Pregnancy during adjuvant endocrine therapy; fertility issues

DR LOVE: Welcome to Oncology Today. This is Dr Neil Love from Research To Practice. Today, we focus on the management of ER-positive breast cancer and we have a great faculty, Dr Erica Mayer from the Dana-Farber Cancer Institute in Boston and Dr Ruth O'Regan from the University of Rochester in Rochester, New York.

Here's where we're heading today in terms of our discussion points. The faculty will be presenting some slides that we're going to be discussing, but also some cases.

I want to start out focusing really on the presentation really from Ann Partridge in your group at Dana-Farber, really representing an international study that was presented at San Antonio, Erica, looking at the issue of younger women who wish to become pregnant, but who are on long-term hormonal therapy and stopping that therapy and allowing these women to become pregnant. We'll talk a little bit more about that in a second. But first, I just kind of want to get your take in general about some of the issues that come up in younger women. I know usually in tertiary centers, investigators have even a higher fraction of younger women in their practice. So before we kind of get into some, particularly issues about fertility and pregnancy, Erica, any reflections on some of the biopsychosocial issues that come up, the family issues, younger children, et cetera? When you know that you're going to be seeing a woman in their 20’s or 30’s with breast cancer, what's going through your mind as you get ready to go see them?

DR MAYER: Yeah, thanks Neil. These are really some of the more complex and yet incredibly rewarding patients to be seeing in clinic. The experience of being diagnosed with breast cancer in your 20’s or 30’s is, you know, downright terrifying and patients come in often very anxious and very scared. But I'm so grateful that during the course of our consultation, we can really provide a lot of guidance and reassurance and organization for how best to take care of their disease.

Taking care of young patients is obviously a team-oriented approach, and so in addition to our typical multidisciplinary physician team of medical, surgical, radiation oncology, we very much rely on a broader team, specifically including social work, including genetics, and additional support services. Social work in particular can be just incredibly helpful with all of the factors and features that are unique to being diagnosed with breast cancer at a young age including how to talk about this with family and children. And also the use of our reproductive endocrinology services.

I think, you know, I'm really grateful that my colleague, Ann Partridge, has pioneered this field of thinking about fertility for our younger patients. And I love when I'm seeing a consult from a colleague from around New England that the idea of referring to reproductive endocrinology, bringing up topics of fertility at the very first visit, it is really done routinely nowadays. And I feel like that was something that she very much pioneered over the past 20 years.

DR LOVE: I'm curious for your thoughts about this, Ruth. When Ann did that presentation at San Antonio, she made a comment that I thought was really great about that we want our patients not just to survive, but to thrive. Any thoughts about some of these issues that come up? I've always been interested in the issue of minor children, particular in patients with metastatic disease. Erica was talking about social services, et cetera, how to deal with children at different ages. Any thoughts about some of these issues that come up in these younger patients, Ruth?

DR O'REGAN: Yeah, I think, as Erica said, it's very, very complex. I think there's so many nuances. What's amazing to me is the amount of times I've seen patients where they've been told by other physicians that they can never get pregnant, for example, things like that. So I think there's a lot of misinformation out there. And I think even, you know, Ann has done a lot of this work, but we have so many options for patients now that really lets us preserve their fertility.

I think, obviously, patients with metastatic disease is another huge challenge. And I think it's, you know, making sure that you have resources available to kind of take care of the children is so important in terms of from a psychologic point of view because it's just such a stressful area. But I think, as we'll hear about later on, for ER-positive metastatic breast cancer and all these women are actually living with their disease although, of course, in younger women, it does tend to be somewhat more aggressive, particularly if it's associated somewhere around pregnancy.

DR LOVE: Well there are a lot of things that we could talk about in that regard, but I picked one particularly because of this presentation from San Antonio. And I thought to get into that, Erica, we could hear about your 38-year-old lady that you took care of. Can you talk a little bit about her?

DR MAYER: Yeah, thank you. So this is a case of a young woman. She is 38, premenopausal, and she was diagnosed with breast cancer 3 years ago when she presented with a breast mass. She went on to surgery and she had a fairly small tumor, 2.2 cm, but she did have an involved lymph node. Her disease was hormone receptor-positive and HER2-negative. She did receive adjuvant chemotherapy, TC x 4. And as we often do nowadays, she received concurrent LHRH agonist for ovarian protection. And then she initiated tamoxifen with ovarian suppression. She had germline testing for genetics. That was negative. And all has been quite well. And then, came in about 2 years into her treatment and wanted to talk more about the idea of starting a family and getting pregnant. So she is now 38. Her diagnosis was a few years before.

DR LOVE: And before we get into the issue of what happened and the issue of pregnancy, I'm curious, Ruth, about this strategy of using concurrent LHRH agonist during chemotherapy that she had. Is that something that you typically do, Ruth? And what do we know about the impact of this on fertility?

DR O'REGAN: Yeah, I do typically do it in patients. So there's data basically showing that patients are more likely to maintain fertility and be able to get pregnant after they get LHRH agonist during chemotherapy. So I do pretty much routinely recommend that to patients. And they do get a little bit more toxicity. But overall, most of them get through it fine. So I think — there's also some data suggesting that it may have a positive impact on outcome in some cases. So I do recommend it and, for this patient, I certainly would have given it to her.

DR LOVE: So then, I guess, did she actually go on the trial that Ann has that really tried to — it wasn't — it was really a trial that followed patients who wanted to become pregnant. I guess the idea was they needed to complete, I guess it was between 18 and 36 months of treatment. She had completed 2 years of treatment. Erica, can you just kind of provide a macro view of that study that Ann presented? And a lot of people were looking forward to seeing it. What was your take on it?

DR MAYER: Yeah. So this is the POSITIVE study which Ann codeveloped with other leadership from IBCSG. And it really was a global, collaborative effort to address this very important concern for our patients. The trial was designed primarily as a feasibility process to see, can we create a framework to allow temporary interruption of adjuvant endocrine therapy, allow time for conception, pregnancy, breastfeeding, if that's what someone wants to do, and then a plan to go back on endocrine therapy afterwards? So the trial was designed to enroll about 500 patients. And eligible patients had to have completed at least 18 months of adjuvant endocrine therapy, and importantly, they needed to want to get pregnant. That was actually one of the eligibility criteria. The trial allowed a 3-month washout of endocrine therapy including ovarian suppression. For my patients who went on the trial, I actually began the ovarian suppression washout a little bit earlier because sometimes it takes more than 3 months for ovarian function to resume. And then the period of time when they were off endocrine therapy, which was at max 2 years, began. And patients could get pregnant in any fashion whether naturally or using assisted reproductive technology, particularly if they had banked embryos before starting treatment. And then, following the up to 2-year course, patients would then resume therapy.

So the primary outcomes that were being looked at with the study were really the feasibility of, can we do this in clinic? Do people get pregnant? Do they have babies? And what Ann presented at San Antonio this past year was, yes and yes. So of the about 500 patients who were enrolled, about three-quarters of them were able to get pregnant during this break period of time resulting in about two-thirds having babies. And I think there were like 300, over 300 babies who were actually born. And Ann makes beautiful slides with pictures of these babies which is fantastic.

And then, Ann and her coauthors did a really interesting analysis to think about outcomes here. Because I think we all worry, are we going to do a detriment to this patient if we are taking them off of their very important adjuvant endocrine therapy? Now, this is a single arm study. You can't create a randomized trial to randomize to get pregnant versus not. But what the authors did, which was quite creative, was to find a matched cohort which they found in the SOFT/TEXT population. And in comparison to very similar patients from SOFT/TEXT who were getting aggressive adjuvant endocrine therapy, there did not appear to be a significant difference in outcomes in terms of disease recurrence. And I think this provides great comfort for providers and for patients that it appears that it is safe to take this temporary interruption to allow for pregnancy with a plan to try to resume therapy once the pregnancy or attempt at pregnancy was completed.

I enrolled a number of patients on POSITIVE. Not all of them were able to get pregnant and have babies. And for the couple who didn't, they went back on endocrine therapy when we decided it just wasn't happening. But it was something that my patients were really enthusiastic and interested in doing. And I think of all the data I saw at San Antonio, this was perhaps the most clinically meaningful and impactful for me.

DR LOVE: Before I go back to Ruth, what actually happened with this woman?

DR MAYER: She’s in the midst of the trying part of therapy. So she's trying to get pregnant.

DR LOVE: Interesting. Ruth, what was your take on this? One of the things that, you know, you have to think about is a number of these people recurred, and the issue of a child, you know, bringing a child into this world with a parent or mother who has metastatic breast cancer is a challenging situation. Is this a strategy that you've done in your practice, Ruth? And what did you think about the data?

DR O'REGAN: Well I took the data, I'm sure it was, I think, very supportive of I think what we've been doing. So what Erica did with this patient is exactly what I would have done. I would have asked her to take 2 years of endocrine therapy and then try to get pregnant after that. I think just one thing to keep in mind, with tamoxifen, you have to make sure that you're off tamoxifen for at least 3 months because there are teratogenic effects of tamoxifen. So I think the study was confirmed with what we're doing. I think we know from other retrospective databases that there isn't an increased recurrence necessarily associated with people who get pregnant after they've had a diagnosis of breast cancer. But, of course, it's going to happen in some patients unfortunately and certainly is a very difficult situation.

DR LOVE: So one final question before we go on, Erica, which is actually the choice of tamoxifen in this patient. Another option might have been ovarian suppression. This was 3 years ago. Today, this patient wouldn't technically be eligible for abemaciclib, but she was node-positive. But what about tamoxifen versus ovarian suppression in this patient? What led you to do that, Erica?

