Introduction

DR LOVE: Good evening, everyone. I’m Neil Love from Research To Practice, and welcome to What I Tell My Patients, as tonight we focus on the management of breast cancer. We have a great faculty today, and as we go through this evening you’ll learn a lot more about them and their patients as well.

This is the second of 10 meetings we’re doing here at the ONS. This is really the fifteenth year that we’ve done this. We’ve used a similar format through the years. Basically we want to make rounds here today. All 10 of these programs have the same format. We have nurse practitioners and medical oncologists, and in some cases gynecologic oncologists as we did this morning. And we’re going to go back and forth between talking about taking care of patients and also new research and really to try to provide a useful update to you that you can translate to your patients about what’s going on right now in breast cancer and what’s going on in general in medical oncology.

Here are the programs that we’re doing here live at the ONS meeting. For your colleagues who are not able to attend we are going to video and audio record this. We’ll put this out for you to listen to afterwards. We know a lot of people end up listening to these while they’re driving in their car or exercising so we tend to de-emphasize slides and emphasize talking and picking peoples’ brains, and that’s what we’re going to do for the next couple of hours with this really great faculty.

Basically over these 4 days we brought in more than 40 faculty members that we’re going to be talking to and learning about how they take care of their patients and hopefully providing some useful information to you, as well, but this is really about making round with quite a large number of really talented faculty people, both nurses, as well as oncologists.

We’ve always done really interactive. There’s no presentations that we’re going to be doing this week. We’re really here to talk and really to try to re-emphasize the key triad in cancer treatment, particularly medical oncology treatment, of the oncologist/oncology nurse and in the patient and their family.

The 2 themes that in general we have this week are (1) what’s new in clinical research and what does it mean to your patients, and (2) how do you apply the biopsychosocial model when you’re working with a patient. What is it about them that makes them — 2 patients maybe in the same oncology situation but 2 different people, different ages, comorbidities, attitudes, socioeconomic factors. And so we’ll get into that and how that affects really patient education.

The other theme that really goes through the whole week that’s been a very important one for us over the years is what we call the bond that heals, which is the idea that the relationship that you have with patients is highly valued by them and even when you run out of things to try to attack their tumor they still have that, and they still have you.

And then last year we started to also talk about that fact that — really to thank you for the work that you do and really think a little bit about the impact that you are having on patients and how profound it is and how grateful people are, patients and their families, for what you do for them. Something that I’m sure you hear every day, but we want to keep it in mind as we go through this series today.

But we’re going to now focus our attention on breast cancer specifically, and we have a tradition that when we — we like to introduce the faculty, and one of the themes here too is how do you get away from all this, how do you deal with — we were talking about this this morning in gynecologic cancers. How do you deal with the stresses and the tragedies that you see every day in practice.

So we’re going to start with Virginia Kaklamani. I’ve asked the faculty to just talk for a little bit about what they do to get away from the job so to speak. Virginia?

DR KAKLAMANI: Neil, thank you so much for having me here, and thank you all for being here as well. Also a reminder, today is Administrative Professionals Day, so if you haven’t thanked you admin support please do so.

So I play tennis. That’s my — I look at that yellow fuzzy ball, and I hit as hard as I need for the day.

DR LOVE: So no pickleball?

DR KAKLAMANI: A little bit. A little bit. Yes.

DR LOVE: So Joyce, you just scooted in from Dallas, got here about a half an hour ago. Your plane was delayed. We weren’t sure if you were going to make it, but really grateful that you are. What do you do to get away from things, Joyce?

DR O'SHAUGHNESSY: Well, very glad to be here, and good to see everybody. I get up to the Northeast to New Hampshire as much as I possibly can. That’s where I grew up, in that area, and I love the coast. I cannot go for a walk on the beach without a bag to pick up the plastic, so that’s my thing, is I walk, and I collect sea glass too along the way, but I have to clean up the beach when I walk.

DR LOVE: I remember when you were in your house in New Hampshire we were doing a Zoom education program —

DR O'SHAUGHNESSY: Yes.

DR LOVE: — and you were like “it’s flooding around my house.”

DR O'SHAUGHNESSY: Oh, yeah.

DR LOVE: I’m like why are we doing this if your house is flooding, but I guess you made it through there.

So Ron, you actually were in our prostate cancer program previously, and now we have you moved over to breast cancer. Can you talk a little bit about how you get away from your job?

MR STEIN: Sure, and thank you all for having me, and welcome everybody. I’m born and raised in Southern California, was in New Orleans 35 years, I made it back to California, and the way I wind down, it’s so awesome to be back at the beach. Besides the beach, I love anything having to do with Dachshunds, the wiener dog, so I’m involved in Dachshund rescue, and I love dog shows, and I love playing with my own dogs.

DR LOVE: So Jamie Carroll, you’re at Mayo Clinic. What do you do up there for fun?

MS CARROLL: You’d think I’d say something outside, but I don’t like winter. I don’t like being cold. So why do I live in Minnesota? Not sure.

No. So in reflecting on this question what do I like to do in my free time, I don’t have a lot of it because my kids are all encompassing. Who else feels like their kids’ Uber driver these days? Yup. So same as Uber, right? You get this message that says come pick me up now, and you drive there, and tips are minimal, and that’s what I do. But all jokes aside I like to work out. That’s the thing that centers me, that brings me joy, so I work out every morning.

DR LOVE: So yeah, you can’t beat exercise, for us and our patients for that matter.

Okay, well here’s where we’re heading here today. We’re going to start off talking about ER-positive, HER2-negative breast cancer, then we’ll talk about HER2-positive disease, then PARP inhibitors in breast cancer, and finally triple-negative breast cancer and particularly the use of immune checkpoint inhibitors.

ER-Positive, HER2-Negative Localized Breast Cancer — Part 1

DR LOVE: So we’re going to talk about first localized ER-positive, HER2-negative disease. In a second we’re going to ask Jamie to present this 40-year-old lady with a 6 cm node-negative tumor. But just to take a step back, Joyce, I’m just kind of curious this is the biggest — we talk about ER-positive breast cancer, HER2-positive breast cancer, triple negative, almost 3 different diseases, as we’re going to talk about tonight and tomorrow night with our special HER2 program, now we’re starting to look at HER2 low. So maybe there’s even going to be more of a breakdown.

But Joyce, we haven’t had that much to talk about in terms of ER-positive disease, and then all of a sudden, because this is the most common presentation of breast cancer, we have all kinds of new things going on, both in local disease that we’re going to talk about, moving therapies that were used in later line into the earlier setting, and new therapies in metastatic disease.

Before we get into all of the details, any global take on what’s going on right now in clinical research in breast cancer, Joyce, particularly in this subset of ER positive?

DR O'SHAUGHNESSY: Well, even with the ER-positive, with hormone receptor positive, HR-positive, HER2-negative breast cancer, there’s really 2 major subtypes, those that are more indolent, grade 1/2, they’re slow growing. These are patients at risk for later recurrence. That’s a very different biology than patients like this with these more highly proliferative, she’s got a recurrence score of 29, these are more genomically unstable, grade 3, and they are tougher. They’re tougher. This is only about 20% of breast cancer. This is where we aim our chemotherapy.

Now we’re aiming CDK4/6 inhibitors at these patients in the adjuvant setting. We’re hoping that we may see KEYNOTE-756, which is preoperative pembrolizumab, the checkpoint inhibitor, with chemotherapy has been tested in these patients who have Grade 3 disease, and we’re hoping that there will be an improvement in disease-free survival. Because we kind of need the next quantum leap for these patients. And I do think the CDK4/6 inhibitors are a very important quantum leap, but we still need more breakthroughs.

For patients that have indolent disease, I’ll tell you, the big thing I see is that late recurrence is oftentimes dictated by more than 10% weight gain. So I watch patients’ weights very carefully and talk to them. And unfortunately for our gals that are already obese they tend to gain weight, or gals that are overweight will convert to obese because our endocrine therapies, unfortunately, and chemotherapy contribute to that. I’m hopeful that the GLP-1 receptor agonist will help, the semaglutides, the tirzepatides will make a huge difference in that regard.

DR LOVE: Wow. I’ve never heard of that one before, very interesting.

So Virginia, another theme that goes across oncology in almost every single one of these programs we get into is looking at the patient’s tissue for so-called biomarkers to help us understand how to manage the case. This morning with endometrial cancer we were talking about MSI, MSI high versus MSI stable, and how that changes so much the way these patients are treated. And we’re seeing the same thing we’ve seen, and breast cancer really started it out with HER2 and ER, but now we’re seeing other biomarkers. And one in ER positive, HER2 negative is the genomic assays, particularly the 21-gene recurrence score, or Oncotype.

Can you talk a little bit, and we’re going to get into this as we get into the cases, but a little bit of an overview of what these genomic assays are looking at and what kind of impact that has on clinical decision making?

DR KAKLAMANI: And I want to differentiate genetic and genomic, and I know a lot of times we struggle with what the difference is. And so when we talk about genetic tests those are tests that we do for hereditary predisposition to cancer. So if you have somebody who has a family history of breast cancer or was diagnosed with breast cancer when they were young we do a blood test that detects mutations like BRCA1 and BRCA2. Those are genetic tests.

But when we look at genomic tests, those are tests that look at the tumor itself and changes in the genes in the cancer, so those are unique to that individual that we’re testing. And so the concept started really 20 or so years ago when we had realized already that we were giving way too much chemotherapy to women with early-stage, estrogen-positive breast cancer.

And we also realized that most of these women did not need the chemotherapy, but how did we identify who those women were? And that’s where the 21 recurrence score, as well as others, came up and found women whose cancers just won’t respond to chemotherapy because they’re not fast growing. And so the 21 recurrence score is able to differentiate the fast-growing cancers versus the slower-growing cancers, and we understood that around 70% of these women just don’t benefit from chemotherapy because those cancers are not fast growing.

DR LOVE: It’s interesting too now in colon cancer you see a similar dynamic with another type of assay, the cell-free DNA, the Signatera assay. And now you see a whole bunch of people with colon cancer kind of following the Oncotype model of figuring out who doesn’t really benefit from chemotherapy.

Let’s start to talk about how this gets integrated into the actual care of patients. This woman actually turned out to have a very large tumor, I guess it wasn’t suspected initially, but it was node negative. She has a recurrence score that almost high. It’s high-intermediate I guess you would say. Can you talk a little bit about her and what happened to her?

MS CARROLL: Yeah. So this is a 40-year-old woman that initially imaging showed that the cancer was much smaller, so she went to up-front surgery. We found that it was a 6 cm, node-negative tumor, ER positive, HER2 negative, localized invasive ductal carcinoma. We did the Oncotype. It came back at 29, so we recommended 4 cycles of chemotherapy for her and then ovarian function suppression.

So in a 40-year-old woman that can be challenging and difficult because a 40-year-old woman is going to have high estrogen levels, and then we put them into menopause oftentimes with the chemotherapy, and then we keep them there with the goserelin. And so she is getting that monthly, and then after chemotherapy we added in tamoxifen for her with the eventual plan to transition from tamoxifen to an aromatase inhibitor. We often start with tamoxifen with ovarian function suppression to see how they’re going to tolerate the endocrine therapy combined with shutting down their ovaries.

