Introduction

DR LOVE: Hello everyone, this is medical oncologist Dr Neil Love and welcome to “Striving for Consensus: Exploring the Current Role of Ovarian Suppression in the Management of Breast Cancer.” For this special program, I sat down with four clinical investigators, Drs Bill Gradishar, Virginia Kaklamani, Erica Mayer and Seth Wander, for a think tank–style discussion on relevant data sets and their perspectives on the use of ovarian function suppression in patients with hormone receptor-positive breast cancer. Before we got down to discussing data sets and relative applications, I asked the faculty to pause for a second and comment on the human dilemma of a younger patient with breast cancer.

Erica, before we start getting into the nitty-gritty of treatment of these patients, anything you want to say generally about dealing with these patients, Erica? You know, very different scenario than the older patient, you know, perhaps in retirement.

DR MAYER: Yeah, thank you for leading off with that. I share a practice with Dr Partridge and Dr Tolaney, and my practice is quite similar. Dr Partridge and I see the majority of our youngest patients at Dana-Farber, so it’s not that unusual to have several patients who are 28, 29 years old. And a large number of our metastatic patients are young women who have young children. So, it’s really a very different patient population than what we might think of. In terms of epidemiology, it’s kind of the average type of woman with breast cancer. These are people who are just beginning their lives, they’re just starting their careers, many of them are just starting their families. And in addition to the need to accurately diagnose and treat and propose treatment plans for their breast cancer, there’re so many other aspects of their lives and their care that we have to think about as medical oncologists. I feel really fortunate that at Dana-Farber we have a really strong multidisciplinary team. We have social workers, geneticists, reproductive endocrinology, all the different parts of the team, really good plastic surgeons, people who can really try to help support patients, not just very specifically in their med onc needs but also in all of the, kind of multidimensional aspects of what it’s like to be a very young woman who’s dealing with this kind of disease.

I also find it quite interesting, as you’ve probably talked about on other calls, with the rates of colon cancer in young patients. And I think some of the work that’s been done to establish frameworks for how to take care of these young people perhaps could be shared in the young patient colon cancer clinics, because I think there’s a lot of shared needs and strategies that would be applicable to both.

DR LOVE: That’s really interesting. Seth, anything you want to add to that, again in terms of the scenarios and issues that come up? We did a program recently at a general medical oncology weekend where we showed a video of a patient who was talking about the effects on her marriage as well as the impact on the young children in her family. Any comments on the challenges in these situations, Seth?

DR WANDER: Yeah, thanks, Neil, and thanks, Erica. I completely agree, there are a lot of unique attributes and challenges to dealing with this particular patient population. And I think the big picture is to really meet the patient where they are, and in thinking about all the toxicity potential that we’re going to talk about today of course, it affects women differently depending on which stage of their life they’re in, kind of where pre-, peri- or postmenopausal. Of course, there are important considerations related to fertility preservation in this patient population that can pose unique challenges in terms of the timing of treatment initiation and the sequence with which we’re going to initiate treatments. And I think as Erica mentioned, trying to bring, to bear all of the skills of our colleagues, in terms of reproductive endocrinology, gynecology, social work, right? Thinking about all of those aspects of treatment to help bring everybody together to address all of these issues. And 1 of the important things that I always try to remember is, we’re in an oncology visit and there might be a limited amount of time in a follow-up, and you’re focused on going through the pathology and you’re focused on laying out the big picture treatment course, but sometimes you miss the forest for the trees and you’re not able to pick up on all of these other concerns that the patient has, things that they might be worried about or things that they might be experiencing once you start the treatment as you’re trying to get to your treatment aspect themselves. And so I think we have to make sure we have time for that and that we’re using all of our kind of ancillary supporting colleagues and staff.

Addition of Ovarian Function Suppression (OFS) to Adjuvant Endocrine Therapy for Premenopausal Patients with Hormone Receptor (HR)-Positive Breast Cancer — Dr Gradishar

DR LOVE: I want to move into the first topic, and Bill’s going to go through the data on that. But I want to chat a little bit first before we get started about the issue of adjuvant ovarian suppression and ablation. And particularly, Bill, the issue, before you go through the data, about who should be getting adjuvant ovarian ablation and who can get tamoxifen alone, which has been kind of an, it’s a very practical question. Our group started to look into this in more depth in the last couple years and found some interesting things. Bill of course is head of the NCCN breast committee. Can you kind of talk a little bit about sort of what the guidelines say, and what your practice is about when you use tamoxifen alone in the adjuvant setting, Bill?