DR MAYER: Well I think that the data we have from SOFT and TEXT as well as the Korean ASTRRA study are all very supportive of the benefits of using ovarian suppression in higher-risk breast cancer. And I generally tend to offer ovarian suppression to my patients with Stage II or Stage III disease and occasionally for Stage I when there's higher-risk features or the patient is really a more versus less person.

The most updated data tends to suggest perhaps a preference for aromatase inhibitor over tamoxifen in these settings, although I will point out that the — it's a little trickier to do that because, at least for me, I tend to try to be very meticulous about the ovarian suppression aspect given that aromatase inhibitors will not be effective if there's ovarian function. So I give my LHRH agonist monthly as opposed to depot. I personally like to check an estradiol periodically to make sure that we're in a good place. So I try to be careful with this. But we do know that there's more side effects with aromatase inhibitor compared to tamoxifen, particularly vaginal dryness, sexual dysfunction, joint symptoms. And for some patients, this really has a detrimental effect on quality of life.

We had looked back on, on the ABCSG-12 data which was one of the older ovarian suppression studies that also looked at adjuvant zoledronic acid. And in that study, patients were randomized to get tamoxifen and ovarian suppression or aromatase inhibitor and ovarian suppression. And there was no difference seen between the 2 arms, nothing meaningful was there. So I often think back on that data to provide support that for some patients, the tamoxifen is a better selection for them.

DR LOVE: That's a really great point about the AI and how important it is to keep the patient suppressed. One more question back to you, Ruth. In what situations in the adjuvant setting in premenopausal women are you not using ovarian suppression or ablation? Or maybe I can just turn it the other way and say, what situations do you use it?

DR O'REGAN: Well I think just I'm going to concur with what Erica said. I think the issue with this approach is there's clearly more toxicity and I would say that we don't actually probably know yet if there could be significant long-term toxicity, particularly with regard to bone health. But I would typically, I kind of — for somebody who's got a high-risk cancer, so we very often send the 21-gene recurrence score in these patients, if they've got a high score that justifies chemotherapy, I'll generally take this approach for those patients. I think there are patients that you can get away with tamoxifen if they’ve got low-grade cancers. Meredith Regan had that competent risk score that utilized patient and tumor characteristics as a means of basically working out which patients actually really benefit from ovarian suppression. And then, I think we're probably going to talk about this, but the data with the Breast Cancer Index that was shown at San Antonio as well. So I think we are getting closer to having a genomic assay that will help us with this decision. But in the absence of that, I kind of just look at tumor grade, recurrence score, those kind of aspects to make a decision.

I think the other thing that comes up is when they're closer to menopause, when they're older, I tend to typically use tamoxifen to start with in those patients. And if they resume menstrual function then have a discussion with them about actually using ovarian suppression. That's trickier because you don't know how, you know, when they're going to go into menopause and how long you have to give them the ovarian suppression for.

Genomic biomarkers in the adjuvant setting

DR LOVE: All right. Well you mentioned biomarkers in early-stage setting and that's actually our next topic. And Erica has 2 cases that I'm going to use to sort of kick off this discussion and then I'm just going to ask you in general any other papers, recent papers or datasets that you think might be worth bringing up here. But I never get talking — tired of talking about Oncotype because it, you know, all the shades of how people look at it are very interesting to me. So let's see what happens with these 2 cases. Erica, let's hear first about your 67-year-old lady.

DR MAYER: Yeah, I agree with you. There're so many shades and this is like what we wrestle with at tumor board every week is how to interpret Oncotype in certain clinical situations. So I brought in a couple cases just looking at kind of extremes of how we might use Oncotype.

First case is an older patient case. This is a 67-year-old postmenopausal woman, very healthy, who had a right mammographic abnormality and, on biopsy, it was a Grade 1 invasive ductal carcinoma with very favorable features, strongly hormone receptor-positive, HER2-negative. On exam, she had a medium size mass, 4 cm. She did have palpable axillary lymphadenopathy with a positive biopsy. She had upfront surgery with a mastectomy and axillary lymph node dissection and had about a 4.5 cm cancer. She had 3 nodes involved. So she has a fair amount of anatomic risk. Now, I think some folks might just say, well there's 3 nodes involved, let's think about chemotherapy here. But within our practice pattern, this is a very biologically favorable tumor and an older patient and so we would always be sending Oncotype here which we did and had a very favorable score of 6. So a single digit score with very favorable features, very much for us in our practice group would be a great reason to say no thank you to chemotherapy and to really focus on optimization of adjuvant endocrine therapy.

DR LOVE: And so when you met with her after you got back this recurrence score of 6, did you say, hey, great news, it's low, you don't need chemotherapy? Or did you bring up the possibility of chemotherapy?

DR MAYER: She, like many of my older patients, was quite set in not wanting chemotherapy in the first place. So when I'm working with a new patient, I'm often trying to get a sense of whether someone is a more versus less and what their personal preferences are. And this is a person who very clearly stated her preferences. So she was delighted with the low score and we were very happy to not really even need to get into it. But I think these are good opportunities to pivot and focus on, well we're not going to use chemotherapy here but the primary agent and the greatest benefit will come from endocrine therapy and extended duration of adjuvant endocrine therapy, and so setting the stage that this is going to be part of our treatment for perhaps up to the next decade. And so that's where I begin those conversations.

DR LOVE: Let me just ask before I go back to Ruth, what would it have taken for you to recommend neoadjuvant chemotherapy? She had a 4 cm mass and palpable nodes.

DR MAYER: Well that's a great question. And in a situation like this with a Grade 1 cancer, had preoperative systemic therapy been needed, we would've been thinking about preoperative endocrine therapy as opposed to chemotherapy as we know that for a low Oncotype or a Grade 1 cancer with these features, the likelihood that chemotherapy would result in a benefit such as conversion of surgery or even PCR is quite low. And so if I need preoperative systemic therapy, I would be offering, let's say, a preop AI and be giving that for at minimum a 6-month course, but likely longer, sometimes in the 9-to-12-month range with interval imaging until, between myself and the surgeon, we've agreed that it's time to move forward to surgery. This patient I met after surgery, so we didn't have the chance for that conversation. But certainly, this is something that we utilize. I also like to do that in a situation where somebody perhaps has some comorbidities and we use that time to really optimize medically how they're doing with their blood pressure and diabetes or other features so that when they get to surgery, they'll really be in an optimal place for that.

DR LOVE: So, Ruth, any thoughts about this case? Would you have managed it the same way? And any thoughts about any other comments from Erica?

DR O'REGAN: Yeah, I would've actually managed it exactly the same way. I think, you know, she had N1 disease, so per the RxPONDER study, I think it was definitely worthwhile sending the 21-gene recurrence score. And with a score of 6, I would not have recommended chemotherapy.

I do think that these are cancers that we really struggle with in the preoperative setting because they really don't respond very well to chemotherapy. And I think most of us lean towards sending these patients to surgery if that's possible. Obviously, the advantage if they did respond to chemotherapy, you could potentially downstage the axilla which would be an important issue for the patient. But I generally have to say the success rate with that in a patient like this is quite low. So I would have taken exactly the same approach. And I think if, in a patient like this that really warranted a preop approach, I would use endocrine therapy as well. And I think the issue here is it does take a long time to actually cause a response so you really have to say, tell the patients that upfront, as Erica said.

DR LOVE: Just out of curiosity, Erica, I don't know exactly when she was treated, but was abemaciclib considered in her situation?

DR MAYER: Yeah, I think we're going to talk about that a little later. But by the criteria from the monarchE study, she doesn't quite meet the criteria of the people who we might be thinking about for adjuvant abemaciclib. So this was before the abema, but I probably would be, if I were meeting her today, leaning away from abemaciclib.

DR LOVE: Well I'm looking forward to talking about that, but we'll get to that in a second, as you said. It's such as interesting issue out there. How about your other patient? You have a premenopausal patient, 43 years old. What happened with her?

DR MAYER: Well I think this is perhaps an area of a little bit more controversy is how we manage node-positive, premenopausal patients, particularly with the use of a 21-gene recurrence score. So this patient is 43. She’s premenopausal. She had a right mammographic abnormality on her screening mammogram, and a biopsy showed Grade 2 invasive ductal carcinoma, hormone receptor-positive, and quite strongly positive, HER2-negative. On exam, this was essentially clinical Stage I disease, about a 2 cm mass, a negative axilla. So she had upfront surgery, breast conserving surgery, and a sentinel lymph node biopsy. At pathology, her tumor was small, 1.9 cm, but she did have a positive sentinel lymph node and a real positive node, macrometastasis. Now based on the RxPONDER data, I think there's controversy about, can you send a 21-gene recurrence score in this setting? And she has a biologically favorable cancer, strongly hormone receptor-positive, so I do send in this setting and was happy to see a low score come back of 11. And I consider this an extremely favorable score. And so in this setting, I although perhaps, I will mention chemotherapy because I feel obligated to, I would discourage use of chemotherapy in this setting. But here's also where the ovarian suppression comes in. So I would be offering this person the kind of aggressive adjuvant endocrine therapy with aromatase inhibitor, ovarian suppression, adjuvant zoledronic acid, all of those sorts of things.

I find it challenging to interpret RxPONDER with these very low scores because we have so much other data that says that single digit scores or scores up to 11 indicate tumors with very favorable biology and tumors that have excellent outcomes. Whereas RxPONDER seemed to suggest there could be a chemotherapy benefit even with the low scores. Many interpret some of the data from that trial and TAILORx as perhaps indicating the effect of chemotherapy in inducing chemotherapy-induced amenorrhea and essentially ovarian suppression. And so it's hard for me to believe biologically that chemotherapy is benefitting with a score of 11 despite the positive lymph node. So in our group, we continue to use Oncotype in our premenopausal, node-positive patients and would interpret the way we always have.

