the more they feel comfort, and they feel trust, and they can have some peace with this state of their disease. Metastatic breast cancer, particularly I think with ER-positive, can sometimes be very isolating for these patients that were in the curative setting, and now they aren’t. One in 8 women get breast cancer, so you can run into any woman, and they may have had breast cancer. Well, a lot of them are in the curative setting, and so this can be very isolating for our patients to suddenly be in this metastatic state, and they can certainly be in denial. So the more we can have a plan I think the more they can have comfort and be able to focus on next steps.

DR LOVE: So I want to talk now about the strategy of managing these patients in the metastatic setting in this situation. Of course, we could talk a lot more about the topic. We again, just dipped our toes into there a little it, but there’s a lot to talk about there in terms of really how to try to begin to prepare a patient to deal with this.

And I guess I’m curious, Komal, too. Do you have patients who regret going through adjuvant therapy? You mentioned before well you don’t want to have any regrets that you didn’t take it. Do you see people who say why did I go through all this?

DR JHAVERI: Yeah, no. That happens a lot actually. This unfortunately happens in a third of these patients who despite doing everything that was discussed with them they still land up being in a boat where they are dealing with recurrence. And again, the why me question always comes up. I did it all, and why me? And I think that’s a very difficult conversation each time that happens because all we can do is offer them the support that they need at that time.

So I completely resonate with what was said. Hear them out. Let them just express their anger, their fear, their feelings at that time because there’s a lot going on in their heads. But at the end of the day I think we have to assure them that there is something for them. Yes, the situation has changed. It’s not curable, but it is treatable, and there are a lot of advances. And we’re here for them as a team to work with them to make sure that we can get them through this phase because there’s only one way to deal with it, it’s actually go through it, right? Because I think dealing with why me is not going to necessarily make you move on, but we need to give them that time because they do need that time.

So I think it’s just providing that support that they need, being a good listener, and I think just having them be able to communicate with you what they’re actually feeling and what their main fears are about this new diagnosis and about the treatments and survival and what’s going to happen to them and their families.

DR LOVE: So Hal, we talked before about — and we showed the slide with the 3 CDK inhibitors that are approved right now in the metastatic setting. Can you kind of provide an overview of what patients go through? You have 2 in terms of palbociclib and ribociclib, kind of similar, and then abema on the other side, different schedule, different approach. Can you kind of paint a picture of the choice of CDK inhibitor in the metastatic setting and kind of what the implications are in terms of managing the patient?

DR BURSTEIN: Absolutely. I just want to echo what you’ve heard from Komal and on the video, which is that these are really difficult conversations, and that sense of could I have done more, should I have done more, is a real thing. And I think most of the time the truth is we can actually reassure patients that they did the right things. ER-positive breast cancer has a relatively indolent history. There are more recurrences after 5 years than there are in the first 5 years. The marginal impact of longer durations of treatment or of aromatase inhibitors versus tamoxifen or of ovarian suppression or even of chemotherapy or not are all pretty small.

And interestingly, what I thought the videotape referred to is really that horrible sense that people have that they’d finally escaped the clutches of this disease, and then it reached out of the grave and pulled them back in, and that’s very demoralizing. But most patients understand that the small things, even these clinically important but not such huge issues, are not really what determine the cancer coming back or not. It’s fundamentally something about the breast cancer, which remember has metastasized before the surgeon met the patient. We’re talking about disease that has been occult at the time of their diagnosis, and there’s something about the biology of that disease that has meant that has persisted despite all of the therapy that they have endured and all of the sacrifices they’ve made.

But those are hard days. And I know all of you deal with this every day of the week, as do we, but those are hard conversations.

DR LOVE: And this tragic situation of a patient 5, 10 years later now having metastatic disease is kind of unique to breast cancer, I would say, in oncology. A lot of the solid tumors you get through 2 or 3 years there are very few relapses. Breast cancer, nobody knows why, but it seems to be different.

Let’s talk about a patient. I want to go back and forth between patients. And I guess, Hal, you and Kelly had a 72-year-old woman who started out — actually it looks like she started out on palbociclib plus fulvestrant and then ended up getting switched over to another one. So Kelly, what happened to her?

MS FISCHER: So our 72-year-old patient who was on palbociclib, and then she progressed with the palbociclib and letrozole. We switched her over to fulvestrant.

DR LOVE: So she progressed?

MS RIKAL: Eventually. Well, next step.

DR LOVE: Okay.

MS RIKAL: She progressed on palbociclib, and then we switched her to fulvestrant. She had a difficult time with her blood counts. With palbociclib you do have to check their blood counts every 2 weeks for the first 2 months that they’re on therapy and then monthly after that.

So she had issues with neutropenia which required a couple of dose reductions. So we were trying to deal with that. So count issues were a big thing for her. And then later we progressed again, and she’s actually now getting the alpelisib because she has a PIK3CA mutation.

DR LOVE: So yeah, we can talk about what happened. It looks she went on a trial with a degrader. Does that sound right? ARV-471?

DR BURSTEIN: Yeah. So one of the classes of drugs that’s emerging in advanced breast cancer are additional so-called selective estrogen receptor degraders, or SERDs. You all know fulvestrant, which is an injectable SERD, but many companies have now been developing orally available SERDs. One of them is FDA approved. It’s called elacestrant, and it is indicated in patients who have ESR1 mutations within their tumor. That’s usually an activating mutation in the estrogen receptor, so it turns the estrogen receptor on even if there’s no estrogen around. I describe it to patients like the gas pedal is stuck to the floor. It’s just constantly driving the tumor forward.

And so this oral medicine elacestrant has been approved specifically for use in women whose tumors harbor ESR1 mutations, which is an acquired mutation. So the footnote point here is you might do genomic testing on the original tumor or at time of initial recurrence, but you have to do that serially nowadays because we are looking for the acquisition of ESR1 mutations which might predispose to the need for a different kind of medicine.

Another example of that class of drugs is a drug which is still a research or investigational drug from a company called Arvinas being codeveloped by Pfizer, which is called ARV-471, or vepdegestrant, and it’s actually a very interesting molecule because it has — it’s got a funny rubber-band shape, and one end of the rubber-band is like a broken rubber-band. One end of the broken rubber-band sticks to the estrogen receptor, and the other end targets the protein complex for degradation. So it sticks to this thing and then it ends up dragging the estrogen receptor to the cell machinery, which degrades proteins. And so it’s hopefully going to be another way to turn off the estrogen receptor even in the setting of these kinds of mutations or resistance to other endocrine therapies.

So there’s a lot of drugs in this space being developed. You’ll hear a lot more about these in the — undoubtedly in the months to come. And these are usually drugs we are using after the class of drugs called the CDK4/6 inhibitors, which have really emerged as the first-line partner for ER-positive metastatic disease.

There have been 3 drugs that have been commercially developed there, palbociclib, ribociclib, and abemaciclib. They have slightly different biochemical properties. Ribociclib and palbociclib cause somewhat more neutropenia. Abemaciclib, as we were talking about in the early stage, tends to cause a little more in the way of diarrhea or GI side effects. But in multiple studies either as a partner with an aromatase inhibitor or as a partner with fulvestrant they have all been shown to radically improve progression-free survival and in many instances improve overall survival as well.

So typically for most patients who have recurrent ER-positive disease our first line of therapy is going to be an endocrine partner with a CDK4/6 inhibitor. And we can go into the details of how we think about specific ones, but that’s kind of our first line of treatment.

And then the second line of treatment we start thinking about some of these other targeted options, including drugs we’re going to talk about in a minute that target the PIK3CA protein or the ESR1 mutation or things like that.

DR LOVE: And again, a lot of these things that we’re talking about I think relate beyond breast cancer in terms of the principles of what we’re talking about here.