DR GRADISHAR: So I think the issue about making therapies in a sense more complicated to address the risk an individual patient may have is based on a variety of factors, and we’ll talk about some of those. But certainly the age standing alone is 1 issue, but not by itself should that be dictating whether you get ovarian suppression or not. It takes into account of course the size of the tumor, the nodal status, other biological features of the tumor. And when you sort of distill all that information and arrive at someone who you think is at an elevated risk, above and beyond just their age, that may by the individual where you think about adding ovarian suppression. If you have somebody with a very tiny millimeter size tumor that’s otherwise ER-positive, I don’t think that’s an extreme, but I wouldn’t put somebody like that on ovarian suppression. They’re not going to probably gain that much, but they will gain a significant amount of toxicity, as already pointed out by others.

DR LOVE: So one of the things as we started to look into this, our way of doing a consensus is we ask a whole bunch of people who normally, people like on the NCCN committee, what they do in their practice outside of clinical trial. And sometimes, some interesting things come up. I want to show you 1 thing, and I don’t know that this is that clearly just defined. But what we found when we started to ask people, when do you use tamoxifen alone? One of the things that we found that is not, I don’t know, I don’t see it that strongly emphasized, but yet when you look at what people do, is a big issue, which is genomic assay, particularly Oncotype. So, globally what they say is, first of all, under 30 or in that range, that may be a different story, maybe in that situation the risk might be enough to consider for a lot of patients. But beyond that, the story we heard was small, node-negative tumors with a low Recurrence Score. And if you look at what people say they do, you see here, we start out with a 0.5 centimeter tumor that’s node-negative, and even with an intermediate recurrent score most people are still doing tamoxifen. We go to 1 centimeter, and you see a big difference based on the what the Recurrence Score is.

That ties into what you were just saying in terms of low risk. But it’s a little more practical Bill. Any thoughts about that in terms of whether or not it should be more prescriptive to look at genomic assays in node-negative patients, and is that really where we’re looking, Bill?

DR GRADISHAR: Well, we do do molecular tests like Recurrence Score in that population. I think that that data that you just showed reflects my comments, that as the level of risk goes up, and again it’s not based on a single factor, age alone, it also takes into account tumor size, other features of the tumor, including the molecular results on the test. That is going to change your prescription of what you think is optimal for the patient. The bigger the risk, the greater the therapy that you’re going to use. It’s going to be more than just tamoxifen. And I think that’s reflected by all the folks that you asked that question to.

DR LOVE: And Virginia, I guess the other issue, and we talk about this all the time in all of our programs, because it’s increasingly important as we see more options, which is allowing the patient to be involved in the decision. When you have borderline situations, maybe talk to the patient about what their preferences are. Would they be willing to go through ovarian suppression maybe for a minimal benefit, as opposed to a patient who would need a big benefit? Any thoughts about how this decision plays out for practical purposes in your practice, Virginia?

DR KAKLAMANI: I think it’s important to involve the patients. And you have to give them, to the best of your ability, the absolute improvement in outcomes with whatever therapies you are recommending. Because ultimately, these are therapies that come with toxicities. And I’ll present some of the data on survival with early menopause in patients. And these are things that we as oncologists are not used to thinking about sometimes because we’re just focused on breast cancer. But there are other comorbidities that come to play. But these patients are going to have a higher risk of having heart disease and asthma and COPD just because of early menopause. And these are things that we need to take into account when we counsel our patients.

DR LOVE: I have to say, I have to ask you, asthma and COPD?

DR KAKLAMANI: I will present the data. I was surprised as well.

DR LOVE: Ovarian suppression? Really? I have never heard that.

DR KAKLAMANI: Early menopause.

DR LOVE: What’s the basis of it?

DR KAKLAMANI: I don’t know.

DR LOVE: Wow.

DR KAKLAMANI: It came from the Nurses’ Health Study and showed that these patients have a lot of other factors that play into their long-term health. And when you have a 35-year-old, you’re thinking of this woman becoming 80. And this is a lot of years of nonexposure to estrogen.

DR LOVE: Still, maybe they smoke more. I assume they corrected for smoking. But anyhow. Get more stress. I don’t know. Anyhow, we’re going to go back and forth today between practical issues and taking care of patients, giving people some things to think about in that regard, and the data. So, Bill, you have a talk put together on some of the key trial data that really relates to this issue. You can go ahead and get started.