DR LOVE: And, of course, in so many situations in oncology including this one, you’ve got to kind of figure out is the result of the test going to change what you do which means you’ve got to talk to the patient. The patient has already decided they're not going to get chemo, maybe it doesn't even matter. Do you think this lady would have been okay going with chemotherapy? And what did she actually do?

DR MAYER: She would have. She was happy not to do it, but she was ready to do it if necessary. But now we're, as you sort of alluded to, into the struggles of managing side effects of ovarian suppression which are not insignificant but we're trying to stick with it.

DR LOVE: So, Ruth, I'm curious about your take on this issue. One of the things that I hear people talking about and has been talked about for a while is the possibility, again, of using ovarian suppression or ablation sort of instead of chemotherapy with the idea that most of the patients in RxPONDER didn't have ovarian suppression and you know, we know that that affects the ovaries so they were missing out on some benefit. Do you bring up — or in what situations, if any, Ruth, do you bring up ovarian suppression sort of as a substitute or maybe you're going to do it anyhow but for, you know, a reason not to give chemotherapy?

DR O'REGAN: I do bring it up and I think I would have managed this case exactly the same way. I guess we're agreeing with Erica all along. But I think with 1 positive lymph node, I think sending Oncotype makes sense because it's really telling you more about the biology of the disease. And I think with a score of 11, I completely agree. I just can't imagine. This is going to be a low proliferative cancer. Why would it benefit from chemotherapy? So I would totally agree with that.

But I think this is a perfect candidate for ovarian suppression. And we probably would say to her, you know, that ovarian suppression appears to — that chemotherapy part of the way it appears to work is by ovarian suppression. So by taking the ovarian suppression, they probably are going to do just as well as if they'd had chemotherapy. So this would be a perfect patient to discuss this kind of approach and I think I would completely agree.

DR LOVE: So Erica, “1 positive node” brings up the other issue which is patients who are just getting sentinel nodes like apparently this woman does. You don't really know how many nodes. This has been discussed a lot. Not only is it relevant to genomic assays like Oncotype, but also when we talk about abemaciclib if you get into number of nodes. Any thoughts about that? How do you translate, you know, if you have a patient like this who just has a sentinel node?

DR MAYER: Yeah, I think that the ability to avoid axillary lymph node dissection has been a wonderful advance in breast cancer and really helped the patients tremendously, but it does put us in this situation where sometimes we feel like there could be a little bit of missing data. We tend to try to get an axillary ultrasound in the majority of our patients who are coming in with a new diagnosis to really, as best we can, clinically stage the patient before they go to the OR. And this sometimes results in a conversation with the surgeon who actually had their hand in there. Did you feel anything abnormal? Did anything else look abnormal? And really try to make sure that we don't have a sense that there is additional disease. And typically, the patient where it's going to make a meaningful difference for adjuvant abemaciclib where we're looking at this idea of perhaps multiple involved nodes, one can often get a sense of whether there's like a 4-node positive cancer or not. This patient had a clinically negative axilla by both exam and imaging before surgery and my surgical colleague who did the procedure saw nothing abnormal at the time of surgery. So we would consider that person to be highly unlikely to have additional nodes. There are calculators that we could use that would even predict it. But just based on clinical features, we felt comfortable.

DR LOVE: One more comment from Ruth. It seems like we talk a lot about 21-gene recurrence score. We have a lot of really good data on that. Any role for other assays? And also assays looking at other questions, for example, duration of endocrine therapy? Any new datasets that came out at San Antonio that struck your fancy, Ruth?

DR O'REGAN: Yeah, I think certainly, there are some people who would use MammaPrint as an alternative to Oncotype. Personally, outside of a clinical trial, I don't typically do that because I just don't think it tells you which patients need chemotherapy the same way that Oncotype does.

There was data with the Breast Cancer Index. So the Breast Cancer Index is made up of the molecular grade index along with what's called the H/I ratio. And the H/I ratio is predictive of kind of benefit from endocrine therapy. So that assay has been used previously to determine which patients are going to have relapses after 5 years of treatment. And also, the H/I index has been used to predict which patients need extended endocrine therapy either with tamoxifen or with an aromatase inhibitor.

What we presented at the San Antonio meeting was an analysis of the Breast Cancer Index from the SOFT trial. And what we showed was that the Breast Cancer Index is definitely prognostic for premenopausal patients treated with endocrine therapy with or without chemotherapy. But also, and this is where it was weird, so in the — for extended adjuvant therapy, a high H/I ratio is predictive of benefit for longer treatment. What we actually found was that low H/I was associated with benefit from ovarian suppression which was completely contrary to what we actually predicted. It is a completely different scenario. And I will, of course, caution that even though it was 1,600 patients in the analysis, it does need to be validated. But it is interesting because you could imagine a scenario where you would send off BCI earlier on. If it came back high, you could say to somebody you need 10 years of treatment. If it comes back low, you give them ovarian suppression and they're done at 5 years. So it does require validation but it was quite interesting data, I thought.

DR LOVE: Certainly, a very important practical question.

CDK4/6 inhibitors in metastatic disease

DR LOVE: Okay, Erica, we asked you to put together some slides and a brief talk, and we'll kind of chat about it as you go along, on CDK inhibitors both in the adjuvant and metastatic setting. We'll start out with metastatic. Both of these arenas have become pretty controversially and interesting so I'm really curious to see how the 2 of you are approaching it. But let me turn this over to Erica.

DR MAYER: Great. Thank you. And absolutely, this has been a surprisingly controversial area in the past year.

So I just wanted to provide some overview of the status of CDK4/6 inhibitors in both the metastatic setting as well as the early breast cancer setting just as a quick review. What do these drugs do? Well Cyclin D and CDK4/6 are complex in the cancer cell that normally phosphorylates the retinoblastoma protein releasing it as a break on the cell cycle and allowing progression from G1 to S. Hormone receptor-positive breast cancer overexpresses Cyclin D and CDK4/6 leading to a lot of phospho-Rb and a loss of control. So here's where we have the 3 available agents that have been developed, palbociclib, abemaciclib, and ribociclib, all of which inhibit the Cyclin D/CDK4/6 complex and allow the hypophosphorylated Rb to reestablish control of the cell cycle.

These drugs were initially developed in the metastatic setting. And this is a table that lists all of the major Phase III trials. There’s been 7 major trials in the first line setting which is indicated by blue and the pretreated setting in combination with fulvestrant indicated in purple. And the trials all have names that honestly, I think we all struggle to keep straight. But PALOMA studies indicate palbociclib, MONALEESA indicates ribociclib, and MONARCH indicates abemaciclib. The trials are all slightly different in terms of patient population and some eligibility differences but what has been really important and unique about these studies is that there is a very consistent improvement in progression free survival in either the first line or the pretreated setting with the use of a CDK4/6 inhibitor in combination with an endocrine partner with a hazard ratio hovering in the 0.5 range. So we've had this data now for several years and this is the data that supported approval of these drugs. First, palbociclib in 2015 and then, abemaciclib and ribociclib in 2017 and has led to widespread use and adoption as a standard of care.

Now despite the very similar results here, we do have some differences in terms of side effects that affect our practice. Both palbociclib and ribociclib, which are dosed 3 weeks on, 1 week off, are more associated with neutropenia not with infections but with a sort of temporary lowering of the white blood cell count whereas abemaciclib is more classically associated with diarrhea. Ribociclib also requires extra monitoring when we started in terms of looking at QT interval and monitoring LFTs. But overall, we consider these all to be well-tolerated drugs. Perhaps because palbociclib, I think, many of us have felt very comfortable with over the years and the earlier FDA approval since then has been really the drug that's held the most market share with ribociclib and abemaciclib having smaller components up until recently.

So this brings us to the more recent updates that we've seen in 2022 which are now creating more of the, shall we say, controversy in the CDK4/6 world. We began to see the overall survival results from the first line studies. First, I want to show you MONALEESA-2. So this was one of the ribociclib studies randomizing first line patients to letrozole with ribo or letrozole with placebo. And the long-term follow-up for overall survival was positive. We saw an improvement in overall survival with the use of ribociclib with a hazard ratio 0.76. Now I think that's great but I'd also say there's even more that we can take out of this figure. First of all, the median overall survival here is about 64 months, so that's more than 5 years. That's the longest we've ever seen for first line hormone receptor-positive disease and really sets a new benchmark for what we can expect for this patient population. Also, we can see that the improvement with the use of the CDK4/6 inhibitor from about 51 months to 64 months. That's like a full year improvement, and it's really hard to show overall survival benefits for hormone receptor-positive disease. So really, I think it's quite remarkable to see such great advances that can benefit our patients.

Now we also saw data from the MONARCH-3 study which is the first line study using abemaciclib. This is not a final analysis, it's the second interim analysis but we do have a look at overall survival here. And we do see actually similar improvements, 54 months to 67 months, hazard ratio of 0.75. It looks quite promising although it actually did not reach the prespecified statistical significance so it needs further maturation. But certainly, this is trending in a favorable way.