I want to come back to you, Komal. We kind of alluded to the issue with the case of neutropenia. Can you just clarify that a little bit and also how the schedules of the CDK inhibitors work? And then another issue that really goes throughout oncology is you may have several agents that work in a very similar way. The CDK inhibitors, you have 3 of them, they look pretty similar, but unless you do a study that compares them directly it’s very hard. You have to compare indirectly, and that we know is very difficult to do, so you’re left trying to make judgments between looking at data sets indirectly. You might think that all of the drugs are the same, but only 1 of them has a positive study.

PD-1 inhibitors. There’s, like, 6 or 7. Nobody believes they are different, but yet you use the one that was studied in the trial because that’s the way it goes.

So again, can you apply that model, Komal, to selection of a CDK inhibitor in the metastatic setting? What are the things that you’re thinking about as you think about the trials of the 3 agents, and then how do you recommend to the patient?

DR JHAVERI: Yeah. So again, I think, as we said, there are 3 CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib. And so when we looked at the clinical trials we designed them for their primary endpoint, which is the main thing that we’re evaluating to say whether this drug is really going to make an impact or not compared to what we were already doing as a standard of care, which was endocrine therapy alone. And across all these studies with all 3 agents we learned that they all caused a significant improvement in progression-free survival, as Dr Burstein was just referring to. And so it did seem like they are a class effect in many ways, right, because all of them try to give you the same progression-free survival benefit, and the hazard ratio, which is the statistical assumption that we look at, looked identical for all 3 of them.

Then how did they look — started looking different? Of course they have slightly different toxicity profiles. And I love our analogies that are coming out on the podium today. I’ll give you 1 more analogy with CDK4/6 inhibitors that I try and explain to my patients about. So I think about them, if you think about a glass of sodas, right, I think about palbociclib and ribociclib as the Pepsi and the Coke, kind of similar flavors and similar tastes in terms of toxicities. They both have more neutropenia. And I think about abemaciclib as a Dr Pepper. All 3 of the soda family but slightly different, right? And so this Dr Pepper gives you more diarrhea and doesn’t give you that much neutropenia. So that’s how I think about them. They are similar, but they have their differences.

And the differences is because they all try and inhibit CDK4/6, which is why they are called CDK4/6 inhibitors, but abemaciclib goes and inhibits other cyclin D kinases as well. So it inhibits cyclin 1, cyclin 9, and because of that differential inhibition of additional cyclin kinases it has a slightly different toxicity profile that we think about and explain to our patients.

Ribociclib has slightly more CDK4 compared to CDK6. It’s more CDK4 selective. But they both cause neutropenia in a similar way.

Why do I think which agent to choose? I think in terms of scheduling that Neil was referring to ribociclib and palbociclib are given intermittently, 3 weeks on, 1 week off. Abemaciclib, on the other hand, we could dose continuously. And so could that be a reason that it behaves slightly differently? It definitely was effective in the early-stage setting. This is the only CDK4/6 inhibitor which was also provided with FDA approval as monotherapy in a late-line setting. But we use CDK4/6 up front, so we don’t think about utilizing single-agent abemaciclib at the backend, but when we were developing that was an attractive data set that we got for abemaciclib. So these are the main toxicity differences and scheduling differences.

When it comes to choice of therapy the only drug that has consistently shown overall survival benefit, which was not the primary endpoint, was ribociclib. Whether it was in the first-line metastatic setting with aromatase inhibitors or fulvestrant, whether it was in the second-line setting with fulvestrant, or even with the NATALEE now in the early-stage setting, at least the results initially in the early readouts have shown that it is effective. So it has consistently shown overall survival benefit.

On the other hand, palbociclib, we were not able to show the overall survival benefit. It could be various reasons. There’s some missing follow up data. We don’t have the power to look at overall survival the way we did with progression-free survival. There could be many reasons. We don’t have head-to-head trials, as Dr Love was saying, to be able to show superiority. But if I have a patient in front of me, and I’m discussing all of the efficacy, and I’m discussing all the data, why not ribo is how I think about it now that I know all of the overall survival benefit. So if I have to think about it I’ll give that.

If a patient develops side effects — for example, with ribociclib we also have to do EKG monitoring, and we look at a value in the EKG, and number called QTc, and because patients sometimes are taking other medications there is a higher risk with ribociclib to make that number go high. If it goes really above 500 there’s a risk of an arrhythmia that you don’t want for your patient. So we test for it up to 3 times in the first 2 months.

If somebody were to develop that or liver toxicity I’ll be very comfortable switching them over; maybe to palbociclib, maybe to abemaciclib. Very comfortable switching them over because I think we know that these drugs work, it’s just that we have a consistent overall survival signal with ribociclib, and this is why my practice has now moved to ribociclib in the metastatic setting.

DR LOVE: So when you talked about the different sodas I know my team over there was laughing because I always get so angry that the Marriotts don’t carry Diet Coke, right? They have Dr Pepper but not — so it’s like regulatory, right? It’s like you’re in a country that doesn’t approve Diet Coke or something.

Anyhow, just again, a theme that goes throughout oncology, progression-free survival or disease-free survival and overall survival. We heard Komal talking about overall survival. That’s different in the adjuvant situation, where you’re looking at the possibility of cure, but in metastatic disease the survival can be greater, but that doesn’t mean they’re cured. So a different situation. Again, patient involvement in treatment decisions when you start to get into these borderline benefits and then toxicities, financial issues, et cetera.

Oral Selective Estrogen Receptor Degraders in the Management of HR-Positive Metastatic Breast Cancer (mBC)

DR LOVE: And in a second I want to hear about your patient who got elacestrant, the oral SERD that Hal was referring to, as we start to move now onto post CDK, right? So typically the patient’s going to get endocrine therapy. It could be an AI if they haven’t had one. If they relapse while they’re on an AI they’re going to get fulvestrant and a CDK inhibitor.

And the other issue is in terms of, Kelly, one of the things that we’ve seen is that the longer the patient stays on the CDK inhibitor the better they’re going to do in the next line of therapy. And it kind of makes sense. People who go on endocrine therapy and then progress, have progressive disease in a year, you would imagine that the next endocrine therapy maybe is not going to work even better. But if they’ve had a couple years, and your patient I think had 3 years, which is a pretty good response there. Do you explain that to patients, as well, Kelly, that the variability in how long this is going to work?

MS FISCHER: Yeah. So for some women they can be on these medications for 8 years and do beautifully, and we have others who aren’t as long, a year, 2 years. That’s still good. So we tend to talk to people about how this line of therapy, your first line of therapy, we hope that this will give you the longest benefit, and then subsequent lines of therapy tend to be a little bit shorter and shorter. So I think that a lot of women in the metastatic setting they kind of have in their mind a list of all of their treatment options that they’re going through, and they’re kind of like ticking it off box by box. And like as you get lower and lower on that list the anxiety builds higher and higher.

So I think that as a provider we have to give people hope while staying realistic at the same time, and it can be challenging in a lot of ways, so…

DR LOVE: So one of the themes in oncology in general, and you’re going to hear this over and over this week, is biomarker-based therapy. So we’ve now moved into an era where we’re looking in the tumor, we’re looking at the genomics of the tumor, the DNA, the RNA, and finding mutations and many other things inside tumors that then lead to specific therapies based on the biologic pathway that seems to be abnormal. So that’s the vision. We haven’t exactly got there 100%, but we’re kind of working our way towards it. And it really relates to when we talk about the issue of a patient who’s progressing on a CDK inhibitor because there’s a new paradigm that most oncology people aren’t even aware of, I mean they are aware, but when we ask them they don’t really have it in their practice, which is a triple biomarker approach. Three biomarkers that patients now need if we’re going to be able to determine what therapy they’re using.