DR LOVE: I’m curious how you talked to her about ovarian suppression specifically and maybe adding in something else, tamoxifen, even an aromatase inhibitor would be a consideration, how you talked to her about it and how you varied the way you talked to her based on who she was as a patient and really a learner. How did that go? What did you talk to her about?

MS CARROLL: Yeah. So this woman we gave the 4 cycles of chemotherapy, shut down her ovaries, and then we added the goserelin with cycle 4 to keep the ovaries suppressed because what we don’t want to do is suppress them with chemotherapy and then have them wake back up only to suppress her again. And so we talked about what this would look like for her, the vasomotor symptoms that can come with menopause, as well as the vaginal dryness is a big thing for a 40-year-old woman.

For this woman in particular what was challenging was the fact that I had treated her best friend with breast cancer, and so a lot of her fears were coming from the fact that her best friend had just went through breast cancer and actually was diagnosed with a metastatic head and neck cancer following her breast cancer. And so this patient had a lot of worry and concern over radiation and what that would do for her when she was taking the experience of her best friend. And so really it’s individualizing care and how you educate patients based on their experiences coming into the consult.

DR LOVE: So it’s interesting, Ron. As I mentioned, Ron also has a lot of experience with prostate cancer. He was in our prostate cancer program last year. This year our program is Saturday on prostate cancer. And there you have kind of a similar issue, when you turn off the testicular function with the same drugs, LHRH agonists working in the brain, really a unique scenario both in breast cancer in this situation and in prostate cancer, where actually a lot of the symptoms are similar.

I’m kind of curious how — again, how you approach the woman who’s about to get ovarian suppression. They may choose to have their ovaries removed surgically. How do you prepare them? And what do you see in terms of symptoms?

MR STEIN: My experience has been that the patient is so eager to combat this cancer. When I’m dealing with a female patient she’s really not too, too concerned about going into menopause. The focus is all on the cancer. When you’re in the middle of that fight you will do anything to shut that down, right? But then symptoms start happening, just like Jamie said, the vasomotor symptoms, vaginal dryness, decreased libido. Those are not easy symptoms to deal with.

I try and catch it on the front end and kind of warn the patient that you will likely get this. This is what you can anticipate, but there are things that we can do and offer you that are safe to combat some of those symptoms if they do occur. And when I’m talking about we’ve had some really great luck with some non-hormone-based vaginal lubricants, we’ve used antidepressants such as venlafaxine to help with the vasomotor symptoms, you can use gabapentin, and generally people do okay, but it’s not easy.

And I’m talking nurse-to-nurse here, we’re not just dealing with the patient, we’re dealing with their partners, we’re dealing with their families, as well, because not only does the vasomotor symptom come in with hot flashes and the decreased sexual desire and the vaginal dryness, but mood swings are also quite probable, okay, and that can impact the dynamic of a family.

DR LOVE: So Virginia, another issue. This woman, Jamie’s patient, was kind of through childbearing, but you see patients who want to have future children, they’re planning to have children, and then they get breast cancer. Can you talk a little bit about some of the strategies that are utilized in these patients to try to retain their fertility, including the use of LHRH agonists, which can be given during chemotherapy to actually suppress damage to the ovaries, and how you do it in your practice, Virginia?

DR KAKLAMANI: So this is extremely important to tackle in the beginning when you’re meeting the patient. You know that many of these patients are going to need chemotherapy, which is going to impact their ability to have children. So we need to ask our patients, not assume that we know the answer, but ask them are you planning on having children, are you planning on having more children. And if the answer is yes the first step is to have them see a fertility expert, and that is before — most of the time before they even had surgery so that we can prepare for potentially going through IVF and freezing their eggs and so forth.

Now once we’re at the point where we give chemotherapy, then giving ovarian suppression during chemotherapy has been shown first of all to be safe, which is extremely important, and secondly to help preserve some of that ovarian function. And the way to think about it is you’re stopping the ovaries from working, you’re blocking them during chemotherapy so chemotherapy, which works on fast-growing cells, is not going to work on the ovaries because all of these ovaries are just shut down. All the cells are dormant, they’re sleeping.

So that’s the second important step. And then after that we really have to think about when the right time is for them to have children. And a couple months ago at the San Antonio Symposium we had a wonderful trial presented called the POSITIVE trial, which was very positive for our patients because it showed that it is absolutely safe for them to have children after a breast cancer diagnosis. So we stop the endocrine therapy, the tamoxifen, ovarian suppression, whatever it is that they’re on, they can have children, and then we can restart the endocrine therapy, and those women did not have a higher risk of the cancer coming back compared to women that continued endocrine therapy.

DR LOVE: So Joyce was talking about the fact that in ER-positive breast cancer you may see very delayed metastatic disease that might occur even after 5 years, and yet now you’re stopping hormonal therapy. Usually you let them have it for a couple years, allowing them to have children. This presentation showed that these patients seemed to do just as well as people who continued therapy. So this short break, I guess a year and a half or 2 years. 75% of the women actually got pregnant in the study, so it worked.

Jamie, have you had people do this in your own practice? I mean the paper was just presented, but a lot of people are already doing it. Any comments on that?

MS CARROLL: Yeah. I mean I think before the POSITIVE study was presented it was a scary thing to stop your endocrine therapy to try to get pregnant, but I have had 1 woman stay on her tamoxifen for the 18 months, came off and had a successful pregnancy, and then she brought in her little girl last week and showed me.

DR LOVE: So another theme that goes through oncology — we’re talking about 10, 15 tumors here, but a lot of what we’re talking about applies to all of oncology in terms of some of the principles that we’re getting into. And one of them is allowing the patient to be involved in decisions where we really don’t know the right answer. I mean maybe there is a risk. It doesn’t sound like a great idea to be stopping your therapy, but the data supports it. But some people look at that and say I’m not going to take a chance, et cetera. But over and over this week we’ll talk about when you get to situations where we’re not sure what to do, involve the patient.

Joyce, I want to get back to also the issue of Oncotype because as Virginia was mentioning, and we were bringing this up in the colon program the other day, because again, they’re starting down the same track, when the Oncotype came out, I think it was like 2004, if you had a tumor that was 1 cm you were getting chemotherapy period. You can imagine the overall risk was maybe 10% in those patients, and yet they still were doing it.

Can you talk a little bit about more specifically right now where we are with this assay, starting out with postmenopausal women? The premenopausal woman is a little tricky because a lot of those patients didn’t have ovarian suppression, so it’s a little harder to interpret. But what about in the postmenopausal patient, Joyce? We started out holding off chemotherapy in node negative, and now we’ve moved to actually not giving chemotherapy to patients who have node positive, something you couldn’t even imagine 20 years ago. Can you talk a little bit about how that plays out in your practice in postmenopausal patients, Joyce?

DR O'SHAUGHNESSY: Yeah. There’s recently a publication in JCO from — ASCO has updated their guidelines on what’s the consensus recommendation about when to use a 21-gene recurrence score, the Oncotype, but also the 70-gene signature, the MammaPrint, and what they say for postmenopausal women is that for node-negative patients, as well as for those with 1 to 3 positive nodes, hormone receptor positive, HER2 negative, that those patients are great candidates for the 21-gene recurrence score. If they come back low risk, which is 25 or less, there’s really no benefit at all from chemotherapy in big prospective randomized trials. It’s really very clear.

And then endocrine therapy is the way to go for those patients. But one could still consider adjuvant abemaciclib, potentially, for those patients. They could still be eligible in the monarchE Phase III trial for adjuvant CDK4/6 inhibitor abemaciclib. That’s a different decision-making point. But then ASCO Guidelines say that for 4 or more lymph nodes positive that there’s not enough data to use the 21-gene recurrence score. So that’s where we sit right now.

DR LOVE: People talk about looking at biology as opposed to anatomy, so the biology of the tumor, the growth rate, et cetera, as opposed to how big it is or whether nodes are involved. And more and more we’re following the biology.

Joyce was alluding to another new development in localized ER-positive disease, which is the use of a strategy that really started out like a lot of strategies, in metastatic disease, and then got moved earlier, that happens all the time in oncology, and that is the use of so-called CDK inhibitors. And Ron is going to present a patient who got an adjuvant CDK. So this is not metastatic disease, this is adjuvant, trying to get a little bit more boost to the antitumor effect by bringing in a CDK inhibitor.

Before you present the case, Virginia can you just briefly comment on what — how CDK inhibitors work, what we know about them for metastatic disease?

DR KAKLAMANI: So the CDK4/6 inhibitors have really revolutionized how we treat estrogen-positive, HER2-negative metastatic breast cancer. They’re drugs that basically stop the cell from duplicating. It’s called cell cycle arrest. And in combination with hormone therapy, such as an aromatase inhibitor, they’ve been shown to improve survival for our patients, and really these are the first trials where our patients have an overall survival of more than 5 years, which we didn’t have before in ER-positive metastatic disease. So we’ve been using them as standard of care for the first-line therapy in metastatic ER-positive breast cancer, and now in the early-stage setting.

DR LOVE: And we’ll talk a little bit about some of the symptoms that get associated with that, but we know there are 3 CDK inhibitors currently being used in metastatic disease. Only 1 of these now has been approved by the FDA to be used as adjuvant therapy, which is abemaciclib. We know that coming up at the big ASCO — the annual ASCO Meeting in Chicago next June we’re going to see another paper with another CDK inhibitor.

ER-Positive, HER2-Negative Localized Breast Cancer —Part 2

DR LOVE: But Ron, can you talk a little bit about what happened with your patient because it’s kind of an interesting story about how she ended up getting adjuvant abemaciclib.

MR STEIN: Sure. Right now this lady’s 47 years old, and she came to us approximately 9 or 10 months ago from England. She was diagnosed at the age of 43. Genetics were negative. Both she and her husband are British, and they had — at the time of her diagnosis they had very small children. And she completed her chemotherapy neoadjuvantly, but unfortunately her surgical pathology revealed a T1cN3 disease, and specifically she had a full axillary node dissection, and 12 out of 22 nodes were positive.

So didn’t have the greatest response to neoadjuvant chemotherapy, but she was ER positive, HER2 negative, and she opted to be treated with ovarian suppression because she was still — and she still is premenopausal, along with an aromatase inhibitor.

So when she came to us about 10 months ago the oncologist I worked with decided to offer her abemaciclib in the adjuvant setting. It had just been approved for use in the adjuvant setting. Previously it was indicated only for metastatic patients, and this lady jumped at the chance to take it. She was very excited.

I also wanted — and I neglected to say that when she was getting her neoadjuvant chemotherapy she could not complete it all because of such bad side effects, including neuropathy.

So we have a younger patient, very high risk. Her family is everything. Both she and her husband are film producers, they’re in LA now, and as I said, she jumped at the chance to take something that may very well improve her chances of disease-free recurrence.

I want to point out that even if a patient, an oncology patient does everything humanly possible it’s always going to be in the back of their mind, right, is this cancer ever going to come back. And this lady, for her, her family and her children were the most important things, and we put her on abemaciclib. Insurance covered it, although it was 4 years post her surgery, and she’s tolerating it quite well.

DR LOVE: And when we heard this case we were talking before we came in here in the faculty room about it, and everybody was like woah, you started abemaciclib 4 years later, but another example of talking to the patient and saying what do you think. I mean we’re not looking at — you can see side effects, but usually not lethal side effects. You can always stop the drug.