Now in contrast to these reports, we also saw at ASCO this past year the updated overall survival analysis from PALOMA-2 which is the first line study using palbociclib. This has a median overall — a median follow-up of 7.5 years. This data is a little difficult to understand in that there was a large amount of missing survival data and that was differentially distributed, 13% missing in the palbociclib arm, 21% missing in the placebo arm. And the thought is that as the study was ongoing and as other CDK4/6 inhibitors were being approved, it's thought that patients may have left the study to try to get standard of care CDK4/6 outside of the trial. There was also more crossover to CDK4/6 inhibitor in the control arm versus placebo — versus the palbo arm, 27% versus 12%. And so the overall survival data seen here was not significantly different between the 2 arms. There was a sensitivity analysis to exclude the patients who had the missing data, but this did not meet statistical significance for improvement. So overall, this was a negative analysis. I do think it's interesting though that at this long-term follow-up of 7.5 years, there's still 10% of patients who are continuing on palbociclib and letrozole from the time when the trial began. And that does mirror my practice where I have a large number of patients who went on palbociclib in 2015 at the time of drug approval and are going strong on it and doing great. So there seems to be some population of patient who benefits from this drug, but we don't see that in this particular analysis. There was also real-world analysis looking at data from the Flatiron database that has also supported an overall survival benefit from palbociclib. But, again, that's a real-world study, not a randomized clinical trial.

So just a table to show us that we see that the palbociclib data for overall survival has not been positive, but the overall survival data for the ribociclib studies as well as the abemaciclib studies that have been mature has been positive. So despite the initial PFS similarities, we do see overall survival diversity in results here.

And I think that's telling us that we have these 3 available agents. They broadly improve progression free survival. This is our standard of care. But despite the PFS similarities, this updated data perhaps suggests efficacy differences although, again, these are cross-trial comparisons and all the caveats that go with that. But based on what we saw in 2022, our practice patterns now may be evolving away from palbociclib and selecting the other 2 agents. And in my practice, I'm often thinking about this, selecting based on toxicity profile. But there's lots of questions here. Do we have a single preferred agent? What do we do after progression on CDK4/6 inhibitor? Do we continue and switch to another CDK4/6 inhibitor like was shown in the MAINTAIN study? Or do we change therapy altogether? And what's going to happen with the introduction of oral SERDs, AKT inhibitors, the very promising antibody drug conjugates?

DR LOVE: So that was awesome to just see it flow by there like that. We've been talking about this all the time. So many things. Let's just chat a little bit about this and then, we'll get into the adjuvant situation. So I always like to kind of start with like what're you doing in your practice? And then, we can sort of talk about some of the other considerations. And, Ruth, I'm curious, how do you go about selecting a CDK inhibitor first line? It seems like a simple question. Now, it seems like it's gotten pretty complicated. Also, do you approach it differently in premenopausal and postmenopausal women? You didn't comment too much on that, Erica. But I think it seems like we have more data with ribo premenopausal. But how do you, right now, outside of a trial, Ruth, pick your CDK?

DR O'REGAN: So I've been pretty convinced by the survival data honestly. So I did change from — I used to use palbociclib a lot and I changed to using ribociclib because really, the toxicity profile is pretty similar apart from the need for EKGs.

I think when you look at this data, I understand there were issues with the PALOMA study but what strikes me is the controlled arms are so similar across these 3 studies. So for whatever reason, this does appear to be like a real difference. So I think for somebody just diagnosed with metastatic disease, I would use ribociclib. I think we're going to run into situations where people are relapsing after adjuvant abemaciclib which I'm sure we're going to talk about as well. But that would be my preference as of today with all the caveats that Erica mentioned about what you do to progression. Yeah, so I think it does appear, based on this and also what we see in the adjuvant setting, that there may actually be differences between these agents that, which I agree none of us really believed because the hazard ratios in the first line metastatic trials are so identical.

To your question about premenopausal patients, so where we have the highest-level data is with the MONALEESA-7 study where they took premenopausal patients with first — in the first line setting with metastatic hormone receptor-positive disease, everybody got ovarian suppression and they either got an aromatase inhibitor or tamoxifen based on physician's choice and then were randomized to receive ribociclib or not. That trial shows a similar improvement in progression free survival as the other studies that Erica talked about and also with survival advantage as well. However, just to keep in mind, you can't give that with tamoxifen because that exacerbated the prolongation of QT interval. So for premenopausal patients, that's the approach I would take, ovarian suppression with a nonsteroidal aromatase inhibitor and ribociclib. For those patients very often after they've been on the ovarian suppression for a while, they'll probably end up getting oophorectomies.

DR LOVE: So, Erica, other groups, write these long guideline papers and stuff and we just ask people what they do. We know it's kind of a simple question but oncologists, that's what they want to know. And it's very interesting listening, you know, we do surveys all the time, we ask people kind of, we were starting to see the shift in investigators and then in docs in practice towards ribo and then ESMO came along and you put up the abema data. I'm curious right now how you're approaching that decision, Erica. Do you — are you as comfortable offering abema? Of course, the other issue about abema obviously, different toxicity profile but different schedule of drugs in terms of treating every day. So how are you approaching it right now, Erica?

DR MAYER: Yeah, I think I'm quite aligned with Ruth on this. And despite being a kind of heavy palbo user for quite some time, the data from 2022 really changed our practice and changed it pretty quickly. So I'm now starting to get used to looking at a lot of EKGs in clinic and getting people started on ribociclib. I do select abemaciclib for some patients if there is a preexisting cardiac issue, if there are electrolyte issues that would affect QT interval. Some patients prefer continuous dosing as opposed to the intermittent dosing and so I might use those features to help make decisions about which ones to use. But I think that it's hard at this point to justify a new start of palbociclib. I will say though on my patients who have been on palbociclib and been on it stably for years, I am continuing that agent. I'm not changing them away from palbociclib if they've gotten years of benefit.

DR LOVE: You know when you show those curves and you have that kind of a tail on the curve there, I was sort of flashing on BRAF patients in melanoma where you see these prolonged responses, targeted therapy. I'm curious, Ruth, do you think some of these people are actually getting cured of the disease, either cured, the disease is not going to come back or cured, they'll be able to live a normal lifestyle even if they — and life duration even if they do develop recurrence?

DR O'REGAN: Yeah, I certainly hope so. I think based on the data, it's very fair to say that there are what we call excellent responders where these patients just basically are living with metastatic breast cancer. I think that's been our goal for a long time. Obviously, they have to stay on therapy but I, and I know this is probably a little quirky, but I very often say to these patients it's kind of like being a diabetic except that you have to have scans and you're taking different medications but our aim is to really turn this into a chronic disease.

DR LOVE: Ruth, what about Erica's question there about post-CDK progression? How do you manage it? Do you continue CDK as you switch over to something else? Will you use another CDK, particularly if there's been an interval or maybe they've gotten other treatment? I guess there's going to be a generation of patients who get adjuvant abema who maybe are going to recur later. What about these patients, Ruth? Any thoughts about CDK after CDK?

DR O'REGAN: Yeah. So I think, as Erica mentioned, the MAINTAIN study took patients — most of them had had palbociclib and they were randomized to receive ribociclib or not, either with fulvestrant or exemestane in the second line setting. And that did show an improvement in progression free survival in favor of the ribociclib. And then, not to steal Erica's thunder, but she presented the PACE study where basically, the same kind of design of the trial but was using palbociclib with or without fulvestrant. And that trial didn't show a benefit for the CDK4/6 inhibitor. But it's really apples and oranges because you are continuing the same CDK4/6 inhibitor in PACE versus MAINTAIN where you were switching. So I think it's a reasonable option for some patients. We know that people are doing this in practice. And then, there's also some retrospective data looking at abemaciclib further out after you've had other lines of treatment. So I think it is an option for patients. There may be some better options but I think it is an option for selected patients.

Obviously, you want to make — determine whether the patients have a tumor with a PIK3CA mutation because that may lean you towards using alpelisib in the second line setting.

Adjuvant use of CDK4/6 inhibitors

DR LOVE: But we'll also talk about newer agents and whether or not maybe they're getting oral SERDs, AKT inhibitors, you know, how that's going to play out and we'll talk about that in a little bit. So we'll go from the complicated to the really complicated. This is like the Talmudic study of CDK inhibitors here. All right. Adjuvant. Try to explain this one, Erica.

DR MAYER: So we have 4 major Phase III trials in the adjuvant setting with CDK4/6 inhibitors. Again, each drug gets at least 1 or 2 trials here. Palbociclib has the PALLAS study and the PENELOPE-B study. Abemaciclib has the monarchE study. And ribociclib has the NATALEE study. These studies are all quite large, but they're a little bit different. They offer different durations of adjuvant CDK4/6 with PALLAS and monarchE offering a 2-year duration, PENELOPE-B was a 1-year duration in a post preoperative setting, and the NATALEE study, which is still ongoing and has not yet reported, offers a 3-year course of therapy and actually uses a reduced dose ribociclib compared to the dosing that we used for metastatic disease. So we've seen at least the first 3 of these trials report and this has had an impact on our practice.

So the most relevant study to focus on is monarchE. And we did have an update from the study presented at San Antonio which I think was really an important piece of data. This was an update at 42 months of follow-up. Just to review the study design, I always find the design of monarchE fairly complex, but the study was for hormone receptor-positive, node-positive, high-risk early breast cancer and enrolled patients into 1 of 2 cohorts, cohort 1 being open first, cohort 2 opening later. And they had very specific eligibility criteria designed to identify high-risk populations. Cohort 1 was high-risk based on having at least 4 involved lymph nodes or having 1 to 3 involved lymph nodes and at least 1 other high-risk feature such as having Grade 3 disease or having a larger size tumor, at least 5 cm. Cohort 2 was built more around risk based on the Ki-67 biomarker. So a patient could have involved lymph nodes, but needed to have an elevated Ki-67 of at least 20%. I think it's important to note that the vast majority of patients in monarchE were enrolled in cohort 1. This was over 90% of patients. And this Ki-67 cohort, cohort 2, was really a minority. It was 9% of patients. And so these patients were randomized to receive their ongoing adjuvant endocrine therapy, either aromatase inhibitor or tamoxifen, with or without 2 planned years of adjuvant abemaciclib.