Komal, we just did a CME program for oncologists just about this. So can you kind of go through — and we’re actually submitting a paper to the San Antonio Breast Cancer meeting about this triple biomarker to increase people’s awareness of it. But can you kind of explain what the biomarkers are, and I mean is it logical when you hear you’ve got a patient who’s progressing on a CDK for a nurse to look at the chart and see if they had it done?

DR JHAVERI: Yeah. Absolutely. So I think we spoke about CDK4/6 inhibitors where it was really an easy choice. Patients with ER-positive tumors, it’s the first-line metastatic setting, we have robust data now that says if you use CDK4/6 inhibitors we really do very well in terms of progression-free survival. And in fact, with the ribociclib program overall survival was over 5 years, which is very encouraging, with just first-line therapy.

But then post CDK4/6 inhibitors these tumors start behaving very differently. And what biomarkers are meant to do is try and give us a snapshot or an understanding of what an individual tumor might be dependent upon. What does it really fueling upon? What is it using to continue to grow and progress? And can we identify that such that we can use that information and provide patients with a recommendation with a drug that specifically goes after that finding? So it’s refining our knowledge to understand what is it that the tumor is thriving on and can we take that away from the tumor. And that’s what biomarkers are really supposed to do.

And so in ER-positive breast cancer post CDK4/6 inhibitors, Hal was just mentioning, one of the ways that we think about is ESR1 mutation. And this is what he was saying; that the pedal is stuck on the accelerator. It’s just down, and we know that it’s using the ER pathway even when estrogen is not there to bind with the receptor. It just keeps going through that pathway and can we use a novel endocrine agent beyond fulvestrant, beyond tamoxifen, beyond aromatase inhibitors to specifically go after that mutation, that ESR1 mutation, which is driving that tumor?

DR LOVE: That’s actually a mutation in the estrogen receptor. That’s ESR. That’s the estrogen receptor mutation.

DR JHAVERI: Exactly.

DR LOVE: So it no longer — it mutates, and now it doesn’t respond to the same endocrine therapy.

DR JHAVERI: It doesn’t. And it still is dependent on that ER pathway. It just keeps going, right, because it’s mutated, but it’s dependent on that ER pathway. So these novel drugs are now being utilized to use that information that we got about ESR1 mutation and really try and impact on the tumor with that. So that’s where elacestrant got approved, and that’s 1 biomarker.

Another biomarker that we think about in hormone receptor-positive breast cancer are mutations in a pathway called the PI3K/AKT/mTOR pathway. And one of the most common mutations that we see in this pathway is the PIK3CA mutation. And about 40% of hormone receptor-positive tumors harbor this PIK3CA mutation. We call them as a clonal or a truncal mutation, truncal meaning whether you test tissue from the primary breast tumor, whether you test tissue from the metastatic site, you are going to identify that mutation if it were present. It’s truncal. It’s always present. It’s not necessarily acquired. There are mechanisms where it can be acquired. We don’t necessarily quite understand how they would behave, but predominantly this is a truncal mutation.

And now we have 2 drugs that are now approved that can specifically go after this mutation and try and use that information to have an impact on patients’ tumor progression-free survival and survival — and outcomes. And these are alpelisib, which is specifically targeting the PIK3CA mutation and capivasertib, which is an AKT inhibitor, which not only can have an efficacy in PIK3CA mutations but other mutations in the pathway, including AKT mutations and PTEN mutations. So together these 3 mutations are about 45-46% in hormone receptor-positive breast cancer, and now we have both of these drugs in combination with fulvestrant approved to go after that.

So these are the kind of information that we use in addition to PARP inhibitors, which we use for germline BRCA mutations. So this is something that we test in the blood, and we see if there is a risk for developing this breast cancer in the family or that patient who is very young when diagnosed, and if they have that germline mutation we have PARP inhibitors that are approved in the metastatic setting and also in early-stage setting.

DR LOVE: So I’m curious. I want to ask Hal in a second about so-called liquid biopsies and also tissue biopsies, but before he does just to come back to you, Melissa, in terms of this new entry, elacestrant, a newly approved drug. We’re going to talk a little bit more about it. But I am curious in general what you’re seeing in terms of tolerability with these patients.

MS RIKAL: Actually, it is quite well tolerated. I have a patient on it now, and she has passion for going to Disney World like multiple times a year, and she still goes, and walks all the parks and does her things. But really in trials in real life we see very low-grade side. So most prominently we can see nausea in about 30% of patients, but that’s, again, very low grade. So I like to just give my patients an antiemetic to have on the front end so that they have that for their own comfort, that they have something on the shelf in case they get nauseous.

But really, something as simple has having the patients take this with food is sometimes effective against the nausea. And they want to take it around the same time each day. It’s a once-daily dose taken every day, so very, very simple. So normally I just say whatever meal is your most predictable meal, which usually I think is breakfast, take it with your breakfast every day, and that should help with the nausea.

We can see musculoskeletal pain. This patient that I have that’s on it, she does have some bone pain, but that was there at baseline. She has bone metastases. I mean, most of our patients in the metastatic setting do have bone metastases, so we’re already treating that. So sometimes you may see that exacerbated a little bit, so managing that pain appropriately.

We can also see a little bit of high cholesterol with this, which we can see with some of the other estrogen — estrogen affecting agents, and some fatigue, just like we do with most of our oral oncolytics. But really honestly very well tolerated.

DR LOVE: So in a second, Komal, I’d like to hear about your 58-year-old lady who actually received elacestrant. What we’re going to present at San — what we’re going to submit to San Antonio is we just took these 3 biomarkers, and we said if this one’s positive, these — every possible permutation, we saw a lot of differences. We’re just going to present it. But the point is that you need these biomarkers in order to even get started.

And Hal, that leads into how you get it. Obviously, we’re going to get tissue at the initial diagnosis, whether or not we’re going to get it later or not depends, but we also now have liquid biopsy. And again, this is a theme throughout oncology, tissue and liquid biopsies. What about in breast cancer, Hal?

DR BURSTEIN: Well, first of all, there are different genomic or genetic tests that you will look at in different tissues. But I think what’s really changing in breast cancer is this idea that there needs to be dynamic evaluation of these markers, so you always want to biopsy a site of metastatic disease at the time of recurrence to prove that it’s metastatic cancer. Any of you who see a lot of patients will know. I had a patient in clinic this morning who we were sure had metastatic disease to the lung, but it was biopsied, and it was a primary lung cancer, and so she had a curable lung cancer. You’ve seen sarcoid or you’ve seen lymphoma or all these other things.

So the first thing is you want to get a biopsy, and then you repeat ER, PR and HER2, and those are all very important mutations for dictating really the pathway that you’re going to pursue. And the pathways for hormone receptor-positive disease look very different nowadays from triple-negative or HER2-positive breast cancer.

The other question is what source of tissue are you going to look at. So Komal just alluded to hereditary breast cancers with BRCA1 and BRCA2 mutations. Of course that’s — you can do any test in any tissue in the body. You can do blood, you can do buccal mucosa, and that will tell you what the hereditary nature of the mutation is. So that’s an important piece of information. And at some point in the course of their illness every woman who has metastatic disease should have BRCA1, BRCA2 and actually a third marker called PALB2 testing because that would make them a candidate for a class of drugs she alluded to called PARP inhibitors.

Then the second thing we want to look at is whether the tumor is carrying a mutation from its genesis, its moment of origin, and that’s where the PIK3CA tumor is defined. You can biopsy a primary breast cancer or a metastatic biopsy site and find the PIK3CA mutations, and those will carry through, usually through the life of the tumor as it evolves.

And the third mutation we’re talking about is what Neil’s pointed out, is the ESR1 mutation, this estrogen receptor mutation. That’s not present in the primary breast cancer. It only arises in the setting of development of resistance to initial endocrine therapy. So you have to check for that serially.