You said she tolerated it well. I’m curious, Jamie, what your experience is with side effects. We hear a lot with abema about diarrhea. The other 2, palbo and ribo, more about neutropenia. What’s your experience clinically with what happens with these patients, particularly now in the adjuvant setting where they don’t have active disease that you can see, so symptoms maybe are a little bit more important? What have you observed?

MS CARROLL: Yeah. I’ve observed that patients are having Grade 1/Grade 2 diarrhea, so that means more than 4 stools a day. They give them — I give them a prescription up front for the loperamide and say fill this because you never want somebody on a Friday/Saturday night to get diarrhea, and now what do you do. You don’t want to run to Walgreens at that time, so give them that prescription, tell them to fill it up front.

Like Dr Love said, diarrhea’s the most prevalent for abemaciclib. You do see some — a little bit of neutropenia/anemias, not like you do with the other CDK4/6 inhibitors. You do see an elevation in their creatinine, but it’s not a decrease in their renal function. It has to do with the renal transporters, so I always check a cystatin C. That’s going to give you a more accurate level of what their corrected creatinine is.

DR LOVE: So Joyce, any comments? One of the things we’ve been talking about this week is how do we look at new research studies. This morning we were talking about the fact that just a few weeks ago there were 2 really important trials presented on endometrial cancer, and this morning the docs were talking about it’s not clear what to do. Everybody’s talking about what to do. We know in a month there’s going to be another study coming out with a different CDK inhibitor, we don’t know anything about what the results are, and then we’re going to have to compare that indirectly because they are not comparing the 2 CDK inhibitors. They’re 2 completely separate trials.

What are some of the things that oncologists are going to be looking for in these new data to try to decide am I going to stick with what’s been done in the past or maybe move to this new strategy?

DR O'SHAUGHNESSY: And it’s difficult. So this study that’s coming out at ASCO is called the NATALEE trial. It’s another large adjuvant CDK4/6 inhibitor trial with ribociclib. We already have the abemaciclib approved for high-risk node-positive patients, and the NATALEE trial is also for high-risk node positive but also lower-risk node positive, as well as high-risk node negative. So it’s a larger group of patients, and also the ribociclib’s given for 3 years rather than 2 years that we give with abemaciclib.

And so when you have 3 years of therapy there’s going to be fewer patients recurring, but we know it’s a positive trial. There was a press release. It’s a positive trial. This is good. So we’re going to have another probably FDA-approved agent.

But it’s very difficult to do cross-trial comparisons, and the NATALEE doesn’t have the length of follow up because with adjuvant abemaciclib we’re out 4 years now. We have kind of mature statistically robust assessment of what the absolute benefit is, what percent improvement in disease-free survival do you get at the 4-year mark having taken 2 years of abema and then stopped. And it’s around 6%, and in the highest-risk patients it’s closer to 7%. And so it won’t be that big with the ribociclib because they don’t have the degree of follow up, but we’ll be looking for the hazard ratio, the percent reduction in the risk of recurrence.

At the timepoint that the NATALEE presents it’ll probably maybe a little shy of 2 years median follow up, and so we’ll go back to the monarchE, and we’ll look at the 2-year mark and kind of see what the difference was in the curves there and do cross-trial comparison. But it’s difficult because it’s a lower-risk population. They’re on treatment longer, so there will be fewer recurrences on those 2 bases, but we’ll be looking for that. We’ll be looking for safety. The ribociclib will very likely have fewer side effects because it just does anyway. Ribociclib has fewer side effects for patients than abemaciclib, but also the dose of ribociclib that’s being used in NATALEE is 400 mg daily for 21 days and then 7 days off, and that’s extremely well tolerated. And so that’s going to be a consideration for some patients perhaps that have struggled with side effects already from their therapy.

And we’ll also look, for example, at what’s the impact on distant metastasis, for example, versus locoregional recurrences. But the truth is we’re going to wait and see, and we’re going to see which patient populations for sure we can give the ribociclib to that we can’t give the abemaciclib to. That’s kind of a no-brainer. It’s a larger patient population so it’s going to expand the percentage of patients that are eligible for getting an adjuvant CDK4/6 inhibitor, for sure, and then patients that we are afraid are going to have trouble with toxicities, that’s going to be another good group for the ribociclib.

But I do think that the long duration of follow up — we know that when you stop the abemaciclib after 2 years the curves keep pulling apart, the benefit continues even after you stop the abemaciclib. We were worried about that. We weren’t sure exactly what was going to happen there, but it came out good. And so that’s very important, and so we are going to need another year or 2 of follow up on NATALEE to see what happens when the patients stop their therapy.

DR LOVE: So so many considerations that need to be individualized to the patient. Jamie, Joyce was mentioning the fact that ribo, like palbo, you give it for 3 weeks and then you’re off, as opposed to abema, where you take it continuously, which to me also brings in the issue of adherence and trying to assess whether or not your patient who maybe on a bunch of other medications is going to get this straight. Any thoughts about what you look for when you sit down with a patient, and you’re saying okay, now we’re going to do ovarian suppression, an aromatase inhibitor, and now on top of that a CDK inhibitor except you’re going to be taking it 3 weeks on, 1 week off. How do you assess patients in terms of predicting whether they’re going to be adherent?

MS CARROLL: So I think understanding if they’re adherent to their aromatase inhibitor first. Patients, many times they’re young, so they do have those vasomotor symptoms, talk to you about joint pain, muscle pain. I like to follow up with them closely. I use my clinical pharmacist so that we call the patient at day 14, see how they’re doing, see how they’re feeling. They get their labs done at that time. So we have closer follow up every 2 weeks for those patients for the first 2 months. If we can get them past the first 2 months usually the adherence is good. They don’t tend to drop off after that.

DR LOVE: So also this is actually the press release we’ve been talking about. This happens all the time in oncology that the first thing you hear about a trial is there’s a press release that comes out saying okay, this — the data — I think they maybe do it for stock reasons or whatever, they have to announce it, and then you know that in the next few months you’re going to be seeing the data, so you’re getting ready. You’re already starting to think about what am I going to want to be considering when I see the data, and we’re going to see that very soon.

ER-Positive Metastatic Breast Cancer

DR LOVE: So I want to talk briefly also about ER-positive metastatic disease. We’ve been talking the last few years about the use of CDK inhibitors, but now we’ve got a whole bunch of new drugs that are out there to consider in these patients who go through their initial therapy that typically will be — will include a CDK inhibitor plus some form of endocrine therapy.

So to get into that we asked Jamie to present the first of these so-called oral SERDs. These are like fulvestrant except they’re pills, they’re oral, and specifically we’re talking about biomarkers, and there’s a biomarker for this, the ESR1 mutation, that we’ll ask the faculty to talk about. But Jamie, can you just summarize a little bit about what happened with this woman and also what you said to her with — I don’t know, maybe the one of the first patients you actually treated with the drug, it was just approved. You had to go look it up and then try to translate it to her. How did it go when you kind of went through this with her?

MS CARROLL: Yeah. So this woman actually started off ER positive, HER2 positive. So she has been metastatic for many years. Her most recent therapy was a HER2-positive therapy, an IV drug. Trastuzumab deruxtecan is what she was getting. Unfortunately she developed COVID, and then she developed pneumonitis, which we know can happen with this drug.

So when she progressed on trastuzumab deruxtecan I biopsied her liver, and it came back HER2 negative. So because she had been struggling with her respiratory difficulties, and now she’s HER2 negative, I thought let’s give her an infusion break and switch her to elacestrant. We knew that she had an ESR1 mutation, it has just been approved in the last 6, 8 weeks, and so she started on this drug.

So similar to fulvestrant, it’s a SERD, but elacestrant is an oral SERD, first to market. There is going to be several that get FDA approved in the next couple of years. What’s different about the oral SERDs is that there’s more GI toxicity than there is with fulvestrant; they just get that injection in their backside. But with oral SERDs more GI toxicity.

DR LOVE: So Virginia, here’s a diagram of some of the different ways that we intervene into the endocrine system that we know will affect the tumor. You can see in the top right there fulvestrant and now these new oral agents. Can you kind of provide an overview of not only what these new SERDs are but also what the ESR1 mutation is, that we’ve been seeing when we send the assay, now we know what to do about it? What is it?

DR KAKLAMANI: Absolutely. So we’re talking about estrogen-positive breast cancer, which means that the cell feeds off of the estrogen, and somehow the estrogen receptor goes into the nucleus and starts producing a lot of proteins that lead the cell to grow, metastasize, and all of these things. So what we’re trying to do is starve the cell, and there’s a few ways of doing it, such as with the aromatase inhibitors, where we’re taking away the estrogen. If we take away the food the cell’s going to die. But unfortunately the cell figures out how to work, and the way it does it in most cases is through these ESR1 mutations.

So ESR1 mutations are mutations of the estrogen receptor gene that make that gene work regardless of whether it has food or not, regardless of whether it has estrogen. And so now we have to find a different way of stopping the estrogen receptor, and that way is with these oral SERDs. So what these mutations do, and you can see this in this diagram, is they change the confirmation of the place where estrogen binds, and this is typically where tamoxifen binds. This is — and so this receptor all of a sudden does not need anything to just turn on. And so these oral SERDs are still able to kind of fit in there and block the receptor from doing all of these bad things that it’s doing.

And the studies that were done show that these drugs, these oral SERDs such as elacestrant, work better than the estrogen therapies that we have, like aromatase inhibitors and fulvestrant, in women with metastatic ER-positive breast cancer.

DR LOVE: So Joyce, we have elacestrant, and also we have camizestrant. There are a whole bunch of other oral SERDs. We’ll see where these land in terms of ongoing research. But in the middle of that at the San Antonio meeting all of a sudden we saw another form of hormonal therapy, capivasertib. This is a mechanism — I call it capi because I have a hard time pronouncing it. But this is another agent, Phase III trial.

So when you think about clinical trials in oncology you have Phase I trials when the drug is first being used to try to figure out what dose, the safety issues. Then Phase II, more patients, trying to figure out what the response rate is. Then if it looks encouraging they go to Phase III. These are large trials randomized against standard of care, and boom, all of a sudden we saw a Phase III trial a few months ago of this capivasertib, and the trial was positive.

Joyce, can you kind of explain how this drug works and whether you think it’s going to be part of our armamentarium moving forward?

DR O'SHAUGHNESSY: Yeah, sure. This is a pathway, the PI3-kinase pathway, super important resistance pathway in breast cancer, resistance to therapies, including HER2-based therapies, estrogen receptor-targeted therapies, and chemotherapy. It’s just a very common way that the cancer cells are either born that way or they can activate that pathway as a way to escape the therapy. Super important.

So we’re all familiar with everolimus. That was the first pill blocker we had of the PI3-kinase pathway. We can still use it, it’s still helpful for some patients, but we don’t have a lot of data with regard to the effectiveness of everolimus after patients’ breast cancer progresses on a CDK4/6 inhibitor, which that’s the first therapy everybody gets. So we can still use it, but that’s the pathway that the everolimus, goes after.

Then the second blocker of the PI3-kinase pathway is alpelisib. And that, as you know, is only for patients whose breast cancer has a PI3-kinase mutation, which is about 40% of patients. And you can find those in the primary breast cancer. Those, for the most part, are there from the beginning, when the breast cancer’s first developing, the PI3-kinase mutations. With the everolimus, we don’t have to choose patients. It’s just if they have estrogen receptor-positive, HER2-negative breast cancer.