So the data that was presented at San Antonio was the longer-term follow-up of the study and what this demonstrated and confirmed was that there was a benefit to the use of the 2 years of adjuvant abemaciclib with about a 30% reduction in the risk of disease recurrence. What's very important here though is that the initial presentation of the monarchE data, which was in September 2020, was actually very early on in the study lifecycle and many of the patients were still receiving adjuvant abemaciclib at that time. The study was positive at that moment, but there was some discussion of, is that study — is that positivity going to last? Once patients finish abemaciclib and they move on from that, are we still going to see a benefit from the drug or is that going to close and long-term follow-up will show no benefit? Especially, because we're talking about drugs that we think lead to, not necessarily cytotoxicity, but more of a stasis situation. But what we see from this long-term follow-up is that the benefit seen at the time that abemaciclib completes is maintained and actually seems to increase almost like a carryover effect. And so as more time passes, the difference between the lines appears to deepen. So I think that his both confirms the initial reports from monarchE showing the benefit but also shows that this benefit is maintained over time as this carryover effect.

Another analysis that was presented was looking at Ki-67 because, again, this was part of the eligibility criteria for cohort 2. And longer-term follow-up confirms that the Ki-67 is prognostic but not predictive of abemaciclib benefit. And in this figure we can see that the solid lines are the high Ki-67, this is actually in cohort 1, and the dotted lines are the lower Ki-67. As we would imagine, if you have high Ki-67 you have more risk and that's why the solid lines are trending more steeply so that's the prognostic aspect of Ki-67. But the benefit when you get abemaciclib, which is the red line, is very similar in both cohorts. So Ki-67 is not telling us whose benefitting from abemaciclib it's just telling us more about risk. And this is the type of data that has led our national guidelines to lean away from making much of the Ki-67 statements.

I'll also just remind people about toxicity. So as we've alluded to abemaciclib does cause diarrhea and in monarchE over 80% of patients had some element of diarrhea. Most people, it was mild or perhaps moderate but there were a number of people with Grade 3 diarrhea. This is why it's really important when we start abemaciclib to be telling patients that diarrhea is a possibility and actually the time course is that it happens early on in treatment within the first few weeks. And so it's important to make sure that a patient has an antidiarrheal at hand, that they are ready to use it, they're ready to communicate with the office if they're starting to experience diarrhea. I think that's a good way to get control on it and prevent people from getting Grade 3 toxicity. All CDK4/6 inhibitors also can cause fatigue. That was seen here too. And we see some neutropenia although not to the degree that's seen with the other CDK4/6 inhibitors.

Now just to remind about the other studies. A final analysis of the PALLAS study, which was a similarly designed study using palbociclib rather than abemaciclib, did not show an improvement in invasive disease free survival. And so this was a negative study. And similarly, the PENELOPE-B study, which was the 1-year exposure in a post preoperative setting, although perhaps a glimmer of a curve separation early on, the curves came together with more mature follow-up. So this as well was a negative study using palbociclib.

So we've learned from monarchE that the 2 years of abemaciclib in combination with ongoing adjuvant endocrine therapy is appropriate for our high-risk node positive patients with hormone receptor positive disease. We have a 30% reduction in the risk of recurrence and our US guidelines, NCCN, and ASCO endorse the use of abemaciclib here and lean away from using Ki-67 to make these identifications. Personally, I think the best candidates for abema not only are people who match the eligibility criteria and the label but also people who are willing to take another 2 years of medicine that has potential side effects and that they have to do this with their endocrine therapy. We don't want this to threaten their ability to adhere to adjuvant endocrine therapy.

But as we've mentioned, there's a lot of questions. We're going to have this generation of patients who will recur either during or after CDK4/6 in the adjuvant setting and how do we approach these patients? Also, it's important to remember these were all node-positive patients. We do have high-risk node-negative patients. They were not included. The label does not include these patients for abema, but is there a role here for an adjuvant CDK4/6 inhibitor? Is abema our only option? We're awaiting the results from the NATALEE study with ribociclib and we'll see if this will also be a possible choice. And for patients who are BRCA-mutated where we have data from the OlympiA study supporting adjuvant olaparib, how do we balance these 2 agents? So great advances, but also lots of interesting questions for us to think about.

DR LOVE: Yeah, I feel like I live in a world of Kaplan Meier curves and progression free survival and overall survival. So interesting across oncology. We just did a 2.5 hour Think Tank on ALK-positive disease in lung cancer, if you can believe we'd do that. And we were, you know, we always get into this issue of, of course, PFS versus survival. So first, let me just start out with what you all are doing in your practices outside of clinical trial and then we'll get more into the theoretical issues behind it. Ruth, could you tell me exactly who you are offering adjuvant abema to?

DR O'REGAN: Well I think as Erica said, people who meet the criteria for monarchE. So to the higher-risk patients, you know, patients with N2 disease, for sure. I'm going to totally agree. I think the Ki-67 issue, because that's the way the FDA approved it, really, really was very confusing. And I have to say, I don't think patients are being turned down for abemaciclib if their cancers have low Ki-67 which I think is good news. And the reason the FDA did that was because there's no survival difference in monarchE right now but they, when they broke it down, there appeared to be some signal that in patients with low Ki-67 they were actually doing, had potentially more events than patients who got abemaciclib which of course doesn't make any sense because it was such short follow-up. So I think we've gone past that. So I think patients that have a lot of lymph nodes positive that are high-risk disease I would definitely discuss abemaciclib with them. I will say, I'm interested in Erica's opinion on this, I've had a lot of difficulty. I've found the diarrhea to be very problematic and also fatigue and I've had a number of patients who just wouldn't go back on it which was somewhat unfortunate I think. And I think just to Erica's last question if they have a BRCA mutation, I would lean towards olaparib over abemaciclib I think mainly because of the trial outcomes and also because of the fact that the toxicity profile I think is a little easier.

DR LOVE: So we'll get into that in a second. But, again, targeted therapy, you have a trial out there in lung cancer with anti-EGFR osimertinib, gigantic PFS, they don't have survival yet. Also a question, Erica, even if you don't have survival benefit if the PFS improvement is enough is it worth it looking at the toxicity of the drugs? Anything you want to say about tolerability? It sounds like Ruth's experience is a little bit rough. What's your experience? I hear a lot of people using preemptive GI meds in people on abema but in general how do people do in the adjuvant setting in your hands, Erica?

DR MAYER: Well, as I alluded to, knowing the timeline of when we can expect these toxicities is really important and making sure that the patient is ready and has all the tools that they need and also that they communicate. I have had a few bad experiences where patients kind of sat on it and didn't notify me when they were having trouble and that got a little complicated. We are working internally with some trial designs to look at new ways to kind of onboard people onto abemaciclib to see if there's a way to either provide prophylaxis or dose escalation in a safe manner that will help kind of overcome that early diarrhea. But I think once people get over that early hump then they settle into more of a steady state and at that point in time, I think the fatigue becomes a more significant toxicity.

I think what's so challenging about doing trials in this space and certainly something that we saw on the PALLAS trial is that we're working with people who are breast cancer survivors. They've been through a lot and now they're getting back to their regular life, to their work and their families and taking care of themselves and it's a very sensitive time to have ongoing chronic side effects such as fatigue or other issues that are holding them back. And people's tolerance for even mild to moderate toxicity is not very high. I think people really will vote with their feet if they're not feeling comfortable on their therapies. And if we're talking about let's say a young patient who's getting ovarian suppression and aromatase inhibitor and zoledronic acid and abemaciclib that's a lot of therapy and we're asking them to do that for years. And so it really requires a lot of supportive care and a lot of encouragement and cheerleading to try to get people to stick with it.

DR LOVE: Also, to give them the opportunity to weigh in on what you want to do whether starting it or discontinuing it. But another question I've had about this since the beginning, Ruth, kind of thinking back to how we looked, viewed adjuvant tamoxifen, adjuvant chemotherapy, you know, kind of back to the metanalysis days, so to speak. The paradigm that I understood before all this was you find out what the hazard rate is of, let's say, either one of those strategies and then you look at the absolute risk and apply the hazard rate to it and then look at the toxicity and see if it's worth it and even going down to very low-risk situations, for example, with tamoxifen people often would choose to do it, yet I don't see that being done here. So I guess the question is first of all, Ruth, would you expect to see the same relative risk reduction or the same hazard rate if you used patients who were lesser risk? Could you calculate a benefit and sort of come up with a risk/benefit equation based on that?

DR O'REGAN: I think we don't have any data in this setting, but I think, and Erica knows this, I do think that there potentially could be patients that have node negative disease that might benefit. How high-risk they would have to be, I guess that's one of the problems here because of the fact that we don't have a biomarker to tell us which patients need the CDK inhibitors either in the adjuvant or the metastatic setting. But I think if you just — if you can quantify their risk, I guess you could extrapolate the hazard ratios from the monarchE study into an earlier-stage setting. But obviously, the lower-risk, if they've got lower-risk cancers, the toxicity becomes an even greater issue. It's interesting because I don't know if there are trials that designed, that are being designed to address this but we've all had patients that have had node negative, ER-positive breast cancer who've had relapses. So I think it's very difficult because this lack of a biomarker is very problematic because right now it appears that whether the cancers are endocrine sensitive or endocrine resistant, they both benefit from CDK4/6 inhibitors.

DR LOVE: So we're actually doing 3 symposia this week at the GI Cancer Symposium. And there, in colon cancer, they use circulating DNA, making a major impact on how they make decisions. Erica, I don't know if you see that ever coming into breast cancer. But also, this question of would you — I was kind of surprised why everybody used the trial criteria. I thought maybe it was financial. I didn't really know why. I guess you could make the argument, as Ruth said, that we don't have data in the lower-risk patient but would you expect the hazard rate to apply, Erica?