And what’s emerged as the easiest way to check for these is a liquid biopsy. So essentially you are taking a blood specimen, and you are looking for the very small fraction floating around in their DNA, which is actually from the tumor. But the technology is such, and I’m sure you’ve all dealt with these reports, but they can now look in the bloodstream for the presence or absence of these specific mutations, and that’s been really helpful as a really convenient way to do this. It usually takes about 2 weeks in my experience to get a turnaround from the commercial labs. It doesn’t require a repeat tissue biopsy, and it tells you a lot.

So if you take care of lung cancer you’re very familiar with all of this. They’re doing it in all their patients now, of course. But increasingly we’re doing this in breast cancer as well.

It doesn’t provide all the information. So not at our panel tonight, but at one of the programs later this week you’ll be talking about antibody-drug therapy — antibody-drug conjugates, and there’s a drug, trastuzumab deruxtecan, which is approved for breast cancers that are HER2 3+ positive or for HER2-low positive cancer, so we’re often going back and testing for HER2 status. That’s on the tumor itself.

And finally, there was a blanket FDA approval for all strongly HER2-positive tumors just a week ago for this same drug. So this means if you take care of particularly gynecologic tumors, where they don’t necessarily routinely test for HER2. You’re going to be calling your pathologist next week and saying every patient you’ve ever seen who has metastatic disease is now got to get tested — have the tumor tested. That’s not a liquid biopsy, that’s a tumor immunohistochemistry assay, to see if they’re going to be strongly HER2-positive and therefore a potential candidate for the same drug.

So this technology is extraordinarily powerful, and we’re not quite there yet in breast cancer, but the other thing you can do with this technology is you can do semiquantitative measurements of cancer burden. So when you measure the liquid biopsy they can give you an estimate of how much tumor DNA there is in the bloodstream. And that actually — we’re seeing small studies not showing that that tracks pretty well with the overall burden of metastatic disease in advanced breast cancer.

So wouldn’t it be great, if you can imagine a time in the future where you check this test, and instead of getting a CT scan to see if the cancer is subtly changing you can tell quantitatively what the burden of breast cancer is, akin to what a tumor marker like a PSA would tell you in prostate cancer or a CA-125 in ovaria cancer. And I think we’re all very hopeful that this sort of platform technology is going to be a very routine part in the future.

DR LOVE: So tomorrow 12:15 in this room you’ll learn why every single patient with metastatic solid tumor, particularly if they don’t have any option, you need to check their chart now and see if they have had HER2 tested because they could be eligible to receive T-DXd and maybe have a great response.

I want to hear, actually, about your case of the patient who got elacestrant, Komal. This is a 58-year-old lady. What happened, and how did she do on the elacestrant?

DR JHAVERI: Yeah, no. So she was detected to have the ESR1 mutation, and we started her on elacestrant therapy. Tolerated it reasonably well; some low-grade nausea that was very easily manageable. But yeah, overall we’ve seen that this class of drugs, they’re oral drugs, some differences in the various different drugs that are being developed, one of which is approved, elacestrant. And the most common toxicity that we saw with that drug was nausea, although only 8% of these patients required antiemetics, so overall very low grade, very tolerable side effects. Some fatigue that you can expect, maybe some hot flashes or things like that.

But we don’t see the traditional side effects that we see with aromatase inhibitors in terms of crippling joint pains or arthralgias or myalgias, or we don’t see very predominant hot flashes or vaginal dryness with this drug. So hopefully this is something that we’re going to see with the other drugs, as well, which have some differences in their side effect profile, but predominantly low grade.

DR LOVE: You had made the point about how important it is to see how long they stay on a CDK inhibitor. How long was this woman on a CDK inhibitor? Yeah.

DR JHAVERI: So this patient was certainly more than 12 months, and that’s what the analysis we had looked at. I think the point of that analysis where we saw what happens if patients stayed on their first-line therapy for at least 12 to 18 months versus those that potentially had the tumor progress early on. I think that’s another way, another surrogate if you will, to say that this is really dependent on the estrogen receptor, right?

If you have an endocrine-sensitive tumor that is sensitive to estrogen therapies, you are going to have response in the tumor for a longer duration of time. And because you’re staying on that drug for a longer duration of time under the selective pressure of the aromatase inhibitors you are developing the ESR1 mutation that keeps that pathway really plugged and making the tumor grow even more.

So when you combine both of that information together, meaning a patient who stayed on this first-line therapy for a long period of time and now also has an ESR1 mutation, that’s the patient that you really think would potentially derive the most benefit from a single-agent new endocrine agent, right? Because elacestrant is a fancy name, but at the end of the day, again, it’s an antiestrogen therapy. It’s just been made to now overcome issues such as ESR1 mutation that not all the other antiestrogen therapies are able to do.

And that’s what we saw with this patient as well. She was on a longer period of time, developed a mutation, is doing really well on elacestrant for a few months now and just has some mild low-grade nausea.

DR LOVE: Interesting. Again, here’s another situation with multiple agents being evaluated. There are a couple other SERDs, camizestrant is one, imlunestrant is another one. Indirectly I guess kind of hard to tell the difference.

Hal, one of the things I thought was really interesting, getting back to what you were saying about monitoring with liquid biopsy, I think it’s with camizestrant that they’re going to look in people who are in adjuvant setting and see if they develop an ESR1 mutation. And then even if their imaging is negative they’re going to switch to a SERD just because of that and see if they do better than keeping the endocrine therapy going until maybe they progress. Any thoughts about that strategy? And also the difference between these.

DR BURSTEIN: At the moment we don’t really know what the clinical differences are between these agents, and so as they work their way through Phase III studies it’ll be important to keep an eye on that and see which ones emerge and make it to market.

There’s a lot of interest in trying to use these drugs in different context. One of them, as you mentioned, Neil, is to look at higher-risk, hormone receptor-positive, early-stage disease and see if by switching to a drug like a SERD, which seems to have activity even if the tumor has this ESR1 mutation, that you might further forestall eventual recurrence of the disease. And in some of the trials they’re actually using another example of a liquid biopsy test for minimal residual disease to see if you can find occult fragments of tumor DNA in the blood, which would ultimately be a harbinger of a likely recurrence in the years to come.

I will tell you, if you’re talking to your patients, these assays, there’s one called Signatera, there’s others that are commercial available, they are all over the Facebook chat rooms, I am told particularly in Los Angeles. Does anybody here practice in California, in Southern California? Is this true? I don’t know if it’s true, but I’ve met a few patients recently. Every Facebook group of breast cancer survivors in Southern California is talking about doing minimal residual disease testing.

I would not do that on a routine clinical basis at this point for a couple of reasons. One is that as exciting as this technology is to find the presence or absence of molecular evidence of cancer we don’t know what the meaning of a so-called false-negative test is. So if you don’t find the DNA you don’t know is that because there’s no cancer or is it because your test was not technically successful? The other dilemma is if you have a positive test it’s usually a true positive, which is to say there is occult cancer somewhere there. But that’s what hormone therapy is designed to deal with, and many patients who have such a finding might still yet not recur or might not recur for years and years and years down the road.

So I would be about overinterpreting clinical results, but these assays are very much part of the cancer network dialogue right now, and they will be more and more built in to clinical trials. There was very provocative data in colorectal cancer about 2 years ago where they decided whether or not to give adjuvant chemo for colorectal cancer based on this kind of analysis. And that was a small but positive study, and it suggests that there’s a path there to really look at these kinds of, again, liquid biopsy tools. But my guess is you’re going to be hearing about this. I would discourage routine use of it at the moment. It’s just not quite there yet for knowing how to use the data to help patients.

DR LOVE: And as you could just see, if you ever want to kind of get your oncologist revved up, instead of giving him expresso just say, “What do you think about cell-free DNA and Signatera?” Really. But the person who did that study’s going to be here Saturday night to explain it in colon cancer. Because in colon cancer it’s not just theory, it’s reality. They are using it. They have Phase III trials to show it works in the adjuvant setting. There are many situations now in colon cancer you’re going to hear about Saturday night where if their MRD is negative, cell-free DNA, they’re not going to get adjuvant chemo. If it is, sometimes they get more intensive. So they’re 2, 3, 4 years ahead of breast cancer.