But the thing about the alpelisib is patients have to have — they can’t really be significant diabetics. They can’t be insulin dependent. If they’re not on insulin their sugar — their glucose has to be well controlled. The hemoglobin A1c has to be less than 6.5%. Even then they get elevation of glucose. There are side effects of alpelisib with nausea, diarrhea, weight loss, et cetera. But I’ve figured out, as many of us have, I always start at 250. I can kind of choose the patients. It’s a very important agent, patients do benefit, but it’s a little bit more challenging in terms of side effects.

And so then this one here, the third one, is the capivasertib (capi), and it inhibits another really important protein in this PI3-kinase pathway called AKT. And about 5% of breast cancers have an activating mutation in AKT, and that mutation really is very powerful. It causes a lot of resistance, aggressive biology. Heretofore we really haven’t had anything specific to block that mutation.

Also, there’s another mutation in the PTEN gene. PTEN is a tumor suppressor gene. When it’s mutated you lose it. It’s gone. It doesn’t work, and now you have activation of this PI3-kinase/AKT pathway.

So in this Phase III trial they actually looked at patients whose breast cancer was progressing on a CDK4/6 inhibitor, and there was about 38% of them that had a mutation either in the PI3-kinase protein, the AKT protein, or the PTEN protein, so a separate group that was molecularly altered, like you knew that that pathway was very, very strong. It was a really resistant pathway. And half the patients got fulvestrant, and half the patients got the oral capivasertib with fulvestrant. There was a very nice improvement in progression-free survival in all the patients regardless of whether they had the mutation, so a positive trial, and even more impressive in those who have one of the mutations.

And so it’s really important because there’s a group of those patients with the PI3-kinase mutation we can’t give them alpelisib because their diabetes is too significant. There’s very little hyperglycemia. With the capivasertib when you block AKT you just don’t get that surge in the glucose. And then for the first time we have something that will block the AKT and also be something for these patients whose breast cancers have lost PTEN. So a very, very important step forward. We don’t know if the FDA will approve it for all comers, hope so. Hope it’ll be available for everybody, or whether it’ll be the genomically altered 38, 40% of patients whose breast cancers have one of those mutations that lead to strong activation of the pathway.

DR LOVE: And this is not an uncommon scenario in oncology. They design a drug to target a specific subset, but they see actual benefit even beyond that, so how does that enter into your clinical decision making?

Also, to mention, again, an issue throughout oncology, changing of receptors. Jamie referred to the fact that her patient initially was HER2 positive. She rebiopsied her, and now she switched to HER2 negative, and that changes the way you approach it.

One of the critical questions any time we see a new therapy, Virginia, of course is going to be tolerability. Joyce was referring to alpelisib, which leads to not just diabetic problems but other symptomatic problems that can be difficult. What do we know about capi? I don’t know if you have clinical experience with it, Virginia, or what’s your take on it from what you’ve seen in the trials?

DR KAKLAMANI: So on the trials, as Joyce mentioned, there didn’t seem to be a lot of hyperglycemia, which is good, but there was quite a bit of diarrhea. And so this is something. The clinical trials are a very controlled setting with very motivated patients, very motivated physicians, and very motivated nurses. When we go into clinical practice things are a little bit different because the patients are not as motivated. They’re also not screened as much. On the clinical trial we need the perfect patient, and those patients sometimes don’t exist in practice.

And so we really need to see what happens when this drug is available and what is really our experience with diarrhea on this drug. So the diarrhea seems to be the one thing that we might end up struggling a little bit with capi.

DR LOVE: One of the trends in oncology is to look at so-called patient reported outcomes. We’re trying to figure out how does this affect people’s quality of life, and more and more we’re asking patients specifically about symptoms, what happened to your pain. Sometimes you see pain in general improves because you’re getting antitumor effect. Other times you see that their life gets dominated by tolerability issues. So more and more we’re trying to look at the patient.

Localized HER2-Positive Breast Cancer

DR LOVE: Well let’s flip over. And we’re going to talk tomorrow night about HER2 across the continuum, particularly the use of antibody-drug conjugates, particularly the use of the revolutionary antibody-drug conjugate, we were even talking about it this morning in GYN, T-DXd. And there not only does it start out in HER2 positive, which is what we’re about to talk about now, but now coming into so-called HER2 low. So these are patients in the past that were considered HER2 negative. You needed, for example, on an IHC test, to have 3+ to be considered positive. 1+ and 2+ was not positive. Well, T-DXd seems to work in those patients. So we’re just relooking at everything. And so some of these ER-positive patients, as they get to the end of endocrine therapy they’re going to be considered for what was an anti-HER therapy, T-DXd, because they’re HER2 1+ or 2+.

But let’s talk a little bit about where we are right now in terms of a lot of the action right now in HER2-positive disease is in metastatic disease, but let’s talk a little bit about how this starts out in terms of localized disease. And in a second Jamie’s going to tell us about this 26-year-old lady who ended up getting post-adjuvant neratinib.

But Ron, can you talk a little bit about the typical course of patients with HER2-positive localized breast cancer, both in HER2-positive disease, as well as triple-negative disease, localized? The usual first approach is going to be systemic treatment, neoadjuvant chemotherapy with anti-HER therapy. I guess, Jamie, is that the way this patient started out? Almost all patients start that way. We know we also have a strategy only in breast cancer, other tumors are starting to look at this, where they give — you start out with a localized cancer in the breast, you don’t send the patient to surgery, you give them systemic treatment, so TCHP is a common therapy, with chemo plus not only trastuzumab but pertuzumab. In the triple-negative situation they will get chemotherapy plus an IO, pembrolizumab.

And a lot of these patients, when they go to surgery, maybe half of them, you’re not going to see any tumor. It’s a path CR. But for those patients — and those patients will do well, not 100% cured but mostly cured. But if they have residual disease even after all this intensive therapy we know their prognosis is not great, and that can be changed by giving another antibody-drug conjugate, T-DM1, which we know further reduces the risk.

So I want to hear what happened to this patient, but first, Ron, can you just reflect a little bit about what you see in your patients who are going through TCHP neoadjuvantly? This is not the most easy experience for somebody to go through.

MR STEIN: Sure. We need to prepare them for potential side effects. The HER2-directed IV therapies can be cardiotoxic, although reversible generally, but we always start out getting an echocardiogram. What I have seen with some of the initial HER2-directed therapies, I’ve seen generally very, very well tolerated compared to the cytotoxic chemotherapy, but I have seen some diarrhea. I’ve seen some hypomagnesemia with it. And then I do have some patients who’ve had some strange things here and there, ocular toxicities that we’ve had to consult ophthalmology about. But generally these are extraordinarily well-tolerated targeted therapies.

When you’re combining it with TC, which is the chemo component, that’s when we’re going to see the typical what we all think of in terms of chemo side effects, the pancytopenias, the peripheral neuropathies, the diarrhea, possible nausea, though not a whole lot with this one, this particular regimen. But we do a lot of education, again, on a lot of anticipatory guidance, especially when it comes to neuropathy and pancytopenias.

DR LOVE: And using only anti-HER agents, for example pertuzumab/trastuzumab, that’s what you would do in a patient who had a path CR because they’ve done well with these agents. And as you say, once you take out the chemo they do a lot better.

What happened with this patient that she ended up actually not only getting neoadjuvant and post adjuvant, but post-adjuvant therapy with neratinib. What happened with this very young woman?

MS CARROLL: Yeah. So this woman was 26 years old, obviously premenopausal. Her initial presenting diagnosis, clinically she had a supraclav node and low cervical nodes. So that patient was borderline metastatic, but she’s 26, we wanted to try to cure her.

So in the neoadjuvant setting we gave her THP/AC, so both the HER2 positive — or HER2-targeting agents combined with the chemotherapy. When she went to surgery she had a good response but did not have a path CR, so we gave her adjuvant T-DM1, so she got 14 cycles of every 3-week IV infusions, and then completed that, and now we’re giving her neratinib.

So for her, she’s really struggling with diarrhea and abdominal cramping. From the ExteNET study we learned that we can give the neratinib and then after that we learned that it’s easier for patients to tolerate it if we dose escalate. So we started her off at 3 tablets, and then each week I’ve added a tablet to her. When we got to the full dose, the 6 tablets, the 240 mg, is when she had the majority of her symptoms. She had to stop due to a noncancer-related surgery, and we restarted and dose escalated again. And right now I’ve got her at 5 tablets, and we won’t go higher than that because it just is impacting her quality of life too much.

DR LOVE: So Virginia, again a situation where it’s an oral therapy, it’s really up to the patient if they want to stop or they don’t want to start it. It’s up to them. You do see a little bit of a boost — or reduction in the recurrence rate with it.

One of the things that’s very interesting is the study suggested even though this is anti-HER therapy that people who were ER positive, so-called triple positive, so they were ER/PR positive and HER2 positive, they were the ones for some reason who seemed to get all the benefit. I’m not sure we have an explanation. But can you just reflect back, Virginia? Again, for patients that want every possible avenue to reduce their chance of recurrence. What is neratinib? And what do you say to patients about the potential benefit, particularly if they’re higher-risk patients and particularly how do you deal with the symptoms, particularly diarrhea?

DR KAKLAMANI: So when we look at anti-HER2 therapy we have 3 different categories. The first is the antibodies, like trastuzumab that we just discussed, and pertuzumab. Then we have the antibody-drug conjugates, which is basically an antibody, and then it has a toxin on it, a chemotherapy on it, and those are kind of the novel ones, the new ones that we’re all extremely excited about. And then we have the tyrosine kinase inhibitors.

And if you all remember how all these receptors work, including HER2, they have an external part. Most of them bind a ligand. HER2 doesn’t for some reason. We don’t know what the ligand is at least. Then it has a little transmembrane part, the part that is inside the membrane, and then it has an internal part, the part inside the cell, and this is where the tyrosine kinase domain is. And this is what really gets activated. And so these tyrosine kinase inhibitors, they work on that domain, so they turn on or off the receptor. In most cases they turn it off, and that’s what neratinib is.

Now unfortunately a lot of these tyrosine kinase inhibitors, because we have them for a lot of diseases, we have them for leukemia, we have them for lung cancer and so forth, they’re not extremely specific, so they don’t just target HER2, but they target other tyrosine kinases. And so by targeting other tyrosine kinases they can cause some side effects, and the major side effect is going to be diarrhea.

And this is really something that we struggled with with neratinib until we had a clinical trial that really only looked at diarrhea in something called the CONTROL trial. And what they did was they just tried different antidiarrheal approaches. They started with loperamide, and then they started with combinations of loperamide and budesonide and so forth, and then finally they said — and those were okay. But then they said well why don’t we just start with a lower dose and then start increasing the dose and see if that work, and that worked the best.

DR LOVE: So Joyce, any comments on management of localized HER2-positive disease, everything from neoadjuvant therapy that we’ve talked about to post-surgical therapy, T-DM1 that this patient got, but particularly this issue of neratinib, when you use it and what your experience is with it?

DR O'SHAUGHNESSY: Yes. So when patients get the preoperative therapy with chemotherapy and trastuzumab and pertuzumab, and they still have considerable residual disease, such as nodes positive, or still quite a lot of disease in their breast, unfortunately they still have a substantial risk of recurrence. And it’s been shown that there’s an 11% improvement in their chances of staying cancer free without recurrence when you bring in the T-DM1. It’s every 3 weeks for 14 doses. It takes 10 months. It’s a long time.