DR MAYER: So a couple of points there. Regarding node-negative disease, I feel like tumor biology is what drives a lot of our risk and whether we anatomically see it in a node or we don't see it in a node, it's still the same biologic disease. So I would expect that the benefits of adjuvant abema would still apply in a node-negative setting although in a more diminished way. However, given that we don't technically have the data that proves that and says that it is tolerable and feasible in the node-negative population is why I would be not offering this to my node-negative patients even if they are higher-risk patients. And I guess I haven't tried it, so I can't tell you if I have trouble with payers. But I do think it's outside of the indication so it's not something that I would be doing routinely. But I would love to see some research work looking at this because given the importance for node-positive disease and given the prevalence of node-negative disease and high-risk node-negative disease, I would love to have more data there.

I think the topic of using ctDNA in the adjuvant setting is really interesting and yet really complicated in breast cancer. Our group presented a trial at ASCO called the CHIRP trial where we used banked samples to look at ctDNA kinetics over time and were able to look at the time when ctDNA became positive and then the sort of lead time until there was the development of recurrent disease. And it was presented more as like a scientific exploration. It was done retrospectively. But it was really complicated work to do and in particular, how we could talk about this sort of research with our patients. It is true, we can do ctDNA in the adjuvant setting. We can detect positivity. It’s possible that that is then a herald of something that’s going to happen, but what we don’t have is the actionability. We don’t have a way to take that result and say I’m going to add a CDK4/6 inhibitor. I’m going to change it to an oral SERD. I’m going to give you some chemotherapy. We just don’t know what one would do in that setting that could change the outcome. That will be the topic of a large amount of research and trials that are being developed. And I’m really looking forward to putting my patients into trials like that, but we just don’t know.

I also think it’s kind of a dangerous thing to be doing outside of trials because we also don’t really have a framework for how to talk about this with patients and how to explore this concept of a risk, this sort of sword of Damocles hanging over somebody. How do we provide reassurance that this is helpful to check and learn this piece of information? So even though these tests are commercially available and they’re certainly marketed to patients. I have patients who learn about it and come in and want to talk about it. I very much discourage sending this type of testing unless or until I have a way to understand the result and manage it with the patient so we know that it’s helping us.

DR LOVE: So I was just flashing back on the GU Symposium going on this week. And last night, gastric cancer became the new breast cancer. Have you ever heard of zolbetuximab?

DR MAYER: No.

DR LOVE: Anti-claudin 18.2 antibody in upper GI cancer. Yesterday, they presented a trial in metastatic, first line metastatic disease. Hazard rate for PFS, about 0.75. Hazard rate for survival, about 0.75. Both statistically significant.

DR MAYER: Wow.

DR LOVE: So now, upper GI cancer, you’re going to have to look at PD-1 and claudin 18.2. It’s like ER and HER2. They’re the new breast cancer. That’s how you’re going to be presenting upper GI cancers. Like, what’s their claudin level? What’s their PD-1 level? Anyhow. All right. Let’s finish out this with your case.

DR MAYER: Wow.

DR LOVE: Yeah, it’s crazy. 45-year-old woman, Ruth. What happened with her? It seems like she kind of got both parts of this. So what happened with her? It looks like she got adjuvant abema.

DR O’REGAN: Yeah. 45-year-old female presented about 3 years ago or so, maybe a little bit more recently, with a right breast mass. Imaging, at the time, confirmed a 4 cm mass in the right breast with suspicious nodes. Her biopsy showed Grade 2 ER-positive, PR-negative, HER2-negative breast cancer with a Ki-67 of 25%. The biopsy was positive for breast cancer. She got preoperative chemotherapy with AC followed by paclitaxel. Underwent a right mastectomy with axillary lymph node dissection and ended up with a 3 cm cancer with like 6 positive nodes. She, per SOFT and TEXT, got ovarian suppression with an aromatase inhibitor, started adjuvant abemaciclib. 18 months later, comes in with back pain and is found to have bone metastases. And the bone biopsy is positive for ER-positive disease.

DR LOVE: So any thoughts about how you might be thinking through a case like this, Erica? Any markers on her? Did she have NGS?

DR O’REGAN: I think eventually.

DR LOVE: PI3 kin — PI3?

DR O’REGAN: Yeah, but not of her PI3 kinase mutation.

DR LOVE: So how would you be thinking about this situation, Erica?

DR MAYER: So we’re going to be seeing more and more cases like this with increased adoption of adjuvant abemaciclib. So first, if I’m meeting a new metastatic patient, as you were alluding to, we need to collect all of our data. So we’d want to get our tumor genomic profiling. We want to make sure her genetics have been done. I assume she was not a mutation carrier. And make sure we understand her disease distribution and her performance status. In a patient who is presenting with bone-only disease, I would be very comfortable staying in our endocrine category of agents. But historically, we might have changed a patient who recurs on an aromatase inhibitor to, let’s say, fulvestrant. If they’ve already had CDK4/6, would you give this patient fulvestrant monotherapy? Well we’ve learned from a variety of studies in the past couple of years is that the outcomes post-CDK4/6 with fulvestrant monotherapy seem to be quite poor. And there’s just less and less enthusiasm to use that agent by itself. And so I think we’d very much bet thinking about, is there a partner targeted agent that we could be giving with our next step of endocrine therapy? If she had a PIK3CA mutation, we would offer alpelisib. Without the mutation, we would not. We do have the option of exemestane/everolimus with an mTOR inhibitor which with the use of prophylactic steroid mouthwash can often be a very well tolerated regimen. We also have the MAINTAIN study that we’ve alluded to before that looks at a switch to ribociclib. The vast majority of patients in MAINTAIN were receiving palbociclib, so this patient isn’t totally captured in the dataset, but it would be a switch in CDK4/6 from abema to ribo. So perhaps, that would be an option as well. I’ll say, in my institution, I’m fortunate to have like a whole spectrum of trials and so this is a situation where I’d be thinking about, is there a trial option for the patient? In particular, an oral SERD or something of that ilk. We may soon have an AKT inhibitor option that could be offered to this type of patient.

I also though am a little concerned that her disease free interval is not very long and she recurred while getting a CDK4/6 inhibitor. And so even though we are talking about someone in the first line metastatic setting, someone with bone disease and we might say, well maybe this person is going to do very nicely for some time. It’s also possible they might not. And we might be looking at disease that has some inherent endocrine resistance and someone who could move quickly through endocrine options and before we know it, we’re looking at chemotherapy. And so I would want to just clarify the HER2 negativity and know is she HER2 0 or is she HER2-low because these are patients who if they really are the patients who fall off the curve quickly with endocrine therapy, I’m going to start thinking about trastuzumab deruxtecan or something a little bit more in the chemo category as an option for her.

At San Antonio, Fabrice Andre gave a really lovely discussion of some of the ER-positive abstracts. And he really made the case that although we think about ER-positive disease as endocrine-driven and we’re focused on our endocrine options, there is a population which is endocrine resistant and they are not going to do well. And so we really need to change our mindset and think about an early pivot to other strategies and other treatment pathways if we quickly identify that that’s where our patient lives. So I think over the next few months with this patient, we’ll learn more about which category she’s living in.

DR LOVE: Yeah, I think a lot of people have this sort of idea in their mind of people who can go to second line, third line endocrine therapy, you know, the diabetic model, et cetera, and do great. But when you look at some of these second line endocrine trials, the control arm doesn’t look too good in a lot of these people, being a couple months PFS. What actually happened with this patient, Ruth?

DR O’REGAN: So she went on ovarian suppression continued, ribociclib with fulvestrant. And we don’t know how she’s going to do. This is too early. But I agree with Erica, I’d be very worried about this patient. The HER2 was 0, so that’s — the T-DXd is not going to be an option for her most likely. Although I’d be interested to know. I have a patient right now who I’m actually re-biopsying because her HER2 was 0 before. I don’t know, Erica, if you’re doing that or not to see if it changes at all.

DR MAYER: I know it’s that whole debate of what is HER2-low and does it really exist? My first step is usually digging deep in the pathology and looking at like every biopsy, every lymph node, just searching for anything that’s like 1+ and trying to find that. I haven’t been doing too much re-biopsy for HER2 because if I can find it elsewhere, I’ll use that. I have to admit, I haven’t tried to give T-DXd to someone who is HER2 0 just to see what happens or to see if it gets paid for. I really have tried to have pathologic confirmation. But there are these hints like from the DAISY study that the benefit of T-DXd may not be limited to this HER2-low, but may be more broadly expanded.

DR LOVE: It’s really interesting too for the general medical oncologist who is hearing different things. Again, going back to the GI meeting last night, we were talking about T-DXd in gastric cancer. And the GI people, they start — the patient starts out a positive HER2 and then they recur. They re-biopsy them and if they’re not HER2-positive, they don’t use anti-HER therapy. And I’m like, well the breast cancer people don’t do that. They’re hearing a lot of hetero — the general oncologists hear a lot of heterogeneity in how people approach this.

Novel agents in metastatic disease

DR LOVE: So Ruth is going to go through something new and really exciting, I think. We’ve been waiting for other forms of hormonal therapy, particularly the oral SERDs. It seemed like it made so much sense and yet, it seems like it’s been a long time. Now, we’re seeing this AKT inhibitor, capivasertib. I’ll be really curious, after Ruth goes through this, how you’re thinking through that. For example, maybe you can clarify for me like what patient would go on alpelisib versus capivasertib. We’ll call it capi. So, Ruth, let’s take a look at the data first. And then, we’ll —  

DR O’REGAN: Capivasertib.

DR LOVE: Yeah. We’ll talk — let’s take a look at the data and then, we’ll chat a little bit about what it means.