DR BURSTEIN: Well, we have our own marker.

DR LOVE: Again, controversial.

DR BURSTEIN: So we have our own marker. We look at lot at, for instance, pathologic complete response in the neoadjuvant setting. So it’s another way of figuring out how much residual disease is there. So if you treat in the preoperative or neoadjuvant setting, particularly in triple-negative and HER2-positive disease, and you achieve a pathologic complete response, we are using that information already to tailor the therapy. And that’s a similar idea, but there’s a lot more data for that than there is for the liquid biopsy at the moment. The liquid biopsy is coming, there’s no question about it.

DR LOVE: So Komal?

DR JHAVERI: Yeah. I just wanted to add on to what Hal was saying. I completely agree that in years to come I think we might see a future where we utilize this information and use this molecular detection even before imaging is showing anything and intervene and make an impact in outcomes. But today it’s challenging because with Signatera what we’ve shown so far in breast cancer is that it’s prognostic, meaning we can tell which would act as a bad actor, which would not act as a bad actor. But we’ve not been able to show yet is if we identify this bad actor what can we do about it.

So having the result is not going to be necessarily helpful because we don’t know what to do with it. All it is doing is generating more anxiety. You only want to order a test if you can act on it, and I think that’s the most important part. The biomarkers that we want to test in the metastatic setting post CDK4/6 we can act upon because we can identify that information, and we can provide recommendations to target that. When you can not do that it’s no point getting that test, and I think that’s where the dilemma is.

So I really get revved up because when I get second opinions, where patients have had that at another institution, and they come to me, and they say what should I do now. I’m like I don’t know. I would have not done it. So that’s the part that I struggle with a whole lot. But one day hopefully Hal and I will have something more meaningful to add on to that.

DR BURSTEIN: Or we’re just going to join the California Facebook chat rooms I think.

DR JHAVERI: I had a patient from Illinois, just so you know. It was not California. But I had the same issue.

DR LOVE: I don’t know if you’re aware of it, but we have a Research To Practice webinar pool, every time we do a webinar, about how long it’s going to take before an oncologist in the chat room’s going to say what about cell-free DNA. And on average, regardless of tumor, it’s within 15 minutes. So it’s a very interesting topic, but anyhow. We don’t necessarily know all the answers.

Alpelisib and Capivasertib in Treatment for HR-Positive mBC

DR LOVE: So let’s go on and talk about — another great model about what happens in oncology when you try to take research and apply is what we’re about to talk about. So Komal told you there are 2 drugs that sort of hit the same pathway except one of them hits both parts of it, capi. I’m just going to try to make it a little simpler. Two things. The other one, alpelisib, only hits one of them. So capi can be used for both, but alpelisib can be only used for one. So far, right? And then interestingly when we asked the oncologists what they want to do if they can use both they say capi. So Kelly, tell me why.

MS FISCHER: Well, so yes. I think that we prefer capi as well.

DR LOVE: Capivasertib, sorry.

MS FISCHER: Yes, capivasertib. So alpelisib is, again, a PIK3CA inhibitor. It has a lot of really harsh side effects, so hyperglycemia being one. Generally we have to check peoples’ fasting blood sugars for the first 2 weeks, so once a week for the first 2 weeks they’re on these medications, and then monthly after that. We also have to monitor their hemoglobin A1C at baseline and every 3 months.

We actually had a patient, Hal and I, who was on a PIK3CA inhibitor, the alpelisib, and within the first 2 weeks of being on this medication she had hyperglycemia in the 350s, and then her creatinine rose also over 1.5. So we had to get her hydration. We had to get her started on metformin. So it’s really tough with the hyperglycemia.

It can also cause rash. So typically we actually prophylactically start patients on cetirizine daily, and actually it’s been a really good way of preventing rash, I found, for the most part. So usually they’re on that for at least the first 2 or 3 cycles, and then if they don’t have rash we can take them off of it.

And also it can cause diarrhea, oral sores as well. So it’s a tough drug.

DR LOVE: So you don’t hear too much about hyperglycemia. There are a bunch of drugs that do it, but I’m not sure if there has been — well, we’ve had them in breast cancer as well. What’s the thinking in terms of why you see hyperglycemia? And getting back to the question of what the oncologists in the survey, the investigators in the survey, preferred. One of the things to me that seemed obvious is capi’s only given 4 days a week, although that has its challenges, and I’m curious how that plays out in terms of adherence. But it seems indirectly, again, it hasn’t been compared to alpelisib, indirectly it seems to have less issues, particularly in terms of hyperglycemia.

So Komal, do you think that’s the reason oncologists are preferring it?

DR JHAVERI: Yeah. I think as oncologists I think we do have now a subspecialty degree in gastroenterology and managing diarrhea now. But I’m not sure we’re very good endocrinologists and dermatologists yet, and getting access to that can be difficult to.

DR LOVE: Ophthalmologists.

DR JHAVERI: Ophthalmologists too. So I think as far as oncologists go our comfort zone kind of stops at metformin, and then if metformin is not controlling the sugars I think we lose it, and we don’t know what to do.

DR LOVE: Yeah, but they do. They do.

DR JHAVERI: Yeah. I think we don’t know what to do. We can’t keep up with all the newer medications. The SGLT2 inhibitors, what side effects they bring. What are the doses we require. What’s the next go-to drug? Will the patient require a third drug? That becomes very complicated, and getting access to the subspecialties may become more challenging in the community than in the academic center. Even in the academic center it’s not been easy to get your appointments to these subspecialties very easily.

And so once you have a bad experience and get scared about it I think it’s very hard to keep prescribing that drug, right, because you worry about that for all your patients.

When you think about capivasertib you are seeing a little bit more of diarrhea, which I think we’re comfortable managing. With neratinib, with abemaciclib I think we’ve become experts about communicating that, educating that, managing that.

We’re seeing some rash, and the rash that we saw in the capivasertib was without giving them that prophylaxis that just Kelly was talking about. So the hope is that maybe we start doing the same prophylaxis in practice for capivasertib, maybe the rash will be less. The diarrhea we can manage, the hyperglycemia was much less compared to PI3K inhibitors, and that’s why I think folks are naturally migrating to something that is giving you similar efficacy, but potentially better toxicity profile compared to your patients.

And your question about why hyperglycemia happens in the first place is while we’re targeting the PIK3CA mutation we also land up in inhibiting what we call wild type, the normal PI3K, the PIK3 that is not mutated. And that PI3K is kind of linked to the insulin pathway, and so when you’re trying to inhibit that you’re inhibiting the insulin pathway, which causes the sugars to go high. So with AKT inhibition, because we’re not directly inhibiting PI3K, we’re seeing a slightly less incidence of hyperglycemia. And so that’s the difference.

DR LOVE: Hal, any comments? And also, again, the relative tolerability of these 2 agents and how you get patients to take a drug 4 days on, 3 days off.

DR BURSTEIN: Well, we had a funny experience. So in your mailboxes, in your offices at home, we just published in the JCO the guidelines for how to pick these drugs. And there was a panel of us, about 10, and we asked everyone to vote which drug you would pick in a very similar situation. And again, there really are no comparative head-to-head data. And every single one of the American oncologists said I would definitely give capivasertib over alpelisib. Now you realize the drug was entirely developed in Europe, they’ve never even given capivasertib, and they all want to give it, and it’s because everybody hates alpelisib. It’s a drug that causes a lot of side effects, is widely perceived as just not that potent a drug. And as Komal was alluding to most of us went into oncology because we didn’t want to be endocrinologists and manage diabetes.