But fortunately it's extremely well tolerated, but they get a big improvement in their outcome. And then unfortunately, though, for patients who still had nodes positive, for example, and if they’re estrogen receptor positive, we know these patients can recur 5, 10, 15 years down the road, and they can also recur in their brain. So they still have residual disease even after — at 3 years, for example, there was a 12% risk of recurrence just at 3 years. We’re waiting on the 5-year data, we don’t have it yet, from the KATHERINE trial that brought us the T-DM1.

So in these patients that are estrogen receptor positive if you block the HER family, not just HER2, because neratinib blocks the entire HER family, and you block the estrogen receptor, you really get excellent improvement in outcome. In these patients who had preoperative therapy you get a 9% improvement in overall survival.

So again, as we’ve been saying here, it’s these patients who have high risk and really want to take everything we have for them to improve their outcome. It’s only 1 year of therapy. Dose reduction on neratinib if you need to do it is if they can get 11 months of therapy, and I think there was a threshold of at least 4 pills, they got the benefit.

ER-negative disease is a lot of patients who have poor prognosis with ER-negative, HER2-positive disease, and in the ExteNET study with the 1-year of neratinib the curves pulled apart. While the patients were getting the neratinib there were fewer recurrences, and then they stopped the neratinib, and the curves came back together again. There was not a sustained improvement in disease-free survival. However, patients had up to 2 years to start the neratinib after they finished their adjuvant trastuzumab. That’s a long time. Patients can recur in that time. So they did an exploratory analysis looking at patients who started their neratinib within 6 months of finishing up their adjuvant trastuzumab, and there the curves pull apart, not huge, but they do pull apart, and then they stay apart.

So if you have a patient that just does not get a good response with preoperative chemotherapy and trastuzumab, they still have a lot of disease, they’re ER negative, they’re going to get T-DM1, it’s not unreasonable for them to take a year of neratinib as well. It’s approved by the FDA in both ER positive and ER negative, but the NCCN Guidelines, I think, really confined it to the ER-positive patients. But it is FDA approved for everybody.

DR LOVE: And people, docs, look at the NCCN Guidelines, they look at UpToDate, they look at the FDA approvals, and they are not always exactly the same.

I want to go on and talk about metastatic HER2-positive and HER2-low disease, but one final comment about adjuvant therapy because Joyce was talking about reducing the risk of recurrence or dying by 11% or 10%. When you talk about adjuvant therapy, and we’re going to talk about it, for example, in lung cancer on Friday night, and many other situations, in bladder cancer, et cetera, where adjuvant therapy — there are 2 different — it’s really a numbers thing. People don’t have tumors that you can measure. You’re really trying to give them numbers on what their likely risk is of recurring and dying of that disease and how the therapy is going to be affecting it.

And there are 2 ways you can look at those numbers. One is the absolute difference, so like for example 11%. So there’s a 1 in 10 chance that you literally will avoid having a recurrence. But another way to look at it is well what fraction of your overall risk is being covered by this therapy, and in that situation it’s actually more like 40%. So in other words, if you look at the remaining risk how much of that risk is taken away by this therapy. And you’ll see people quoting both numbers. Some are higher than the other, but what the patient really wants to know is what’s the actual — I’m going to take this therapy, what’s the chance that I’m going to avoid dying or recurring of the disease.

HER2-Positive and HER2-Low Metastatic Breast Cancer — Part 1

DR LOVE: Let’s talk a little bit about metastatic HER2-positive and now HER2-low breast cancer. And here we have another factor that has to be considered and specifically very, very important in HER2-positive disease, which is brain metastasis. And before Ron talks about his 49-year-old lady, Virginia maybe you can just provide a little bit of an overview of the issue of CNS mets, specifically brain mets, in people with HER2-positive metastatic disease and how you think through therapy in a patient who has brain mets. Are you going to radiate it? Are you going to take out the brain mets? And do we have systemic therapy maybe that can be used? We know in lung cancer we do that all the time. We hold off on radiation, we give treatment. What about in HER2-positive disease? How does brain mets affect the way you approach therapy, Virginia?

DR KAKLAMANI: So HER2-positive breast cancer is probably one of the most common if not the most common breast cancer to unfortunately eventually metastasize to the brain. Around 50% of patients with metastatic HER2-positive breast cancer will develop brain metastases at some point, and typically that happens when we move from our first-line therapy to our second-line therapy, so relatively soon. And a lot of times that’s our limiting factor in treating a patient, what their brain disease is doing.

So we tend to look at the brain disease and try to treat it by itself, but at the same time we also have to take into account what the systemic disease is doing, the liver metastases, the lung metastases, and so forth. So I try to look at the brain metastasis and treat it locally with radiation, targeted radiation, with surgery if I need to, so I involve the neurosurgeon, I involve the radiation oncologist. This is really where a team is so important, and a lot of times a neuro-oncologist, who knows a lot more about the brain than I do.

But one of the things to think about is a lot of our drugs historically we thought that they don’t go into the brain, and the reason for that is this thing called the blood-brain barrier and our bodies protecting our brain from all of these toxins by creating this blood-brain barrier. But unfortunately if cancer cells that are big cells go into the brain that means that that blood-brain barrier doesn’t really exist as solidly as it otherwise exists, and so a lot of our drugs actually do go to the brain, and they can treat brain metastases.

So the way I approach it is I want to look at local therapies, but I also want to give my best systemic therapy because if the systemic therapy works for the systemic disease there’s a good chance it’ll work for the brain metastases as well.

DR LOVE: So we’re going to now present 2 cases, 1 from Ron and 1 from Jamie, but before that, Joyce, can you just kind of provide an overview of really 2 of the key post local therapy strategies used in metastatic HER2-positive disease, the antibody-drug conjugate T-DXd, and the so-called HERCLIMB regimen that includes the TKI, we’ve been talking about TKI, tucatinib? Can you just talk a little bit about what we know about these 2 strategies, Joyce, in terms of efficacy, tolerability, and also the ability to directly affect brain mets?

DR O'SHAUGHNESSY: Yes. So the first treatment for HER2-positive metastatic breast cancer is trastuzumab/pertuzumab and a taxane. That’s always first still. And then second line we have a very important Phase III trial. Because it used to be we would give T-DM1 second line, but now T-DXd (trastuzumab deruxtecan) is much more effective than T-DM1; big improvement in survival. So that’s become our second-line setting.

Patients with treated brain metastases were allowed on the trial, and the patients across the board did very well. We don’t have a large data set to show how well the T-DXd works for brain metastasis. For example, let’s say you did a brain MRI, and you found a couple/3 small metastases, patient’s asymptomatic, you don’t have to do radiation first, you can give therapy to see if it works.

There was a small trial done called the TUXEDO trial that did that, with untreated brain metastasis, and they gave the T-DXd and showed — it was a small trial, like 14 patients, but showed very, very substantial reduction in the brain metastasis with the T-DXd, so very, very exciting data, making that, I think, a very reasonable option for patients with brain metastasis.

And then we have the regimen that’s generally used in the third-line setting now, and that is the oral inhibitor of HER2 tucatinib, and it’s given with capecitabine and with trastuzumab. I call that the tucatinib triplet. And that has very, very strong penetration into the brain. They did a trial called the HER2CLIMB trial, and 50% of the patients had brain metastasis, half of those had not had treatment for the brain metastasis, so they were untreated active brain mets, and there was a very substantial reduction — like a 50% response rate and improvement in survival.

So a lot of us are using that regimen. We’ll even do it second line if the patients, for example, have primary brain metastasis, they have no disease, for example, outside the brain, or very, very little outside the brain where that’s the dominant site of disease that’s going to be the life-limiting site of metastasis. But generally speaking the TDM — the T-DXd second line, because they both look quite effective in the brain, but the higher level of evidence is with tucatinib, the tyrosine kinase inhibitor of HER2, along with capecitabine and trastuzumab.

DR LOVE: Let’s talk a little bit more about tolerability of these various regimens, but one more point, Virginia. We were talking this morning about antibody drug — we’re going to be talking about antibody-drug conjugates all week. This morning we were talking about tisotumab vedotin used in cervical cancer. Here we’re talking about T-DM1 and T-DXd, both antibody-drug conjugates, and yet when a trial compared the 2 there was no comparison, the T-DXd did way, way better. Can you talk about how you explain to a patient, Virginia, what an antibody-drug conjugate actually is, and like how does a drug like T-DXd work, or how do we think it works?

DR KAKLAMANI: Yeah. So the antibody-drug conjugate is an antibody, like trastuzumab, in this case trastuzumab, and it has a toxin on it. So what happens is this molecule goes into the cell, and then the toxin gets released inside the cell, and then it kills the cell. So we call it the trojan horse approach, and for whoever remembers Iliad, that’s what the Greeks did to beat the Trojans, they took a horse, and inside there were these little soldiers. And they gifted the horse to the Trojans. The Trojans didn’t know any better, they took the horse inside of their city, and then at night the soldiers came out, they opened the gates to the city, all of the other soldiers came in, and Troy fell.

So this is really kind of what these antibody-drug conjugates do, but they’re a lot more eloquent than a Trojan horse because this little toxin actually gets excreted outside of the cell, and then it goes to the nearby cells that may not be HER2 positive, and it kills those cells too. So it’s really brilliant in how these antibody-drug conjugates work and why we use them in so many diseases.

DR LOVE: Yeah, so this is really targeted delivery, though, of chemotherapy. And Jamie, we know that you — although it’s not as much as I.V. chemotherapy you can see chemotherapy-type side effects. Premedication for GI problems is recommended. I’ve heard people talk about hair low, although I don’t know how common that is, and particularly of course, and we’ll talk a lot about this tomorrow night, interstitial lung disease.

But in terms of the acute effects, Jamie, how would you compare it? What do you see, for example, compared to IV chemo?

MS CARROLL: I think they’re a lot more tolerated than IV chemotherapy. With the T-DM1 I do see sensory neuropathy, as well, and so sometimes that leads to stopping the dose or reducing. I think that side effects from trastuzumab deruxtecan are a little bit more profound than T-DM1 side effects, but we do know that T-DM1 is a very powerful drug. I describe it to patients as kind of a chemo bomb. It’s coupled together and delivers it directly to the cancer cell. So that — with T-DXd we know that there is some bystander effect, but with T-DM1 there’s a lot less systemic side effects.

DR LOVE: So Ron, your 49-year-old woman presented with mets to the bone, nodes, liver, and brain, and lung, previously treated with a whole bunch of therapies, including niraparib and T-DM1 that we just talked about, but then I guess about a year — more than a year ago she had progression and was started on T-DXd.

Can you talk a little bit about how — what you said to her when you were talking about beginning the T-DXd, how you prepared her for it, what she was like as a patient in terms of how she retained the information, and then how she’s done?

MR STEIN: Sure. I’d like to first say that this patient is a registered nurse, and her husband is a registered nurse, so although they’re not in the oncology arena they’re very familiar about how the body works and pharmacokinetics and pharmacodynamics. We explained — when we were about to start the T-DXd we explained the mechanism of action kind of like what Jamie said, the benefit of the T-DXd. I mean this lady had already failed T-DM1, and so it was nice because this diagnosis was in 2017, this lady has been on treatment for the last 5 or 6 years. When the T-DXd came around for the metastatic setting in HER2 positive, before the 1+ or 2+ IHCs, it was like a miracle drug according to the studies when it was presented head-to-head with T-DM1.