DR O’REGAN: I like the capi. I can never pronounce these drugs when they come out. So just to start with just, we talked about MAINTAIN earlier, and this is just to show you the curves from MAINTAIN. So this was basically patients who essentially had prior palbociclib were randomized to endocrine therapy without ribo. And you can see, there’s about a 3-month improvement in progression free survival for the patients who got ribo. I didn’t put PACE in here, but I’m sure Erica can talk about that.

And then, it’s to remind people about alpelisib. So this is the data from SOLAR-1 where patients in the second line — or in the pretreated setting whose cancers that are PIK3CA mutation got randomized to receive fulvestrant or fulvestrant with alpelisib. It showed a very nice separation of the curves in favor or alpelisib with an 11-month or so progression free survival in the alpelisib arm.

The BYLieve study specifically looked at alpelisib in patients who’d had prior CDK4/6 inhibitors. The primary endpoint was disease control at 6 months which was 50% which was within the trial parameters and the progression free survival here was 7 months. A little bit lower than in SOLAR-1, but I think it definitely illustrates that using this drug in patients who have had prior CDK4/6 inhibitors does make some sense.

So this is FAKTION, so this is looking at capi shown here which, again, this is in the pretreated setting. So patients were randomized to receive fulvestrant alone or fulvestrant plus capivasertib. And you can see, the curves separate in favor of the AKT inhibitor for a difference of about 4 months up to 10 months, as you can see. And this has been presented a number of times.

We now have survival data from this trial as well, again, showing the curves separating in favor of the AKT inhibitor shown here and I think what’s about a 5-month difference in progression free survival for the AKT inhibitor. Now initially when they presented this, when they looked at alterations of the PI3 kinase/AKT pathway, they didn’t find that was predictive of benefit from this AKT inhibitor. But the subsequently, by using some different technology to determine activation of the pathway, they actually did find that the benefit appeared to be more dramatic in patients whose tumors had alterations of the AKT pathway.

This is the CAPItello study. Again, this was patients with pretreated disease and 50% of patients had received a prior CDK4/6 inhibitor. And again, they were randomized to fulvestrant plus placebo or fulvestrant plus the capivasertib, as you can see shown here.

And again, we see the same kind of data shown here, this nice improvement in progression free survival from 4 months up to 7 months in the patients who got the AKT inhibitor.

And looking at, again, this AKT pathway altered population using the definition they used on the trial. Again, you can see that the difference is very, very similar to the intent to treat population, as you can see shown here. So, again, I think another exciting agent that targets this pathway.

And then, the oral SERDs. I didn’t put up all the trials here just in the interest of trying to get them all on one slide. But there are a number of randomized trials looking at different oral SERDs. In the pretreated setting and almost in all of these studies, they compared it to either fulvestrant or standard endocrine therapy of physician’s choice. I’m going to focus a bit more on EMERALD in a second, but this was the one randomized Phase III trial that compared elacestrant with fulvestrant. And basically, what we know from these drugs is that they do appear to have greater efficacy than other endocrine agents in patients whose cancers have ESR1 mutations which are mutations of the estrogen receptor. EMERALD, of course, all patients had to have a prior CDK4/6 inhibitor. The benefit was relatively modest when you looked at progression free survival, just under 2 months difference in favor of the elacestrant. But, again, there was a — when you looked at the patients who had ESR1 mutations, which was about 50% of patients in this study, they did better, as you can see when you look at progression free survival, on the oral SERD. These are 2 of the negative studies shown here. So you can see looking at these different SERDs that in the intent to treat population, there is no difference. But, again, there is this hint across these trials of the ESR1 — in patients whose tumors had an ESR1 mutation that these drugs do appear to be more effect. And there was another randomized Phase II study presented at San Antonio which I didn’t add here with a different oral SERD that actually did show an improvement in progression free survival.

So just updating on the EMERALD study, we looked at the progression free survival already. What was shown at the San Antonio meeting was a breakdown of the benefit of the oral SERD compared to standard endocrine therapy based on how long patients had previously received a CDK4/6 inhibitor. And essentially, what it showed was that the longer patients had been on a CDK4/6 inhibitor in the first line setting, the more benefit they got from the oral SERD, as you can see shown here, which I think it quite interesting.

And this was to, particularly in patients whose tumors had ESR1 mutations. You can see quite dramatic separations of the curves in favor of the elacestrant, particularly in patients who’d been on longer durations of oral CDK4/6 inhibitors. So I think definitely a very interesting finding there.

So I think just to summarize, I think there’s a lot of very interesting agents out here. The oral SERDs, I think overall there was a little bit of disappointment, I think, initially just because the benefit was relatively modest. But there’s certainly a greater benefit in patients whose tumors have ESR1 mutations. And, again, we’re waiting for first line studies where they’ll be combined with CDK4/6 inhibitors. And interestingly, there’s actually adjuvant studies going on with these oral SERDs as well. So I think they are going to be very interesting agents. And I think looking at the EMERALD study, based on this, if you had a patient who had been on a CDK4/6 inhibitor for a long period of time, particularly if their cancer had an ESR1 mutation, when this drug is approved, I think certainly, this would be a good option for patients because the toxicity profile is reasonable, I think, compared to some of the agents that we have. And I think just to mention, obviously, doing genomics and seeing if they’ve got PIK3CA mutations, #1, but also now perhaps an ESR1 mutation will be important.

DR LOVE: So a couple of points, Erica. First, in terms of the oral SERD. It seemed like it always made sense because I think there was a dose response relationship with fulvestrant, but yet there’s a limit to how much you can give IM. I think the other agent that Ann was — that Ruth was referring to from San Antonio was camizestrant which is, I think, the other one that has a positive trial. And I think there are now Phase III studies looking at that.

Any thoughts about the oral SERDs, Erica, and in what situations you would be thinking about it? Do you think we’re going to have these available in the near future? It seems like patients with — ESR1 patients would be particularly somebody you’d think about it. I know there are ongoing studies looking at them. How do you see them fitting into practice over the next year, Erica?

DR MAYER: Yeah, this is a really interesting area right now for advanced hormone receptor-positive breast cancer. It’s a very compelling mechanism of action for these drugs. And I think we’d all agree that having a new and improved endocrine agent would be of substantial benefit for patients. It’s been a bit of a horse race with all these different agents. And when we make tables of like oral SERDs, they seem to like come and go a little bit based on how the trials are doing. And I’d also add, there’s other ER-targeting agents such as CERANs and PROTACs which are also in development.

The data at San Antonio with camizestrant was quite interesting in the SERENA-2 study where 2 different dose levels of camizestrant were compared to fulvestrant and seemed to show improved outcomes. I think one thing that’s really interesting here though is the variability of the ESR1.

We know that ESR1 in contrast to PIK3CA which is a pretty static mutation, ESR1 is a kinetic mutation and it’s a sign of resistance. So when patients are starting first line endocrine therapy, very few of them will have an ESR1 mutation. But after 6 months of, let’s say, AI and CDK4/6, close to half of patients will have a detectable ESR1 mutation in their cancers. And so the idea of in particular use of oral SERDs for ESR1 populations is quite compelling although we don’t know that the benefit is exclusively limited to these populations.

I think that, exactly as Ruth pointed out, the data with the EMERALD study has perhaps improved in favor over time as we see more and more maturity. And also, I really liked this particular slide we’re looking at with the — seeing the benefits in the population who perhaps has more endocrine sensitive disease and had a longer period of time on their previous therapy. We are anticipating that we may see elacestrant as an approved agent in 2023. And if so, I would be excited to use it in my practice, particularly in these patients who have more endocrine sensitivity as demonstrated by prior duration on their previous therapy. But I think for the other agents, we really need a lot more data to demonstrate what their benefit is and how we would place them and also how we might use them in combination with other therapies. We among others are going to be opening the adjuvant SERD studies and I’m excited to try these agents in the adjuvant setting, but it is a big leap to move away from our very well-established standard adjuvant endocrine therapies and move a patient to something new and still in development. So I think there’s a lot more we need to learn about these agents.

DR LOVE: So adjuvant SERDs. I know there was at least one study out there looking at people who couldn’t tolerate, I guess, Ais. But adjuvant SERDs, like really SERD alone in the adjuvant setting or augmenting maintenance, whatever? What kind of strategy for adjuvant SERDs, Erica?

DR MAYER: Well there’s a variety of trial designs that are ongoing. Some take patients immediately when they’re starting endocrine therapy, randomizing to SERD versus standard of care provider choice endocrine therapy. There’s also studies that are picking patients up a little bit later, perhaps after they finish their adjuvant abemaciclib, and randomizing at that point to SERD versus treatment of provider choice. And then, as I alluded to before, we may have late recurrence trials where we are using a biomarker-driven strategy looking for the presence of ctDNA and then randomizing to SERD versus not. So a lot of different ways where a patient perhaps could get exposure to one of these agents.

DR LOVE: So I want to also get back into capi but also, the issue of tolerance of these new agents, Ruth. So first of all, do you see anything? With fulvestrant, the biggest issue, I think, was the injection. Any tolerability/quality-of-life issues with oral SERDs that we’ve been able to observe so far, Ruth?

DR O’REGAN: Yeah, I think there’s some GI issues, particularly nausea, but I think they’re relatively minor. But you don’t get that with fulvestrant. I think people always talk about the injection site pain with fulvestrant, but I don’t, at least in my patient population, it hasn’t been a huge issue. So I think you are potentially choosing a little bit more toxicity, but appears to be pretty manageable.

I think where we really struggle more is with the agents that target the AKT pathway — PI3 kinase/AKT pathway where there really is quite a lot of toxicity, particularly with regard to hyperglycemia and other issues, I think, with both alpelisib but also with capivasertib as well.