And patients don’t like it because in America diabetes carries a stigma and nobody wants to be thought of as having diabetes or having to manage blood sugars. And so there seems to be less.

Now I think some of that is because we don’t look for it because if you check — if you give somebody the script, and they take 4 days of capivasertib, and then they stop for 3 days, and then they come back to your clinic on day 7, their blood sugars are back to normal. So if you don’t look for it you don’t see as much hyperglycemia. But it does seem to be a better tolerated product. It was approved in November/December, and we’ve now had several patients starting that therapy.

It does require keeping tabs of this, and you’ve got to tell patients to really get a little notebook and keep track of which days they’ve taken the medication. But so far it seems to be well tolerated.

So when we wrote this guideline everyone’s like well, we always give capi. And then the steering committee that looks at the guidelines was like well wait a second, I don’t see any clear data that one is absolutely better than the other, so we had to say that in the text as well.

But I think it’s the drug to beat, for the moment, because Komal will tell you that there’s another drug in this same class that she presented the big oral presentation for at San Antonio called inavolisib, which is another PI3 kinase inhibitor. And that study, which she can tell you about in a moment, but I’ll set the table for you, looked at combining that with a CDK4/6 inhibitor in the same group of about a third of the patients who have a PIK3CA mutation in their tumor. And what did that show?

DR LOVE: Hold on. Hold on. Hold on. Wait.

DR JHAVERI: He’s like, Neil, I got this.

DR LOVE: I’m trying to control the flow here. Hold on.

DR BURSTEIN: We’re running away from Neil. The inmates have taken over the asylum.

DR LOVE: Okay. Well, so let’s — just to set — it was kind of an interesting story there we can maybe talk about for a second, because we were actually doing a symposium at San Antonio with Komal where we heard this story that there’s a press release that came out the day before the San Antonio meeting. In oncology, again, a theme. You’re going to see a lot of slides this week. When a trial’s positive they notify everybody right away, before they publish it, present it, et cetera, they put out a press release.

So the press release came out the day before the San Antonio meeting, and the San Antonio people are like we can’t wait until ASCO to see this data. We’ve got to figure out a way to get it presented, and Komal presented it 2 days later. I don’t know how they pulled that off. But what it was was combining second-line and third-line therapy, giving it all at once. So we could spend a lot of time talking about it, but bottom line was it did look encouraging.

DR JHAVERI: Yeah.

DR LOVE: You mentioned the fact that PIK3 is present at diagnosis. So do you think that this may be happening in the future? And how well is it tolerated when you added it in on top of it, this other PIK3 thing?

DR JHAVERI: Right. So I think these 3 drugs were given together in the first-line setting for a distinct group of patients, patients who have had recurrence on or within 12 months of their endocrine therapy and harbor a PIK3CA mutation. So unlike what we were talking about biomarkers, where we tested both CDK4/6 inhibitors, now we’re saying for this group of patients should we find this information up front, because when we give the 3 drugs together and compared it to fulvestrant and palbociclib there was more than doubling of the PFS.

The PFS was 7 months in the control arm, which was fulvestrant and palbo. So those patients really had a very poor prognosis, did not do well. They are recurring and then having the PIK3CA mutation. But when you add the inavolisib, the PIK3 inhibitor drug to this, it was 15 months. And so I do think that this might be appropriate for this group of patients with this PIK3CA mutation, and we’re waiting to hear from the regulatory agencies about that.

DR LOVE: And again, in terms of this, for example, the rash and hyperglycemia, you have alpelisib here, capi here. Like where was this?

DR JHAVERI: So a very, very good question. Inavolisib does have hyperglycemia. Now the patients that were enrolled had a very different criteria.

DR LOVE: Right. They had to have low A1Cs. Right.

DR JHAVERI: Exactly.

DR LOVE: Okay. Low A1C to get in the trial.

DR JHAVERI: Right. With capivasertib we allowed a hemoglobin A1C of 8%. So you could be a prediabetic/diabetic and a hemoglobin A1C of 8. When we did that with alpelisib we did that with 7, hemoglobin A1C of 7. When we did that with inavolisib we did that with a hemoglobin A1C of 6. So certainly differences there. There was hyperglycemia seen.

The biggest difference that struck me was that there were no Grade 3 rashes. So we did not see a whole lot of Grade 3 rash with inavolisib. I cannot comment necessarily on the degree of hyperglycemia in patients with a hemoglobin of more than 6 because they were not included in the trial. But when we looked at the discontinuation rates it was very impressive. It was 6%. 6.8% of these patients had discontinuation of the study drug due to side effects, which is reasonable tolerable for a 3-drug regimen I think.

DR LOVE: So this was the press release, and then it was presented and I think published already, right? Did I see the paper? Do you have the paper out? No, not yet?

DR JHAVERI: So not yet. It’s in the works.

DR LOVE: Right. Okay. So eventually we’ll see that soon, as well, and it could be that next year we’ll be talking about triple endocrine therapy. In myeloma they’re up to 4 drugs, maybe going for 5 I think, but you guys are not too far behind.

I want to hear about this — is it a 56-year-old patient who got capi? Right. Kelly, you have this patient with Hal? 56-year-old.

MS RIKAL: I think that might be mine.

DR LOVE: Yeah. 56-year-old who got fulvestrant/palbo, then fulvestrant/everolimus, capecitabine, the usual drug, afterwards, and ended up on capi.

DR BURSTEIN: So this is a — you know how your parents said they love all the children the same even though they probably have a favorite? You’re all high achievers. It was probably you.

But in your practice you have a few patients who are really quite special and become friends, and this is one of those patients. I met her as an early career physician, and she had early-stage disease and recurred in around 2015, and she had ER-positive metastatic disease. And she works full time. She had at the time middle school-aged kids, a mother in Florida. And her number 1 priority has consistently been to be able to do all the things she wants to do as fully as possible without intravenous medication if at all possible.

And fortunately her tumor biology and her treatment success has allowed her to do that. But it’s a great chance to remind us that one of the most important clinical lessons is to use endocrine therapy, and now endocrine therapy and targeted treatments, as long as you possibly can. There is such a qualitative difference in the patient’s life when they are able to put a medicine in their pocketbook and travel, when they’re able to take medications at home, as opposed to the tyranny of coming in every week or 2 weeks out of 3 or every 3 weeks for chemotherapy.

And even though we’re all very excited about these newer antibody-drug conjugates that you’ll be hearing about and already know a lot about, if you didn’t know that this was a very exciting, bioengineered molecule, from the patient point of view it’s chemotherapy, right? It’s intravenous. It makes their hair fall out. It makes them sick to their stomach. It makes them tired. They have low blood counts. They have to come in.

So this patient really exemplifies that. She has had multiple lines of endocrine therapy. She had an aromatase inhibitor and palbociclib, and that went on for years and years and years and years. And then she progressed, and she had fulvestrant. And then she had fulvestrant with everolimus, which is an older drug that targets the same pathway really that we’re talking about. And then she went back to a different CDK4/6 inhibitor, she had abemaciclib for a while.

DR LOVE: You skipped an oral SERD trial.

DR BURSTEIN: Yup.

DR LOVE: What was that?

DR BURSTEIN: Well, then she had capecitabine, which is an oral chemotherapy drug, and then she was on an oral SERD. It wasn’t actually one of the ones in your slide deck, but one of the emerging oral SERDs that she had.

And so then this fall — we knew all along that she actually had not had a PIK3CA mutation, but she was one of the 3% or 4% of tumors that had an AKT1 mutation. And so when capivasertib became available — her tumor markers had been a very robust predictor of her disease burden, and it was up to about 2400 in January, and we started — and she was having more bone pain and things. So we started her on capivasertib. And did you make a slide of the —

DR LOVE: I didn’t make a slide, but it went down to 200 from —

DR BURSTEIN: It went down to 200 —

DR LOVE: — 2,800.