So we explained the bystander effect kind of like the bomb getting delivered into the cell but then also having this added bonus of hitting any other surrounding cells as well. We talked about side effects, of course. The main thing we get concerned of is the interstitial pneumonitis. We have now — based on evidence, we do regular chest CTs on these patients. I have only seen 1 particular patient get this. She was a metastatic patient, obviously, straight HER2, hormone negative, and she actually passed away. Yeah.

DR LOVE: That is a terrible situation when a therapy that you’re giving actually leads to a patient’s demise. On the other hand, so many patients like this one. How is she doing incidentally?

MR STEIN: Well, at the time, Neil, that you had me prepare this she had been doing so well, and just last week we found that on her brain MRI she had progression.

DR LOVE: Wow.

MR STEIN: And I’m not going to actually blame it on the T-DXd because the rest of her metastases to the liver, the lungs, the node, have all been kept in check. So just like Dr O’Shaughnessy had said I feel like this — my patient, this woman, is now almost textbook because now what we’re going to into is the tucatinib/capecitabine and trastuzumab regimen.

But although it will likely hopefully get her some response, and I’m going to be optimistic about it, we’re kind of running out of options on this lady, and it can be quite heartbreaking. She’s now 49 and really has been — up until these brain mets became worse. She continued to work as a full-time nurse on the floor. And I also wanted to add she has maxed out on the amount of radiation that she can get to the cerebellum, so that is no longer an option.

DR LOVE: So I think people can hear in the tone of your voice how you feel about taking care of this patient.

Let’s talk a little bit about HER2-low disease, though, because — and again, tomorrow night we’re going to get into much more depth about that, and you really wonder how far are we going to be able to go with drugs like this. Maybe much farther than we thought in the past.

But Joyce, can you talk a little bit about — now we’re talking about patients who in the past have been considered either ER positive, HER2 negative or just triple negative, and now we’re saying they’re HER2 low, either 1+ or 2+, it doesn’t seem to make much difference. Can you talk about the sequence of therapy in a patient who’s HER2 low, first hormone receptor positive, hormone receptor negative? What are they likely to receive in sequence if they’re HER2 low? And where would T-DXd fit in?

DR O'SHAUGHNESSY: And so this is helpful because we have these results on the chart already. Because we can go back to a primary breast cancer, and if it says HER2 1 or 2+, and if they did a FISH the FISH needs to be negative for them to be HER2 low otherwise they’re HER2 positive, right, or a metastatic biopsy that says HER2 1 or 2+. That’s the definition of HER2 low, again if the FISH is negative.

So what’s the treatment? If they’re estrogen receptor positive we give them as many regimens of endocrine therapy as we can. We want to give them the CDK4/6 inhibitor, then we want to block the PI3-kinase pathway. We went to use elacestrant if they’re ESR1 mutation, so an activating mutation in the estrogen receptor. We may come back to a second — another CDK4/6 inhibitor. And there are other options we have. We may use everolimus, et cetera. So we really want to use endocrine therapy.

And then, unfortunately, their disease becomes resistant to endocrine therapy, and we want to go on to chemotherapy. And usually the first thing we go on to oftentimes is capecitabine, oral capecitabine. If they have more severe disease you might go to an IV taxane or even a combination of a taxane with a second chemotherapy agent. But usually — but then if they’re HER2 low the next therapy, the second-line therapy, the second chemotherapy, is the T-DXd, because it’s been compared to single-agent chemotherapy other options, and it blows them out of the water, including massive survival improvement. So it really is super important that we have to get the cardiac echo and make sure that they have a good heart. If they have a history recently of interstitial lung disease we would not come in with T-DXd. But those would be the only kind of contraindications I would think of. So it’s the — it’s endocrine therapy first, then usually capecitabine, and then next is T-DXd because of the Phase III data.

For triple-negative breast cancer patients, again that have the HER2 1 or 2+, and it’s FISH negative, the first thing we want to know for those patients is, is the metastatic disease PD-L1 positive. If you don’t have good metastatic disease to test you can go back to their primary breast cancer and check for the protein PD-L1 because those are the only patients that have benefit from pembrolizumab in the first-line setting in combination with chemotherapy.

 So that’s the first treatment for the PD-L1 positive is chemotherapy and pembrolizumab, and then if they’re negative for PD-L1 they get chemotherapy unless they’re germline BRCA, unless they have an inherited BRCA mutation, in which case we would give them — consider olaparib for them in the first-line setting if they’re PD-L1 negative. But then having had that, again in the second-line setting the choice is the T-DXd because that was done in this trial called the DESTINY-Breast04 trial, where in the second-line setting the T-DXd was compared to single-agent chemotherapy and had a massively better outcome than giving another chemotherapy agent in that second-line setting.

DR LOVE: So Virginia, of course there’s another antibody-drug conjugate used in breast cancer, sacituzumab govitecan, and it’s not associated with interstitial lung disease, at least to the extent that we’ve seen with T-DXd. How do you decide, for example in a patient who’s triple negative, what’s going to come first T-DXd or sacituzumab? And can you comment a little bit about what Jamie was talking about, trying to pick up ILD before it becomes symptomatic and how you think through the whole issue of managing people who actually develop ILD?

DR KAKLAMANI: Yeah, absolutely. So sacituzumab is another antibody-drug conjugate but the antibody part of sacituzumab is against a receptor called the TROP2 receptor, so totally different from the HER2 receptor, and now this drug is approved both for triple-negative breast cancer and estrogen-positive breast cancer. And we struggle in deciding which one we want to do first, and I think we all have our preference, so my preference tends to be for the triple-negative breast cancer patients because there’s more data with sacituzumab. I prefer sacituzumab as my first ADC (antibody-drug conjugate) to use, and then I will give — if this is HER2 low, I will give T-DXd,

In ER-positive disease I’ll do the opposite. I will give T-DXd first, which really is approved before sacituzumab is approved, and then I will move on to sacituzumab.

But it’s also important, again, to involve a patient with those decisions. The 2 drugs are different as far as side effects. T-DXd will have more nausea. Sacituzumab will have more diarrhea. Sacituzumab will have more neutropenia. T-DXd will have ILD, 10 to 15% of patients on T-DXd will have some degree of ILD. And as far as something that all our patients care a lot about is hair loss. Sacituzumab around 50% of patients will have some degree of hair loss, and with T-DXd it’s less, around 30%. So those are things that if we struggle with that decision we can talk to our patients and ask them because both drugs are extremely effective, and they lead to improvements in overall survival, which is what we look for.

DR LOVE: So Joyce, in terms of patients who do develop, or you pick up the ILD, the clinical dictum I’ve heard is if they have symptoms they’re not going to get it again. It’s going to get stopped, you’re going to give corticosteroids, and that’s it. But if they — you pick it up when it’s just in the imaging stage, and they don’t have symptoms, you consider the possibility. You stop it at that point, give them the corticosteroids, but then if they stabilize out maybe retreating, for example particularly patients who are having a great response. And I’m hearing a lot of good stories, not just the trial papers, I’m hearing cases of people who really do well.

How do you approach the use — the issue of screening for ILD using imaging, Joyce, and do you buy into this concept if they have symptoms they’re done?

DR O'SHAUGHNESSY: Yeah. Yes. That is the current guidance that we have. It’s kind of a hard stop. If someone gets any cough, shortness of breath, even fever, you have to ask for that — ask about that all the time, and then you get the CT scan, and if there are changes on the CT scan compatible with ILD then you permanently stop the T-DXd, treat with corticosteroids, maybe get a pulmonary consultation to see if a bronch is necessary, and unfortunately then the patient’s done with the T-DXd.

And so to try to avoid that you get CT scans, noncontrast CT scans every 6 to 9 weeks in a woman even if she doesn’t have any lung metastasis, she just has liver metastasis or bone metastasis. You just get the noncontrast CT scans every 6 to 9 weeks because you want to try to pick up ILD early before there’s any symptoms so then you can hold the T-DXd, treat with steroids, and then resume it. They say within 30 days you can resume the same dose, but it’s hard to get a CT scan to resolve in 30 days so mostly it’s longer than that. You want to see it really resolve, and then you can resume the T-DXd but at a lower dose. So I think that’s mainly what motivates me to get the noncontrast CT scans as a chance to keep going.

They’re doing more studies to see if patients are just very, very early symptomatic, and you catch it early, and you treat it, we may be able to do that. But as Ron said, patients unfortunately do die of ILD, and so we have to be very cautious.

DR LOVE: And we’ll talk tomorrow night. For example T-DXd is being used in lung cancer, and there you have a people already with pulmonary symptoms with chronic obstructive lung disease, and then they’re starting out, they’re symptomatic before you even give them T-DXd, making it more of a challenge.

HER2-Positive and HER2-Low Metastatic Breast Cancer — Part 2

DR LOVE: Well let’s bring in the other major advance in the metastatic setting that we’ve been talking about, the tyrosine kinase inhibitor tucatinib. I’m curious what your experience has been with it. But let’s start out with this 57-year-old woman who actually received the HERCLIMB regimen. What was her situation when she started that, Jamie, and what are some of the things that you went through with her?

MS CARROLL: Yeah. So this woman was originally diagnosed as early stage. We gave her chemotherapy combined with HER2-targeting therapy, and she had a path CR. So it’s heartbreaking when they come back with brain metastasis because we know that our drugs did not get through that blood-brain barrier. And so for this patient her presenting symptom was actually a seizure. So she went to the emergency department, and MRI was done. We started her on first-line treatment, THP. She did get Gamma Knife to the brain, so like we talked about earlier, local therapy to the brain, and then she had progression.

And so with symptomatic progression we switched her to this HER2CLIMB treatment. So capecitabine and tucatinib are oral, and then trastuzumab is your every-3-week infusion. Now this woman’s social history is she is the primary caregiver of her 2 grandkids. And so for her when we combined all 3 drugs her quality of life tanked. Tucatinib and capecitabine both have diarrhea as one of the primary side effects, and so when I was talking to her about quality of life and how that’s very important, she said, “Jamie, I just can’t do this.” And so I said, “Okay. What we’re going to do is we’re going to drop one of the oral drugs.” And the drug that I chose to keep was the tucatinib because we know that that one gets through the blood-brain barrier very well, and we know that she has brain metastasis.

She has now been on this regimen for 9 months and doing really well with really good quality of life. She’s able to take care of her grandchildren, and she’s able to do the things that she wants to do, and she’s sustained treatment just with the tucatinib and the trastuzumab.

DR LOVE: Any comments? We were talking this morning, and again, one of the themes that we always get into every year are minor children and grandchildren of patients with cancer, particularly difficult cancers that are not going to be curable. Do you find that this woman is as close to her grandkids as many mothers are to their kids? And how old are the kids? And any thoughts about what they understand about what’s going on?

MS CARROLL: The grandkids are teenagers, so I think that they do understand. She brings her granddaughter with her frequently, so she’s hearing the conversation that I’m talking with her grandmother about.