DR GRADISHAR: Sure, and thanks. I’m going to try and fly through some of this. I think it’s probably fairly well known by most people.

So I think if you go back in history back into the 70s when adjuvant therapy first came out, we saw the effects of systemic therapy, usually combination therapy on the risk of recurrence. And even when those early trials were analyzed, there was this hypothesis that perhaps one of the effects of the chemotherapy may actually be on the ovaries making patients, reducing their estrogen and affecting them.

If you look at the data from those early trials and also included in the overview analysis shown here, you can see the impact of chemotherapy, particularly in ER-positive younger patients where the risk reduction is notable. So again, it added more fuel to that notion that part of the effect of chemotherapy may be affecting the ovaries.

And then, of course, we had much larger datasets that we’ve heard about for many years. This was just updated at ASCO a year ago looking at the effect of ovarian suppression versus not in those who either didn’t get chemotherapy or were still premenopausal after the completion of chemotherapy. And ovarian suppression clearly reduced the risk of recurrence.

You could look at that effect whether patients were younger, in this case less than 45, or still viewed as menopausal but older in the 45 to 54 group. And again, the magnitude of benefit is somewhat greater in younger patients, but the effect is still seen regardless of the age of menopause.

And then node status, getting to the point that we were talking about before we started this. If you have a higher risk based on clinical features, the magnitude of benefit from some intervention is usually greater. And that’s true with ovarian suppression as shown here where the node-negative patients clearly have an impact with ovarian suppression, but the magnitude of that benefit is greater in the patients who have more risk, positive nodes.

And the effect on mortality, there was clear indication as well that if you look over a long period of time, the effect is about 10%. That’s a 20-year follow-up. If you look at a shorter interval, it’s harder to see that effect. And one of the things that I’m sure we’ll talk about is convincing patients to stay on ovarian suppression for extended periods of time.

One of the issues that comes up is if you elect to do ovarian suppression, how long should it be administered for? There’s been a number of different studies that have looked at this. We’re just going to touch on a couple of them. This is the HOBOE study in 1,000 premenopausal patients with hormone receptor-positive disease who got endocrine therapy plus triptorelin, a GnRH agonist, or the third arm with the same plus zoledronic acid. And with the follow-up beyond 5 years, there was improvement with the addition of an AI over tamoxifen. If you look at the bottom of the slide, disease free survival 85%, 93% and 93%. And, again, triptorelin in this case was given to patients for 5 years.

Now if you look at the ASTRRA trial which looked at goserelin for 2 years, and the slide on the right is a bit complicated but nonetheless, it’s a trial that looked at about 1,500 patients who are under the age of 45 with ER-positive breast cancer who did receive chemotherapy. And they were assessed to determine their menopausal status and then randomized to tamoxifen alone or to tamoxifen plus ovarian suppression using goserelin.

And with 2 years of ovarian suppression, the impact was demonstrated. So probably based on the data we have, a minimum of 2 years although most guidelines would suggest longer. If you look at the disease-free survival at 8 years, it’s pretty clear that there is an impact with the addition of ovarian suppression to tamoxifen in this population.

Of course, the trials that we look to to really inform us are the TEXT and SOFT trial shown here. And the TEXT trial, in many cases, there were similarities and there were distinctions and nuances between these experiences. These were populations that were all postmenopausal. The clinician had the opportunity, based on his own gestalt, to give chemotherapy or not. And in the TEXT trial, patients were randomized to either tamoxifen and ovarian suppression or exemestane and ovarian suppression for 5 years. And then, of course, in the SOFT trial, it was actually asking the question of what the additional benefit was from ovarian suppression. So there was an arm with tamoxifen alone, and then tamoxifen/ovarian suppression, exemestane/ovarian suppression. And there was actually a joint analysis to look at the additive effect, if any, of using an AI rather than tamoxifen with ovarian suppression.

So we’ve had long follow-up of this trial. And the overall survival was probably enhanced with the effect of ovarian suppression. We have now long-term follow-up, originally, the data was presented at 5 and 8 years, clearly demonstrating that the addition of ovarian suppression to tamoxifen reduced the risk of recurrence and death. And then the question became whether you were adding something by utilizing an aromatase inhibitor over tamoxifen. And there was a similar incremental improvement in outcome with an AI over tamoxifen.