DR BURSTEIN: — like in 10 weeks. Just an extraordinary response. And I think, first of all, it’s a marvelous thing when you can be offering — she’s now had 4 drugs that didn’t exist when she was diagnosed with metastatic disease, and she has now received each of them for reasonably long periods of time. It’s a great time to be in oncology.

But this drug, capivasertib, is really good in the small subset of patients who have an AKT1 inhibitor. That was Nick Turner in the development of this drug had shown that in some small exploratory studies as well.

So it’s really gratifying to see new drugs coming along, being able to link, we’ve talked about it several times now, but the cell-free DNA testing and the clinical intervention. And if you take care of CML patients you already know this story, you have a drug like imatinib. They have CML, 99% of the disease goes away. We haven’t really had that too often in breast cancer, but if you pick the right patient and the right drug you can see really extraordinary things, and hopefully there will be more and more examples of that in the time to come.

DR LOVE: So you said it’s a great time to be in oncology, and going back to these videos we did of these nurses the other thing we asked them is what do you say to patients about clinical trials. They all talk about that. And I’d say it’s a great time to be involved in a clinical trial. And if you’re in a situation where your patients don’t have access to clinical trials right now there’s a great chance that they could be missing out on a great opportunity. There are tons of cases like that. You hear about people who just go from trial to trial, particularly where you have a lot of trials, obviously. Amazing that after all that she has this dramatic response. It’s just incredible.

And we’re not trying to overstate it because I think actually, Melissa, you had a patient also who had capi, and it sounds like you had more problems with that patient. This patient did fine tolerability with the capi?

DR BURSTEIN: So far she’s done very well. In fact, she feels better because the bone pain is in response. But there clearly are side effects of these medicines, and I assume she is going to be an exceptional responder, as they say sometimes, because of the biology of her disease.

DR LOVE: Yeah. So I’m curious what happened with your patient. Also, how do you try to get them to take it 4 days on, 3 off? Adam Brufsky says he tells the patient they can take the weekend off, so that’s kind of a cool way to look at it. Your patient, a 54-year-old woman, I guess was on a clinical trial.

MS RIKAL: Yeah. She was actually newly metastatic, and we put her on capivasertib as part of a triplet trial first line. It’s a little bit different than what we’re seeing in the standard of care setting. It was combined with palbociclib, as well as fulvestrant.

DR LOVE: So it was a triplet up front, kind of like your study except it was capi and not this other new one that’s not even approved yet, right?

DR JHAVERI: Correct.

DR LOVE: Right. But she was on a similar strategy.

MS RIKAL: Yeah. And she was actually pretty sick just from her disease when she came to us. So she had pleural effusions, she had pericardial effusions, and so we got her on as quickly has we could. But she actually went into the emergency room 4 days into treatment for chest pain/concern for tamponade from other effusion, and actually they caught this hyperglycemia. Her blood sugar had shot from totally normal to in the 260s.

So just kind of a unique situation in that we usually don’t catch the hyperglycemia until they’re a couple weeks in, when they’re coming into the clinic for the day 15 fulvestrant shot visit. Fortunately, it was very well managed. We were able to put her on metformin, and within a week it was back to baseline.

But she has had a dramatic response. All of her effusions have improved. She had a PleurX catheter. That has been removed. No more signs of pericardial effusion. But she’s actually interesting too because she has — I don’t know if you all have seen this with your patients, but she has pretty significant nausea and diarrhea just on her dosing days, and then she feels great on the weekends. So with other patients I’ve seen on this the nausea/diarrhea have kind of lingered a little bit, but hers just melts away.

So it’s a good and a bad thing in that she is able to time it out where she takes it Monday through Thursday and is able to enjoy the weekends a bit more. But I can see with a more noncompliant patient that being a concern simply because they might say, “Ugh, I feel great when I don’t take it, and I’m just going to not take it a couple more days.” Or something like that.

DR LOVE: Interesting. Interesting. I see she’s a traveler too. She just went to the Virgin Islands. People were trying to get out of Nashville or something?

MS RIKAL: Yeah. Yeah. She’s a lovely single woman, unmarried, no kids, no plants, no dogs, so she has — she’s self-employed, and she travels for her job. And so it’s very important for her to have side effects that are very well managed so that she can maintain her income, and she is a single income, but also that’s her quality of life. She simply told me from the get-go that she doesn’t care if she lives or dies, she has nobody like that is dependent on her living, but she wants to live well and be able to go and do the things that she wants to do. And so we’ve been able to optimize diarrhea management, nausea management. Her hyperglycemia is under great control. And so I think the key is just managing the side effects appropriately.

DR LOVE: Yeah. That’s kind of the flipside of another theme here we’re going to go into, and tons of discussion in the nursing interviews, which is patients with minor children. Unlike her, the other end of the spectrum, the patient with children. We’re going to talk a lot about that.

I want to just finish out with a couple other thoughts. The first relates to what happens after endocrine therapy, when people finally get through it. I think the case we just talked about, the patient got capecitabine, an oral chemotherapy that’s been used for many, many years, often the first therapy.

But Komal, I’d like you to just kind of give us a little bit of a preview of what we’re going to talk about tomorrow night. Because we kind of saved that for tomorrow because we’re going to talk about ADCs. Actually, Melissa’s partner, Erika Hamilton, will be there as well. And we’re going to get into in depth what happens after hormonal therapy tomorrow night. But can you give them a little bit of a preview, and particularly in terms of kind of what’s coming up in the future? Tomorrow night also we’re going to talk about HER2-low, which is relevant in ER-positive disease. Can you kind of give us a little preview of what all that’s about?

DR JHAVERI: Yeah, no. I think we started off with hormone receptor-positive disease recognizing that targeting the estrogen receptor is very, very important, and that’s why we have so many novel endocrine agents that we’re currently developing, approved and newer ones.

But then we also learned that resistance to these endocrine therapies, and we discussed PIK3CA mutations, we talked about ESR1 mutations, and that’s where all these targeted combination therapies came into play.

But once these tumors have seen the CDK4/6 inhibitors with endocrine therapy, these targeted combinations for these biomarkers that we target, and we start thinking about them as being refractory, something that is not responding anymore to this antiestrogen-based combination therapies, that’s when we start thinking about using chemotherapy. And we think about using single-agent chemotherapy sequentially. And in that space, in that area where we’re trying to do this, we now have 2 antibody-drug conjugates, and you’ll hear a lot about that, I’m sure, tomorrow, trastuzumab deruxtecan for HER2-low tumors and sacituzumab govitecan that we can use for these tumors because they now have shown survival benefit, something that we have never seen post-CDK4/6 inhibitor with chemotherapy. We’ve seen eribulin give us some overall survival, but that was pre-CDK4/6.

This is the first time we’re seeing this overall survival benefit with these 2 antibody-drug conjugates, and many more that are coming in the way of newer drugs, maybe targeting the same targets, so maybe HER2 or TROP2, or newer novel platforms of antibody-drug conjugates, which is very, very exciting. So the hope is down the line that maybe similar to what we do with chemotherapy right now, where we use sequential single-agent chemotherapy, maybe we’ll be using sequential antibody-drug conjugates, and hopefully that will have further impact on outcomes for out patients.

DR LOVE: So a final topic. And we know from having surveyed people over the years that 25-30% of this audience has been in oncology less than 5 years, and so one of the topics that is relevant to everybody, but particularly people who are new to the field, is how to take care of yourself. And that’s a theme that we’ve always had in ONS.

And Kelly, I’m curious what your thoughts are about Jessica Mitchell, who’s a GI nurse. She’s done a lot of our GI programs. She wasn’t available Saturday night. But here’s the way she takes care of herself.