DR LOVE: Yeah, I was going to ask you, it seems like there would be patients biomarker-wise, I guess, we’ll have to see if it gets approved and how it’s approved. But at least in terms of the data, it looked like everybody benefited from capi. But, again, as you said, the people with the AKT abnormalities more. But within the AKT abnormalities you put there was PI3K. So, for example, Ruth, how would you indirectly compare alpelisib to capi in those patients?

DR O’REGAN: I think that’s a great question. I think certainly in the FAKTION study, they used a lot of different methodologies to determine activation of the pathway. Because initially, when they presented that data, they didn’t see — that was not predictive of benefit from the drug. So I guess — I haven’t used capi. Maybe Erica has. I think if its toxicity profile is a little easier than alpelisib, I might choose that first in a patient who had alterations of the pathway. But I think if they have a PI2 kinase inhibit — mutation rather, I think I still probably would lean towards alpelisib because it was quite a dramatic improvement in progress free survival on the SOLAR study.

DR LOVE: So, Erica, I’m curious about what you know. I don’t know if you’ve used capi in terms of what the tolerability issues are. But also, with alpelisib because I hear this every day from oncologists in practice. How do we do this so the patient will tolerate it better? What’s your experience with both of these agents?

DR MAYER: Yeah, I actually — I haven’t really used capi yet although certainly excited to try it out with patients if possible. But I agree, alpelisib is a challenging drug. And on the one hand, it’s not technically chemotherapy, but the experience of receiving this drug for patients sometimes resembles or even is worse than some of the chemotherapy strategies just with the difficult to manage toxicity.

But there actually was a small study at San Antonio that I thought was really interesting called the METALLICA study that was looking at the idea of trying to address the hyperglycemia that we tend to see with alpelisib. I have tended to give prophylactic metformin when I start patients on alpelisib in addition to the prophylactic antihistamine that we use to prevent rash. The metformin study studied this a little more formally and gave patients metformin 1,000 twice a day, which honestly is more than I usually use, but started that a week before they started their alpelisib and then monitored rates of hyperglycemia and showed a very dramatic decrease in the rate of Grade 3/4 hyperglycemia seen than compared to what we saw in SOLAR-1. And so this is one of the things I came away from San Antonio, sort of tucking away thinking like, this I can really use in clinic. So I’ve started trying to do this now with patients and really thinking about how we can use prophylactic drug strategies to try to modify or reduce some of those emergent toxicities. But it’s hard. And the days of just sort of starting someone on an endocrine agent and it was sort of easy and straightforward, I think those are behind us. And now, each step requires a very specific paired strategy and very specific guidance for preparation and prophylaxis and monitoring for these patients.

DR LOVE: So I want to close out with just briefly reviewing a couple more cases. We were talking about HER2-low. Of course, this is a huge issue now ever since the ASCO meeting. Ruth, you have this 59-year-old lady. She was HER2 1+ by IHC, metastatic disease, gets a bunch of hormonal therapy, anastrozole, fulvestrant, palbo, everolimus, exemestane, capecitabine, and now, T-DXd. What was her situation when you started the T-DXd and what happened?

DR O’REGAN: So we started the T-DXd. She’s got disease in her liver and bones. So we started about 6 months ago. And now, this is when she came in with disease progression in her liver and bones, unfortunately, after about 6 months of being on the drug. So I think based on the data from the TROPiCS study that has been presented a couple of times, we have the option of sacituzumab for this patient. Other options I think would be other chemotherapies that she hasn’t had before. But I think given the data from the TROPiCS study which showed an improvement in progression free survival with sacituzumab compared to kind of standard single agent chemotherapy, those patients had not had T-DXd, but it did show a nice improvement in progression free survival. So that would be my choice for this patient.

DR LOVE: So I’m just curious. When she got the T-DXd, any tolerability issues? We hear some patients who get GI issues. Did you use preemptive GI meds? Any alopecia?

DR O’REGAN: Yeah, she had some alopecia. But otherwise, she tolerated it pretty well actually. But unfortunately, it worked only for 6 months which in this setting, I don’t think is horrible because she’s had a lot of prior chemotherapy.

DR LOVE: So I guess another issue that comes up here is sequencing of T-DXd in HER2-low patients, Erica. Of course, that’s also an issue with what used to be triple-negative, but HER2-low, but the issue, as played out with this patient, of T-DXd versus sacituzumab which is used in both. How do you usually approach that in your hormone receptor-positive, HER2-low patients? When do you bring in T-DXd, Erica? And how do is vary based on the clinical situation? Do you think more about it earlier if they have liver mets and a lot of disease? How are you doing it?

DR MAYER: Yeah, I tend to give it as Ruth did in this case and would prioritize T-DXd over sacituzumab for a hormone receptor-positive, HER2-low patient. And that’s the opposite of what I do in a triple-negative, HER2-low patient where I prioritize saci over T-DXd. I tend to try to give T-DXd pretty early if I can. And so using it post-capecitabine would be quite consistent. The data from DESTINY-Breast04 in comparison to some pretty active chemotherapy choices like eribulin was so striking. And in general, I think using your best agent as soon as you can makes sense. It does require a lot of monitoring for pulmonary toxicity, so I usually get a chest CT about 6 weeks into treatment. I’ll say, I actually restage patients every 9 weeks, not every 6 weeks as was done in the study because it’s just too much. But I try to keep a really close eye on the pulmonary situation to make sure we’re not having an emergence of ILD. And thankfully, I haven’t seen a lot, but of course we want to look carefully. And there’s also alopecia with T-DXd which for some patients, that’s something the drives some of the decision making. And if that’s a meaningful important toxicity, then we do have other choices that one could offer instead. But I’d say that having T-DXd available in my clinic has been wonderful. And I can think of a couple cases recently where I was using it in a kind of Hail Mary fashion where it really did the job and kind of pulled people out of a difficult situation. So I’m immensely grateful to have this as a new tool.

DR LOVE: One of the docs, one of the general oncologists on the video we had last night for the GI meeting said T-DXd is like chemotherapy except it works. I thought that was kind of funny. Anyhow. Your colleague, Dr Burstein is always telling me that I bring up clinical situations that never occur or rarely occur and this is one of them I always like to ask people which is upfront therapy in a patient who is hormone receptor-positive, but also BRCA-positive, Erica, which is the case, we were talking about younger patients, with your 35-year-old patient. So I’m curious how you sort of thought through her adjuvant therapy in light of the fact that she had 2 positive nodes, 2.5 cm tumor and a germline BRCA1 mutation.

DR MAYER: Yeah. So thanks. This was a high-risk patient who got preoperative chemo and despite that, had residual disease. And we could calculate the risk score, the CPS-EG score being at least 3 which is a higher-level score. And she’s also a mutation carrier. And so in the adjuvant setting, we have a lot of tools available. And the question is how to use our tools. And we sort of alluded to this before, but 2 of the most compelling tools we have in addition to endocrine therapy is the oral PARP inhibitor, olaparib, which has shown progression free and overall survival advantage in the OlympiA study, and abemaciclib, as we’ve talked about. In situations like this, as Ruth has mentioned, we prioritize the olaparib because that’s really a tremendous benefit including overall survival. So that’s what I would lead with here. I’d give a year of olaparib. But you can actually then start abemaciclib. In monarchE, the window to start abemaciclib was pretty long. And so for a patient who does a year of olaparib, I still think they’re eligible to initiate adjuvant abemaciclib if they meet other high-risk criteria. And so I try to do a sequence with people if they can tolerate it.

DR LOVE: So, Ruth, have you used olaparib in the adjuvant setting and how does that play out?

DR O’REGAN: I actually have to say I have not used it yet, but I would certainly use it in a patient like this. And I think, as I alluded to earlier as Erica just said, if you’re in a situation where you’ve, I guess, choice between olaparib or abemaciclib, as Erica said, maybe you could do both. But I would use olaparib based on all the reasons that Erica said.

DR LOVE: So final case from Ruth, a 60-year-old woman with metastatic disease, she’s got a PI3 kinase mutation and an ESR1 mutation, just as we were talking about, on liquid biopsy. She’s on fulvestrant and alpelisib, as I think she would generally be in the community. But now, she has progressive disease. Ruth, this sounds like the antre way to one of these new drugs you just talked about. What did you actually do with her?

DR O’REGAN: Well, you know, obviously, they’re not available, right? So I would put her on a clinical trial if there was one available. But I actually gave her — I talked to her about capecitabine or everolimus with exemestane. She elected to everolimus, so that’s what she’s on right now. But I think based on the data that we’ve talked about, I think I would be very interested in giving this patient an oral SERD, I think particularly because she’s got an ESR1 mutation. I don’t know that we’ve got data in patients with PI3 kinase mutations, but I would imagine they were enrolled on the study. I think also, you could consider capi in a patient like this as well, so I’m hoping we’ll have those available soon. And I think we’ll be stuck with the issue of how we sequence these agents. But the bottom line, it’s a patient that will probably end up getting all of them at some point.

DR LOVE: So final comment from Erica. You can give this patient chemotherapy as well. I’m curious what you think the likelihood is that she would benefit from everolimus/exemestane with an ESR1 mutation.

DR MAYER: So I think what I find really compelling is that she’s been on the fulvestrant and alpelisib for 9 months. And I think that indicates that she still has endocrine sensitivity. She certainly has endocrine options. You could even give tamoxifen and everolimus based on the TAMRAD study. And the patient’s told us what she wants. She was offered an oral chemo, she was offered endocrine. So she’s already expressed what she’d like to do. And I think that her voice is super important. So I absolutely agree that based on what we have as of this very day, I’d be offering her an everolimus-based option. But I’m excited that there’s going to be a lot more to come this year and a lot of other choices that someone like this could benefit from.