And you can look at the data at 8 years. This is the disease-free survival. Again, an absolute improvement in outcome with an aromatase inhibitor of about 4 percentage points.

And then with the longer follow-up at 12 years, again, there is an incremental improvement when you look at overall survival and distant relapse free interval with an AI over tamoxifen. And similarly, looking at the SOFT data alone, again we see disease-free survival on the left, overall survival on the right. And again, there’s an incremental improvement with the addition of ovarian suppression over tamoxifen. And certainly with exemestane over tamoxifen in combination with ovarian suppression, another incremental improvement in outcome.

If you look at the comparisons between the ASTRRA trial which was, again, 2 years versus SOFT which was 5 years of ovarian suppression, you can see that the populations are similar with respect to age, lymph node positivity. The small fraction of patients that did have HER2 overexpression, the duration of ovarian suppression was different but the impact was similar suggesting that you have to give probably at least 2 years, but most of the data would suggest longer is better.

Now you can put all these data together, and this includes the ABCSG trial, SOFT, TEXT and the HOBOE trial that I mentioned. And again, sort of a meta-analysis from the Oxford Overview. And if you look at distant relapse free survival on the left and overall survival on the right, there’s clear indication that the use of an AI plus ovarian suppression incrementally improved distant relapse free survival. Certainly in the short-term, overall survival is not as clear to be demonstrated.

So when we look at how we utilize this in practice, guidelines give us some guidance. I’m not going to make you read all of this, but touch on a couple of things.

For the candidates, as we were discussing at the outset, we have to look at a variety of different features and determine whether the risk of recurrence is high enough in conjunction with their age, looking at grade, lymph node involvement, perhaps molecular tests will influence us. And then, of course, we have to assess their ovarian function to make sure, and we’ll touch on this I’m sure, expand on this as we go through this, to make sure indeed that the effect of ovarian suppression is shutting down the ovaries. There are a variety of ways of assessing this, and I know we’ll talk about this. We’ve talked about the duration, minimum of 2, probably 5 is better.

And if you look at guidelines, whether it’s ASCO, the ESMO guidelines or the NCCN guidelines, you’ll see a suggestion that although there is data suggesting you can give less frequent GnRH agonist as a way of suppressing the ovaries, most would recommend a monthly shot. And there is data suggesting 3 maybe equivalent in terms of estrogen suppression. However, there are caveats. There’s a fraction of patients that don’t have complete shutdown of their ovarian function. And it may be that in obese patients, there is less of an effect.

So again, the duration has been addressed by a number of different societies including ESMO, ASCO and the NCCN. And, again, if you look at the guidelines that are available, they’re all settling in at ideally 5 years. Ann Partridge has surveyed patients in this age group about their willingness to go beyond 5 years. And there is some interest in patients to even consider longer durations.

So when you think about how we would prescriptively suggest incorporating ovarian suppression, I would submit that it’s not entirely crystal clear, but it’s a gradation of risks that drives what we do. So in the examples that Neil was showing at the outset, maybe somebody with an itty bitty tiny tumor only needs tamoxifen. But as the risk of recurrence goes up, then we start adding in additional things including ovarian suppression and, of course, even more recently, the use of CDK4/6 inhibitors based on the monarchE and perhaps downstream the NATALEE trial.

And of those things that we incorporate, again, we try to distill risk based on clinical features, some of which are outlined here, and then incorporate that as well into molecular tests that may inform us about our decision-making.

So there are tools that one can use. This is a tool that’s readily available that perhaps Erica can comment on later. Again, you can make a decision based on numerical values that may help decide if a given patient has sufficiently high-risk and what quantitatively they may gain by going on ovarian suppression by using one of these tools.

We talked in the examples at the beginning, does everybody who is premenopausal necessarily need chemotherapy? Would the use of molecular tests help inform that decision-making? And we know based on the different large trials that have been done including RxPONDER and TAILORx that we can decide who really needs chemotherapy. But there’s still a gray area. And that may be an area where ovarian suppression may be used in lieu of chemotherapy and achieve the same effects. And, of course, there are a number of trials that are looking at this.

The one in the US that has really gotten our attention is the NRG trial looking at premenopausal women where, based on their clinical features and nodal status as well as their Oncotype result, they would be potentially eligible. And if so, randomized between chemotherapy plus ovarian suppression/endocrine treatment or ovarian suppression and endocrine therapy alone. And this may clarify that issue of whether we can safely administer to a subset of patients, who might otherwise be getting chemotherapy, endocrine therapy alone achieving the same effect.