MS MITCHELL: You have to like feel passionate about helping people and having relationships, but you’ve got to put boundaries as a provider on that too, right? You have to have self-care. You have to be able to leave the office at 5 o’clock and go into your other life that doesn’t involve death and dying.

You cannot live this 24/7. You have to have a balance, and of that balance doesn’t exist then I do think you have a burnout potential, right? But if you can feel like I come to work and I do good, and I feel filled up, and when I leave I give my attention to my family or myself, and I explore these hobbies that fill the other part of my being up, I think then it’s sustainable. Because it’s an incredibly rewarding occupation, but you just have to be careful about that balance because it’s an intense job.

DR LOVE: What do you do?

MS MITCHELL: Lots of things. I have a rule. I leave at 5 every day.

I’ve done this for 20 years. Because I give 110 when I’m here and 110 when I’m at home. So when I’m at home I have 2 kids, they take a lot of my responsibility, but I love to do other things. I’m a huge chef, I love to cook. I love to garden. I do a lot of like more meditative stuff. I do a ton of yoga. I just try to find that inner peace so then my well is filled up every day.

I think it’s important just to like — like how do you take care of a patient to the best of your ability, be compassionate, but also balance taking care of yourself, right?

DR LOVE: Kelly, any thoughts?

MS FISCHER: Yeah. I think it’s all about balance. I have to say, though, working with Hal we laugh a lot, and there’s a lot of — actually there’s a lot of joy in the tough times. So I think when you work with a physician who’s amazing, and you can laugh with and chat with like in between patients, it really —

DR BURSTEIN: You can have the rest of the week off. That’s fine.

MS FISCHER: That’s what I was getting at. It really makes all the difference. I’m not just saying that.

Outside of work I have a 10-month-old, so she keeps me very busy, and my husband. And I really love walking, Peloton. I love reality TV, and I watch the Real Housewives and everything Bravo. So that’s really what kind of like keeps it all together, so…

DR LOVE: Actually, for many years we would show pictures when we introduced the faculty at the beginning of what they did to get away. So now we’re kind of like bringing it to the end.

So Komal, any thoughts? What’s it like for you being an oncologist? And do you hear people say — how often do people say to you isn’t it depressing?

DR JHAVERI: Yeah, no. I wish I had the rule that Jessica has about leaving at 5. I don’t think I’ve ever made that in 20 years. But what I would say, I think, the way I think about it is I completely agree. We all talk about happy wives, happy lives. I think the same applies to everything we do in life, right? I think happy doctors will make a happy practice, a happy patient, and you want that. You want to be healthy and happy so you can provide your best. You can only provide your best if you are loving what you do, and you’re happy doing what you do. So it’s very, very important to take care of ourselves.

And the way I think about it is I’m probably 100% clinician one day, I’m probably 100% researcher one day, I’m probably 100% mother or a wife one day. I don’t think I have been able to necessarily say I’m perfect 100% doing all these responsibilities, but I’ve really been able to be happy with being 100% clinician one day and maybe doing 80% of my motherly jobs. Or being 100% mother one day, and that day was not my clinic day, and I was able to make that work for myself and have that balance.

And certainly having hobbies, anything that makes you happy, and it doesn’t have to be any particular form. I started skiing in my 40s when my kids started skiing. I started playing tennis with my kids when they started playing tennis. And I play squash with my husband because I wanted to not forget about him when I started doing what I do. So I think anything that keeps you happy and going is very, very important because only when you are happy can you provide the optimal care or do everything that you do in that particular role very well.

DR LOVE: Melissa? And also we’d appreciate some feedback. We’re trying different — we always do this at ONS. Let us know on the evaluation or send us an email if these topics are useful or not useful. We’d love to have your feedback.

So any thoughts, Melissa?

MS RIKAL: I was just going to say I think we all go into oncology for a reason, and for most of us it fills our cup to go into work and be with our patients. But I have seen significant burnout, and I’ve been there. And I think the important thing, too, is to remember that there are so many different fields in oncology. As nurses, I mean, one of the beautiful things about our career is that we have all of these options. So I used to work inpatient acute leukemia, and it contributed to a lot of burnout. I loved it, but those patients were really, really sick. Now I work in outpatient oncology, and yeah, my patients are sick, too, but it’s a very different day in and day out practice. And so I think just remembering that there’s so many cool options with what we do for a living.

DR LOVE: Hal, any thoughts? I agree with Kelly. I’ve always seen you using humor a lot, but I wonder kind of what’s underneath that.

DR BURSTEIN: It’s a dark scene. Cancer is a tough disease. Many of you may have seen the British royal family’s experience of cancer this past year. Did you see the video with the princess? I thought it was a very powerful video. She talked about what the first nurse here spoke about in the video. She talked about the shock. She talked about how hard it is to tell it to the children. She talked about how it affects your family immediately. She talked, and I realized their lives are very different from everyone’s in this room except for Komal’s life.

But she talked about how you can’t work, and so much of what brings people joy and gratification and of course income is work. They talked about chemotherapy, and there’s no way to make this easy, even if you’re the heir to the throne of the United Kingdom.

And I found that a very powerful and poignant reminder of what it is we do and why it’s a hard job. We struggle with this. I’ve been on innumerable committees at our hospital about physician burnout and nursing burnout. We know there are certain groups that are more vulnerable to this. Moms with younger kids are much more vulnerable to it, just the demands on their lives. Early-career faculty are more vulnerable to it. We’re trying to come up with ways to mitigate it.

But it’s very compelling work, and I think that it may sound a little trite, but it really is a great privilege to have the resources that oncology has these days, to have the opportunity to have longitudinal care for our patients. That is not unique to oncology but is very special.

And one of the burdens that’s been placed on all of you and ourselves is that healthcare around this country is collapsing. People cannot find a primary care doctor. I mean do you not get this like every day, somebody says I need to see a gynecologist, I need to see a primary care doctor, can you call your friends? All this kind of stuff. And we’re lucky to be able to connect most of those people to good things, and there really is a very deep satisfaction in caring for people even if we’re not always successful and not curing their disease.

But it is a hard job, and I think that all the things that you’ve heard about and people have mentioned are really important. If you don’t have a solid life outside of the clinic it’s hard to be fully present and to give your patients all that they’re hoping you will give them.

So I encourage all of you to take that time. Don’t go to the ONS tomorrow, go see a museum. They’re all free in Washington. You don’t even have to pay. It’s great. The mall, you can walk down the mall. Go find a congressman and tell them a piece of your mind or whatever. There’s some great restaurants in Washington. Go rowing on the Potomac. I don’t know. Take the week off. Like nobody knows you’re away. I mean they know you’re away, but they don’t know what you’re doing. I can assure you at ASCO the doctors do not all hang out for every one of those meetings that they go to. They’re like, oh, we’ve got Taylor Swift tickets. Or that kind of stuff. That’s what makes it all more —

DR LOVE: Final comment from Komal.

DR JHAVERI: Yeah. I just wanted to say that it’s okay to talk about it or to get help if you really thought that talking it out would help, right? Not everybody can adapt the way they want to adapt or do everything else that somebody else can do. Some people have a different way of managing their burnout or how they deal with it, and some people just keep it within them. But now people are really — have the resources to be able to get that help. So if you feel like this is something that is bothering you please talk about it and bring that to the attention of whoever needs to.

And if you have to make a change to feel happier you should make that change. If something is not keeping you happy it’s okay to accept that and move on. While change is a fear, it’s really important for yourself. So I think yeah, just recognizing who you are, how you deal with it, and asking for help when you need it is going to be very important. I think we should keep — we should all keep that in mind.

DR LOVE: So after you take your run tomorrow morning at 5 am and grab a little breakfast we’ll be here at 6. We’re not just going to talk about endometrial cancer, right? We’re not going to talk — as you can see from tonight, this is beyond any specific tumor. I’m not sure where it’s going but join us please. Thank you so much to the faculty.