DR LOVE: So Virginia, any comments about the HERCLIMB regimen and also the issue of tolerability? You have 2 drugs in there that can cause symptoms, particularly diarrhea, capecitabine and tucatinib. You heard the story here. Can you talk a little bit about what we know about this regimen? Would you ever use it without radiating the brain, just to give systemic treatment the way they do in lung cancer for brain mets?

DR KAKLAMANI: Yeah, absolutely. So the benefit of this regimen is that it’s mostly oral, and so the patient can take it at home. If they come in for their infusion of trastuzumab every 3 weeks at least they just come every 3 weeks, and they get 1 drug, they can even get that subcutaneous, and so that really decreases the time that they’re in clinic.

The downside is we can’t control what the patient does. We don’t know when they start taking the medication. We don’t know how they’re taking it. We don’t know if they’re taking it correctly. We don’t know if they’re having nausea/vomiting, and they’re throwing up some of those pills. We don’t know how compliant they are. So those are things that always make me a little careful, and I need to make sure that it’s the right patient. I need to know that I educate them well, and I need to know that my nurse or my pharmacist calls them frequently to check up on them and make sure that they’re still taking their medications correctly.

Now the major issue with this regimen, as Jamie mentioned, is going to be the diarrhea because we have 2 of the 3 drugs causing diarrhea, and then we just have to change the dosing. And I would have done the same thing. I would have lowered or stopped the chemotherapy, kept the targeted therapy because I think that’s the most important part of the regimen, to be able to get the patient through this kind of treatment. And based on the data that we have from HER2CLIMB we don’t really have to do localized therapy in the brain for this patient. We can definitely give this regimen and watch the brain, and in many cases, as Joyce mentioned, we will see a response in the brain.

DR LOVE: So does it seem like we’re covering a lot of stuff here tonight? And this is not just breast cancer. I mean all week it’s the same thing. I mean it’s great news, phenomenal news for patients, but really a challenge for oncology specialists, particularly if you’re in a situation, which most people are, where they’re seeing multiple types of cancers. I you work in a general medical oncology office these docs are scrambling around. It seems like there’s almost a new approval every week that they have to consider. So great, great news. We’ll see where things are heading. Maybe we can really make a dent in this disease. But meanwhile there’s a lot of stuff to keep in mind.

PARP Inhibitors

DR LOVE: And speaking of that, let’s talk about something else we’re going to be talking about in a bunch of different cancers, which is the use of PARP inhibitors, Joyce. And maybe you can just provide, before we hear about Ron’s case of a patient with a triple-negative tumor who has a BRCA1 germline mutation, maybe Joyce you can just paint a little bit of a picture of what PARP inhibitors are, and in what situations are they used in general in oncology, and of course this really started out with ovarian cancer, which we’re going to be talking about I think tomorrow or Friday. I lose track of what days we are here. But can you kind of tell us a little bit about PARP inhibitors, Joyce?

DR O'SHAUGHNESSY: Yes. In breast cancer there are 2 oral PARP inhibitors approved by the FDA, olaparib and talazoparib, and these are oral agents that inhibit this enzyme called PARP, and PARP’s a very important DNA repair enzyme. And there’s this concept called synthetic lethality, and it’s like the Achilles heel of the cancer if you can tell what is the DNA repair problem in the cancer. For example, if women have inherited a BRCA1 or BRCA2 mutation then they don’t repair the DNA by — they can’t repair double-strand breaks, and so they accumulate mutations, and that’s why they’re very high risk for getting breast cancer, ovarian cancer, other cancers. That’s the Achilles heel of that cancer. It accumulates all of these breaks in the DNA that cannot be repaired because they’ve lost BRCA1 or 2.

It turns out then, those cells become very dependent on the PARP enzyme, the PARP protein, to repair the DNA. So when you come in with an inhibitor of the PARP enzyme you have taken 2 legs off of that table, and the table collapses. And so the table is kind of teetering with the loss of 1 leg, you take another leg away of the DNA repair table, it collapses. The cell just dies. That’s called synthetic lethality. It’s the holy grail. It works extremely well against patients — for cancers where there’s a BRCA1 or 2 mutation there.

So they’re both approved in the metastatic setting for patients who have metastatic breast cancer that’s HER2 negative. Whether it’s hormone receptor positive or triple negative that’s something we’ve got to know about the patients, right, is that we’ve got to test and make sure we don’t miss the germline BRCA mutation even if they have no family history of breast cancer. But even more importantly one of them, olaparib now, has been shown in a trial in the early breast cancer, the OlympiA trial, for triple-negative patients or hormone receptor positive, HER2/neu-negative patients that are high risk, to improve the disease-free survival, so to prevent recurrence of disease I believe it’s 8.8%, almost 9% absolute improvement.

And it’s still early. It can even get bigger over time. It also improves survival, the chances of just staying — completely staying alive from breast cancer. So very, very important for high-risk patients now, for early breast cancer, again the imperative of knowing who has one of these genes so we don’t miss the opportunity to give this to patients.

DR LOVE: And I think one of the things that we’ve learned, and I think we first saw this with ovarian cancers, sometimes you have mutations that are only in the tumor, they’re not germline. You can have BRCA, what’s called BRCA somatic mutations. So this is not in every cell in their body, it’s just the cancer. Those people seem to respond really the same as the germline patients. They have the same abnormality.

Again, before getting into a real case, Virginia can you talk a little bit about tolerability and toxicity issues with PARP inhibitors, both acute problems that you might see in the first couple months, and also long-term considerations?

DR KAKLAMANI: Yeah. So these are oral medications, and as with many oral medications they can have some GI side effects, such as nausea. Most of what we see is blood counts decreasing, and we’ll see the white cell count, the red cell count, sometimes the platelets as well, decreasing. So that’s kind of the major side effects. But talazoparib, for example, has also been associated with very a small number of myelodysplastic syndromes and leukemia, so that’s always something we need to talk to our patients about. But otherwise they’re pretty well tolerated medications, and as Joyce mentioned they really have revolutionized our treatment of BRCA1 and 2-positive breast cancer.

DR LOVE: Incidentally, you see me kind of flipping through the slides because I’d rather hear them kind of tell their vision of this than to kind of go through the slides. But please feel free to consult the slides afterwards. They’re on our website. For those of you online they’re in the chat room.

Ron, let’s bring in a patient who actually got a PARP inhibitor, and she actually got it in the adjuvant setting. Hopefully we’re trying to improve her cure rate as opposed to the metastatic setting where we’re trying to extend survival and palliate the patient. What happened with this lady?

MR STEIN: That’s correct. So before we start out, just like Neil mentioned, this was given in the adjuvant setting. Olaparib was first approved for breast cancer patients in the metastatic setting for BRCA1 patients. But this lady actually had her diagnosis in 2017, it’s kind of a similar situation, and here she is 5 years later transferring care to us, to another oncologist I work with, and she had done everything. She did her neoadjuvant chemotherapy. She did her bilateral salpingo-oophorectomy, got her kids tested, genetic testing and everything.

Well, she relocated to California, and so when we saw her at the beginning of 2022 olaparib had just been approved in the adjuvant setting, so I know we’re 4 years out, again, but hey, is it one of those situations that potential benefits may outweigh the risks associated with the drug. We decided to offer her the adjuvant olaparib, and she was all for it. We did extensive education on it. We checked her — per the package insert she’s coming to us every single month. We’re checking blood work on her and make sure she’s tolerating it.

It happened to be generally she did very, very well on this drug, and she was a very, very tough 49-year-old, hardworking woman, had excellent family support, raising her kids, continued to work full time. Other than some abdominal discomfort, which did not necessitate a dose reduction, we didn’t see any — she tolerated this extremely well, and we were checking blood work on her every month. We did not even see barely a drop in the hemoglobin and hematocrit.

She’s not typical. Patients, both metastatic and adjuvant, my other patients I have on this drug sometimes require blood transfusions and dose reductions. The cytopenias I see the most are with the red blood cells.

Anyway, the thing that’s really interesting about this, she had some abdominal pain, and she went to the emergency room; this is 9 months into adjuvant olaparib. And they did a CT scan and lo and behold diagnosed with renal cell carcinoma. Completely unrelated we think, too either the breast cancer or the BRCA carrier status. But when she hit that year of the adjuvant olaparib she begged “can I please stay on this?” And we kind of had to tell her no, there really isn’t evidence beyond 1 year. That’s how it is approved in the adjuvant setting.

She had a very low-grade renal cell carcinoma. I happen to also work in the GU department doing prostate cancer, so it was easy. I got her right in with the urologist. She had a partial nephrectomy, and she’s rocking and rolling and doing absolutely great.

DR LOVE: Joyce — and of course it’s a little unusual to start it so late, but again when you get into the issue of maybe other people wouldn’t have even offered it to the patient, but this patient elected to receive it. Joyce, can you talk a little bit about your experience using adjuvant olaparib and also the issue that we’ll talk about in ovarian cancer of the question of does it increase the risk of AML and MDS? There were some data in ovarian cancer with heavily pretreated patients who’d gotten a lot of chemo suggesting an increased risk of this problem. It doesn’t seem like it’s much of an issue when it’s used earlier. But I’m curious what your take is about that issue and in general what your experience is with patients receiving adjuvant therapy in terms of tolerability.

DR O'SHAUGHNESSY: So adjuvant olaparib, when patients first start it, low-grade nausea can be a problem. It’s managed by — I have a patient, for example, she has 4 young kids at home, worked full time as a teacher, and started the adjuvant olaparib, and she was low-grade nauseated for a full 3 months. She took prochlorperazine a couple times a day. She worked full time. And then 1 day it was gone. It just went away. That was a little longer than I usually see, but you do have to be proactive and really help the patients with nausea knowing it’s going to generally go away for patients.

And then the anemia, as Ron said, is the other thing we have to look for. That is best handled with a dose reduction, the anemia, but a minority of patients need a dose reduction. It’s only a year of the olaparib, so generally once a patient gets used to it it’s actually quite well tolerated. And the great news in the OlympiA trial was that there was no increase in the risk of getting a secondary leukemia, AML, or myelodysplastic syndrome comparing the chemotherapy alone arm, the patients who got the chemotherapy who did not get olaparib, versus chemotherapy who did get the year of olaparib afterwards. No increase in the dreaded complication of MDS or AML.

DR LOVE: So 1 final topic, and speaking of having a lot to talk about, this is really just the top line. I mean we’re not talking about everything tonight. We’re talking about the most important things but not everything. There is a lot going on.

Immune Checkpoint Inhibitors

DR LOVE: But we did want to get into a relatively new change in therapy for localized triple-negative disease and really for the first time in breast cancer you see immunotherapy, checkpoint inhibitors, moving into the earlier-stage disease.

Before Ron presents a patient, a young woman who actually had received this so-called KEYNOTE-522 regimen, maybe Virginia you can paint a little bit of a picture of what this regimen actually is, how it’s used, and what kind of impact it has on the long-term outcomes of patients with localized triple-negative disease.

DR KAKLAMANI: Yeah. So the 522 regimen is a regimen used in the neoadjuvant setting in patients with triple-negative breast cancers that are at least Stage II, and this is a pretty intense chemotherapy regimen. It uses a taxane. It uses carboplatin. It uses an anthracycline and cyclophosphamide together with pembrolizumab. And then after the 8 doses of the chemotherapy — or 8 cycles of the chemotherapy, then patients have their surgery, and then after surgery they continue receiving pembrolizumab for another 9 or so cycles, so it’s a lot of treatment for our patients.