DR LOVE: Before you get to your cases, maybe we can just pick up on a couple things that came out as you were talking. First, I wanted to ask Erica if she could talk a little bit about the tool and also globally what the factors are that you put in. And also, I’m really curious what the tool says as the risk goes down, Erica, in terms of absolute benefit. And do you factor in potential increases of mortality because of ovarian suppression?

DR MAYER: So in full disclosure, I’ve never used the tool before. It’s not something that we in our practice here tend to use. But I think, Bill, you brought up some of the really important points that go into our decision-making about recommendation of ovarian suppression. And, of course, what we’d want to add to that is the patient’s feelings and what their willingness is to do OS and for how small or large a benefit would that be acceptable.

I do think though one thing I’d love for us to talk about a little bit is the ASTRRA study a bit more. I find it so interesting that the hazard ratio for improvement with the addition of ovarian suppression to tamoxifen is basically identical to what we see in TEXT for OS/AI versus tamoxifen despite it only being 2 years. It feels like some of the guidelines were published before the ASTRRA study was really public and the data was available. So I actually have found that information extremely helpful in clinic as I’m offering OS to patients. I can see well, we can try it but if this is tough and if we have trouble, if we can at least get 2 years done, then we can feel good about that. I’m wondering if others are using that data and if they would consider that to also be appropriate.

DR LOVE: Seth?

DR WANDER: Yeah. Thanks, Erica. I actually wanted to also ask everybody, and I’ll show this data a little bit later in my section. One of the interesting things about ASTRRA too is when you look at the hazard ratios by age, the most benefit I think it was like 45-ish. Whereas the younger patients seemed to maybe even get less benefit. So one of the questions, and I think this comes up when you’re having the discussion with your patient, in addition to all the things that Bill mentioned, all of the different risk factors that have to come into play in terms of nodal status, Oncotype, all the other risk features, is the 2-year data for ASTRRA really to some extent focused primarily on those patients who are closer to perimenopause and that maybe that benefit wouldn’t be quite as clear for the much younger patients in their late 30s or in their early 40s. Are we kind of helping primarily those women who are in their kind of mid to late 40s? And this was something I was going to bring up later, but we can also chat about it now. It’s the same version of that question about the benefit of cytotoxic chemotherapy for those intermediate range Oncotype. The hypothesis would be that maybe it’s most in the women who are closer to perimenopause who are more likely to be shifted over into menopause and perhaps less beneficial to the women farther out from natural menopause who would be likely to regain their cycles after a few treatments of chemotherapy.

DR LOVE: So I want to get into Bill’s case, but this is such an interesting point that we’ve just raised. Virginia, any thoughts, again, in terms of duration of treatment?

DR KAKLAMANI: So this treatment is not easy for patients, and it’s definitely not easy for 5 years. And sometimes, I wonder is 3 months of chemotherapy worse than 5 years of ovarian suppression. And maybe it’s not. But I will try to get them to at least 2 years with my goal to be 5 years. Sometimes, we extend it past the 5 years for our younger patients. Because if you have a 35-year-old, and we know that these patients just because of their age, regardless of any other genomic issues, they have a higher risk of recurrence. And you give them 5 years of ovarian suppression, then first of all, they don’t want to go back to menstruating, so that’s one of the issues. And secondly, what do you do at those 5 years? If you’ve given them an AI, do you put them back on tamoxifen? Because now, they’re going to be premenopausal. So those are things in clinic that we deal with all the time, and we really don’t have any answers to.

DR MAYER: Yeah, I think that’s a topic that the Alliance is working on designing a trial. When you get to that 5-year mark and you’re still premenopausal, should you continue on ovarian suppression? And what I do now is I put people on tamoxifen. But you’re right, it’s like a yo-yo for the patient to be premenopausal and postmenopausal and the hormone swings that go with that.

DR LOVE: So again, before we get into this case, I just have to throw out to Seth. Any thoughts about whether cell free DNA is going to fit into this equation at some point?

DR WANDER: Yeah. Thanks, Neil. I think yes. Certainly, we’re going to add circulating tumor DNA in some of these MRD assays as they continue to become more mature into the list of factors that Bill was alluding to in terms of measuring risk. And I think this will allow us in a highly personalized way to start to think about who needs to go beyond 5 years, who might benefit from continued ovarian suppression. Might there be additional opportunities to add back in CDK blockade or risk reducing chemotherapy down the road similar to what they’re starting to do in models in GI cancer and colon cancer. And so I think we’re still a bit far away from that. We believe in the power of these MRD assays in terms of prognostic implications, but we have a ways to go in terms of determining their clinical actionability. But I do believe that this is an area where they will start to generate data and where this will help clinicians and patients make some of these difficult decisions around these transition points.

DR LOVE: Does anyone know whether or not people have looked at patients at the 5-year point on endocrine therapy to see if any of them are MRD-positive? Has that been looked at?

DR WANDER: I’m not sure that they’ve looked specifically at a cohort designed in this particular question which is, I think, a really interesting question about some of these very young patients who might be on the fence of going back into kind of pre- or perimenopause after pulling off ovarian suppression. I think we have very strong prognostic implications of these MRD assays across kind of early-stage breast cancer patients in general. And I think it’s an excellent question to look specifically at some of the intermediate or high-risk very young patients to determine kind of what interventions might be warranted. But I’m not familiar with that particular focus group of patients. I’m more familiar with the global data regarding prognosis for these MRD assays. But I suspect that that prognostic value would extend very much into that patient population. And then, you have some obvious actionability questions that could be interrogated.

DR LOVE: Yeah, seems kind of strange to have a positive MRD after 5 years, but I guess anything is possible.

Case: A woman in her mid 20s with HR-positive, HER2-positive intraductal carcinoma (IDC) who received ovarian suppression with TAC chemotherapy and concurrent trastuzumab/pertuzumab followed by tamoxifen

DR LOVE: Bill, I was so happy when I saw this case here because this is one of the things I think needs a lot more discussion, which is endocrine therapy in the patient with HER2-positive disease. So what happened with this very young patient, 25 years old?

DR GRADISHAR: Yeah. So when I met this patient, who I actually saw this week, she was a — she is a — well she’s older now but at diagnosis, she was 25 years old. She’s an attorney. It’s always nice to walk in the room and the daughter, the patient is there with her 2 physician parents, one of whom is an oncologist.

DR LOVE: Wow.

DR GRADISHAR: So in any case, she self-detected a breast mass. Her mother confirmed it. She underwent imaging. There was a 2-cm mass, no suspicious nodes. Again, the physical exam was consistent with what they had already observed. She got a core biopsy that was ER-, PR- and HER2-positive. Germline testing was negative. She elected to undergo bilateral nipple sparing mastectomy. And she was found to have a 2.2-cm infiltrating ductal carcinoma, 1 of the nodes was positive. And she was subsequently treated, this was a while back, several years back, with ACT chemo and concurrent trastuzumab/pertuzumab. And then I left open the question of the endocrine approach in this patient. I know what she got obviously, but if you wanted to discuss that.

DR LOVE: Yeah. So Virginia, maybe you can take a crack at it. So I guess this is in the preneoadjuvant days?

DR GRADISHAR: Correct. Yeah. This is, to be completely open, this is 10 years ago. So this —

DR LOVE: Okay, well, that’s great.

DR GRADISHAR: She’s now 36, I think.

DR LOVE: That’s great that we have that follow-up. So Virginia, how would you be thinking through a situation like this? And how do you think through adjuvant endocrine therapy in general in patients who are HER2-positive?

DR KAKLAMANI: So this is a subset of patients that we really need more data. We have data in the metastatic setting and combining anti-HER2 therapy with endocrine therapy, even CDK4/6 inhibition that seems very promising. But when you look at the adjuvant setting, these patients, even though they were included in some of these trials, there were not enough for us to have great information on. We also know that these tumors are driven mostly by HER2, but some may be also driven by ER. And I bet you if we did an intrinsic subset and intrinsic analysis, the tumors that are luminal would likely benefit more from the endocrine therapy that the tumors that are HER2-enriched. But we don’t have that data in the adjuvant setting. So this patient, I would talk to her about ovarian suppression even though there is lack of data, mostly because of that positive lymph node. And I’d definitely try to put her on an aromatase inhibitor if she decided to go with ovarian suppression. She’s too young. I don’t think that ACT chemotherapy would put her into menopause.

DR LOVE: So Erica, I’m kind of curious, again, how you think through adjuvant therapy. Do you like the idea in general of if you’re going to give chemo, probably you ought to be using ovarian ablation/suppression also, in general, ER-positive, HER2-positive?