But the reason this regimen was approved was this trial that you’re seeing here that compared the same backbone of chemotherapy without the pembrolizumab, without the immunotherapy, and it showed that not only was the rate of pathologic complete response higher, this is the first time, the first trial in triple-negative breast cancer where the pathologic complete response was 64.8%. This was almost unheard of. Up until now we had a 50% pathologic complete response. But it also improved event-free survival, and this is the main reason why the FDA approved this regimen.

DR LOVE: So Joyce, what about autoimmune toxicity? Again, we’re going to be talking about that. We talked about it this morning. Checkpoint inhibitors now are used in most solid tumors so we have these issues, not only the autoimmune toxicity but also people have had prior transplants are not — for example a renal transplant, or heart or liver transplant, cannot receive these drugs.

Can you talk a little bit about the spectrum of autoimmune issues that come up when you use checkpoint inhibitors, not only in this scenario but any other scenario in breast cancer, metastatic disease, as we were talking about before?

DR O'SHAUGHNESSY: Yes. There are 2 issues. One is the issue that’s mostly what we see is a patient who has no history of an autoimmune disorder, and then the other issue is patients who have a history of an autoimmune disorder, okay? So the first one, I’ll tell you want I tell patients. I sit down and write this all down. Here’s what I say. I say 15% chance you’ll have permanent low thyroid from the pembrolizumab. You’ll need to be on thyroid for life. Then I say there’s a 1-2% chance of either having hepatitis, pneumonitis, or colitis. We’ll be able to find those right away and that those are generally reversible. I usually stop permanently the pembrolizumab when that happens, treat with steroids, it goes away. It can take 6, 8 weeks of steroids, which you hate in the middle of your preoperative chemotherapy, but it’s usually reversible. But we’re very vigilant about that.

And then I say then we get into the super rare, the less than 1% or less than 0.1%. You can have permanent loss of your adrenal function, permanent loss of your pancreas function, insulin-dependent diabetes, or permanent loss of your pituitary, your gland. The glandular stuff tends to be permanent.

Then I say but you can have inflammation of anything, so we always have to ask is anything weird going on because we have to scan it and figure it out. For example, I had a patient whooshing, whooshing in the head, whooshing, and we got a brain MRI, a little inflammation, a little encephalitis. We stopped the pembrolizumab, gave her the steroid, she’s fine. So just vigilance. That’s what I say, and I do tell patients that there was a death from encephalitis, there was a death from pneumonitis in the adjuvant/neoadjuvant setting, so we have to be very, very vigilant.

And then the other issue is patients who already have had an autoimmune disorder, so they have an active serious autoimmune disorder, ongoing Crohn’s, ulcerative colitis, et cetera, they’re just simply not candidates because it generally worsens your autoimmune disorder. But if they have a history of skin psoriasis, maybe a little — remote history of rheumatoid arthritis, it’s very well controlled at this time, the recommendations usually are to work with the patient’s autoimmune physician, their rheumatologist, their dermatologist, and to very, very carefully watch them, as long as there’s a lot of good medications that can reverse it if it gets really bad.

I saw a patient today. She has a history of psoriasis and psoriatic arthritis, and going the literature search, getting up to speed, and it is recommended — she’s well controlled right now. It’s recommended that she get an opportunity to get the pembrolizumab, but it’s also very likely it’s going to flare. So they’ve got to be really plugged in with their physicians.

But because this improves the cure rate quite substantially, it’s about a 7% improvement in event-free survival, it’s a big improvement, and it seems to be getting bigger as time goes on, we have to give patients the benefit of the doubt.

DR LOVE: It kind of reminds me of those commercials you see on TV where they go oh, it can cause this, this, this, and this, and this, and you’re like woah, I don’t know if I want to be taking that. But I suppose we also say what’s the chance you’re going to cruise through this with no problem.

DR O'SHAUGHNESSY: I would say that there’s about a — well really about probably 95% chance you’re not going to have anything serious happen because there’s a 15% on the thyroid, but I don’t consider that serious, you just take a pill, and we have to watch it, though, every 3 months watch it for a couple of years. But there’s probably 95-plus-percent chance patients are going to do fine with it.

DR LOVE: So as long as we’re going through all the downside, what about actually — we’re doing 2 meetings Sunday at the American Urologic Association. We actually have a patient who lost their kidney transplant because they wanted to try an IO. They had metastatic bladder cancer and hoping that it wouldn’t cause rejection. What about people with prior transplants, Virginia?

DR KAKLAMANI: I would consider that a contraindication. I mean these drugs work by empowering the immune system to kill the cancer cells, and all we’re trying to do in these transplant patients is to slow down the immune system, so we’re working against ourselves by giving these drugs.

DR LOVE: And now we’re — actually we’re talking Friday morning about hepatocellular cancer. Now there’s a positive adjuvant trial using an IO in HCC. We’re talking about that Friday morning. And again, so many people have had hepatic transplants, so they’re not going to get it, but maybe resection.

All right. Well let’s hear about what happened with your 42-year-old lady, Ron, who actually got the 522 regimen.

MR STEIN: Sure. She had localized triple-negative cancer. She got the neoadjuvant regimen pursuant to the KEYNOTE trial. The only thing we really struggled with initially was her thyroid and the associated fatigue. It got a little bit hairy because we had to determine well was it really your hypothyroid causing the fatigue, was it a little bit of both, was it the chemo.

This lady was extremely fatigued, and she didn’t want to go on. And we really had to encourage her. We got her on levothyroxine. We even just — we wanted her to push through this regimen so much so that we got an endocrinology consult. That’s certainly not my forte, is managing hypothyroidism. But she was really, really happy, and we were pleased that she went through. She completed it without incident, and she had a complete pathologic response, and she was thrilled.

Now she is just about to finish up her adjuvant pembrolizumab. We’re checking thyroid function about every 6 weeks.

DR LOVE: So Jamie, any thoughts about we’ve talked about lots of different strategies in the up-front localized setting of adjuvant therapy. Any comments about life after adjuvant therapy? We know that particularly with ER-positive breast cancer, but just in general that the disease can come back, and if it comes back it’s often not going to be cured. Can you talk a little bit about how you counsel patients in terms of coping with some of the stresses that they deal with after they finish adjuvant treatment?

MS CARROLL: I find that patients struggle with being at our clinic weekly, every other week, every 3 weeks, and getting that reassurance that everything’s okay or the cancer is getting smaller when it’s in the neoadjuvant setting. And then in the adjuvant they’re on pembrolizumab, so they’re coming every 3 weeks, and they’re either seeing a provider or they’re seeing a chemo nurse, and they’re still getting that reassurance. And then that adjuvant period ends, and then those patients come every 6 months because they’re on endocrine therapy, or they’re triple negative, and we just surveil them every 6 months. So I really try to talk to patients that this periods of time can be really challenging, when you’re not seeing somebody so frequently and getting that reassurance.

And so I try to tell them that I’m here. You can portal message me any time, which we’re not supposed to tell them that, but I want to be there for them. I want them to feel like there is still somebody in their corner that’s cheering them on, and that I’m here if they have things that come up that they’re worried about. I want them to talk through that with me. So for those patients I really try to counsel in the change in frequency that they’re going to be seeing a provider and getting that reassurance.

DR LOVE: So we talked about the bond that heals, and you can hear it in your voice, you can hear in both of your — all of your voices in terms of what you’re communicating to the patient and what that means to the patient.

I want to just finish out with maybe a vision for the future. I’m going to start with you, Joyce, and ask for you to predict what we’re going to be talking about next year. I mentioned cell-free DNA. That’s my first question. I’m sure you have plenty of other things to talk about, but I find this a very fascinating technology. I’m not sure if it’s really gotten to breast cancer yet, but you’re hearing it, particularly in the GI cancers. What is cell-free DNA? Do you think it has a future in breast cancer? And what are other research endeavors right now that have you excited?

DR O'SHAUGHNESSY: Well, I think that the cell-free DNA is going to revolutionize cancer over the next 5 to 10 years. Both of these tests, called the MCED tests, which are the multicancer early detection tests, that actually can pick up cancers in say high-risk individuals before you can find it on a scan. But these are patients, for example, that may have a family history of pancreas cancer or ovary cancer, and we don’t have good surveillance for that, and so they can get annual tests and then get a full workup.

There are several different companies that are making those, and they definitely are helping patients. We have some ways to go on those. We’re not picking up enough Stage I cancers yet, and the sensitivity isn’t quite there, but that’s going to — we’re just at the beginning. It’s going to just revolutionize. So we’re going to be having patients come in, new patients come in with this positive test, and they don’t have cancer yet. But it’s an opportunity to pick it up early, find it early, treat it early, and have more cures.

And then for our patients who have breast cancer in the early stage setting, women want to know. They want to know am I clear. Am I clear? And it’s not ready for primetime, in my opinion. I’m not ordering these tests. Now the MRD (minimal residual disease). It’s a blood test looking for circulating tumor DNA, and generally they go back to the original breast cancer, sequence it, and pick out 15 to 30 mutations in that woman’s particular cancer, and that’s what they look for in the blood, to pick it up early.

And I’ll just give an example. Unfortunately, we just got word yesterday that the ZEST trial was closed, the GSK trial of adjuvant niraparib, a different PARP inhibitor for triple-negative breast cancer patients who had finished up their chemotherapy, high-risk patients, start looking for the ctDNA in these asymptomatic patients who have no evidence of disease. And then if you find a positive one do a scan — do scans, make sure they don’t have frank metastatic disease, and then randomize them, half get niraparib and half do not get that, to see whether you can save more lives by bringing in a PARP inhibitor early. It was not confined to germline BRCA, just to triple negative.

But unfortunately it turned out that the testing, the MRD test, the Signatera test, was not sensitive enough to pick up the ctDNA super duper, duper early. When it was being found it was on the scans, it was already metastatic, and they screened over 2,000 patients, and they only found a few, like 26 patients that were positive. So it’s not quite there yet, but it’s going to happen. This is going to revolutionize — because the idea is this: there’s trials going on, HR positive, HER2 negative, high-risk patients, they’re on endocrine therapy. Let’s say they’re 4 or 5 years out or 3 years out, and they missed that opportunity for the CDK4/6 inhibitor, and then you do the ctDNA. If you find it you randomize them to CDK4/6 versus not.

And the hope is that rather than wait until their frank metastatic, where they get median progression-free survival of 2 years with the CDK4/6 inhibitor, maybe if you bring in the CDK4/6 inhibitor when it’s just microscopic disease they’ll have a great deal longer length of life because you’re suppressing that — maybe even curing some patients, but at least suppressing that tumor before — it’s much more difficult for it to become resistant when there’s not that much of it.

So I think this is going to revolutionize our cancer world.

DR LOVE: And if you want to understand kind of what this really means clinically just think about PSA in prostate cancer. I mean we don’t have that in breast cancer. We don’t have that in most tumors, but PSA is a great marker. It comes back way before the tumor comes back. Hopefully, maybe we’re going to be in that situation in the future with ctDNA.

So I want to thank the faculty so much for coming tonight. Thank you all for coming. Come on back tomorrow morning, we’re going to be talking about diffuse large B-cell lymphoma. Have a great night.