DR MAYER: Yeah. As we know, our decision-making regarding recommendation for adjuvant chemotherapy has evolved over the past 10, 20 years. And the features that would lead us to recommend chemotherapy, be it a genomic risk score or here, the high-risk pathologic features or anatomic features, generally are quite aligned with the features that would predict risk and that also tend to influence our desire to escalate adjuvant endocrine therapy. So I would agree with Virginia. I would also be recommending the addition of ovarian suppression in this situation.

I’m thinking though, if we — so whatever Bill did was great because here she is 10 years later and she’s doing great. So we’re thrilled with that. But if she presented today and for a 2-cm HER2-positive, we’d probably be thinking about some sort of preoperative systemic therapy. Would her result at the time of surgery influence our decision-making for endocrine? If she had a pathologic complete response, would we think about some de-escalation of endocrine therapy or not? Personally, I might lean towards still recommending the same course, but my thresholds to make adjustments or to remove aspects of the endocrine plan might be different. But I think that nowadays, we’d probably have a little bit more information here.

DR LOVE: So I guess one piece of information that might be interesting to ask Bill about is the patient’s thoughts about future childbearing. Before he answers that, I’ll just mention. We were talking about this being 10 years ago. We just did a survey of investigators related to how they approach adjuvant treatment of HER2-positive disease. And we actually did a very similar study of investigators that we reported at San Antonio in 2019 as a poster in terms of what numbers they give to people and what they do in terms of the management of primary HER2-positive disease. And the interesting thing was the first survey, so we’re going to try to put something together for San Antonio this year to kind of compare what we saw in 2018 to what we’re seeing right now. But the interesting thing was we did the survey 1 month before the KATHERINE trial. And that was 2018. It seems like it was 20 years ago. So 5 years ago, people were not using neoadjuvant therapy. It’s not that old, right? It seems like it’s been around forever, but there it was black and white. People were not really — it was just about to flip. And obviously, the KATHERINE study is a lot of what happened. So Bill, I’m curious what happened, you know, 25 years old, what her social situation was, what her thoughts were about future childbearing and what actually happened.

DR GRADISHAR: Well, I can divulge that she has 3 children now.

DR LOVE: Wow.

DR GRADISHAR: So that tells you that she — and twins account for 2 of the 3.

DR LOVE: Wow.

DR GRADISHAR: So she was not, she was married but had no children at the time of diagnosis. She did get ovarian suppression during chemo. And then she started on tamoxifen because she was actually very eager to get pregnant afterwards. And that’s when she had the twins. And then she subsequently went on ovarian suppression, tried that with an AI. Did not tolerate it. And then went back to tamoxifen, got pregnant again. And then she’s done well since. She’s on tamoxifen right now.

DR LOVE: What an incredible story. What was the sequence of events when you gave her the tamoxifen the 2 times? How long had she been on treatment? How long was she off before she attempted to get pregnant? She was able to conceive without any additional support?

DR GRADISHAR: Yeah. To the best of my recollection, she didn’t need any fertility maneuvers to get pregnant. She was on tamoxifen for a couple of years at which point, she tried to get pregnant and was successful. And delivered, then went back on ovarian suppression. We tried an AI, she didn’t tolerate it. She went back to tamoxifen. And then downstream, she got pregnant again. And now is on tamoxifen alone.

DR LOVE: When she looks back over the last 10 years and you look back, how much of an issue was ovarian suppression when she got it in terms of tolerability or complications? Did she have issues?

DR GRADISHAR: Well, I think she felt menopausal. So in a very young woman, as we were discussing at the very beginning, those kind of issues can be very problematic. And she was willing to go along with it for a period of time, but her day-to-day life became very, for her as an individual, her day-to-day life became very problematic as time went on. So that’s why it was discontinued. And things like hot flashes were really becoming very prohibitive for her.

Case: A woman in her late 30s with HR-positive, HER2-negative IDC and no nodal involvement who received postoperative chemoradiation therapy followed by tamoxifen and is considering ovarian suppression

DR LOVE: So I always love it when investigators present cases. You all have such a phenomenal eye for fantastic cases. I love this next one. Bill, 38-year-old woman.

DR GRADISHAR: So this is a 38-year-old Hispanic female who presented with a large breast mass clearly evident on physical exam, mammogram showed the same. There were no palpable or visible lymph nodes on the imaging. She was still regular with respect to menstrual periods. Germline testing was negative. She had an ER-positive, HER2-negative tumor. The nodes were uninvolved. She had a skin sparing mastectomy, sentinel node biopsy with 5 nodes negative. And she received postop ACT followed by chest wall radiation therapy. And then started on tamoxifen. But again, we were doing this in a stepwise fashion. And the question of ovarian suppression.

DR LOVE: So Virginia, I’m curious, if this patient was interested in numbers. We have patients who are oncologists, obviously. What kind of numbers would you give to this patient in terms of what the additional absolute benefit might theoretically be by adding in ovarian suppression on top of tamoxifen in this very interesting case?

DR KAKLAMANI: So this is a tough one. And actually, my colleague just called me a couple of hours ago to give me a very similar case, a 5.7-cm tumor lobular carcinoma, and asking me, should I give her chemo? Should I not? She’s 42 years old. And we’re having this whole big discussion about, should I order a genomic assay or not? And Bill here didn’t, which I typically do, but for these young patients with larger tumors, there’s 2 issues. First, they’re young and the data is not, not a lot of data in women under the age of 40. And then, 5.1 cm tumor. Again, not a lot of data in T3. So this tends to become an issue.

So as far as the benefit from ovarian suppression here, this is a patient that received chemotherapy, and so in the higher-risk group based on SOFT and TEXT. And so I’d probably give an absolute benefit of maybe 5% or so.

DR LOVE: So you mentioned also the other case of lobular. I had actually just written that down, Erica. We were contacted by an advocacy group. I didn’t know there was an advocacy group that focused on lobular cancer. And I talked to them and it really made a lot of sense. They felt like nobody is studying our disease. They all tell us we have ER-positive, HER2-negative disease, but we know it’s different. So is it different? For example, in this situation, Erica. And do you think, you know, I was thinking to myself, in order to kind of get separated out, they kind of need a marker or some treatment that’s unique to lobular which I guess there really isn’t at this point. But any thoughts about lobular, Erica?

DR MAYER: Yeah. I’m really grateful for the breast cancer advocates who, in particular, there’s a few who are really such amazing leaders in trying to push the topic of lobular breast cancer. We, of course, enroll patients with lobular disease on trials, but we don’t have trials specifically for lobular. So it’s very hard to look at our existing research databases and say things with statistical strength and power about what our expectations are specifically for patients with lobular cancers. We do know that these are cancers that are very endocrine driven and so they tend to be quite sensitive to endocrine therapy and less sensitive to chemotherapy. We also know that you can send genomic testing, that the tests are valid and that they work for lobular just the way they would work for ductal or other subtypes.

And so when I am taking care of someone with lobular disease, I do think that genomic testing is very helpful to really try to clarify if there is a reason to be considering chemotherapy or not. And if not, I do think these are situations when in particular, I do like to lean into a more comprehensive endocrine plan which may, in a younger patient, include ovarian suppression.

DR LOVE: So, Bill, what’s the follow-up to your patient? And I don’t know what the timing was in terms of her case, but what was your thinking in not getting a genomic assay?

DR GRADISHAR: Yeah. So she did have a ductal carcinoma. We were seeing her as an opinion after the chemotherapy. So we’re still negotiating with ovarian suppression. She’s on tamoxifen, tolerating it well. So we’ve talked to her about ovarian suppression as a possibility for further decreasing risk, but we haven’t sealed the deal yet.

DR LOVE: Do you think even at this point, a genomic assay or an Oncotype would be helpful, Bill? If she were lower risk, would you be more comfortable sticking with tamoxifen?

DR GRADISHAR: Yeah, it might help. But I guess I don’t want to find out that the chemotherapy shouldn’t have been given. That would be a little bit of a problem, I think.

DR LOVE: Well, a 5-cm tumor, though. It may be reasonable to think about it.

Role of OFS in Preserving Fertility and/or Ovarian Function in Premenopausal Patients — Dr Mayer

DR LOVE: Alright. So we’re going to move on to 2 specific areas where we’ve seen a lot of interesting data over the last few years, really having a big impact. Thinking about this woman now with 3 little children is really a great thought that she was able to survive the treatment and have a family. Fantastic situation there. But we’re going to move forward a little bit. And Erica, I thought you’d be interested in some of the things that we asked, particularly because Ann was part of this survey, in terms of sort of the POSITIVE strategy that you’re going to talk about in a second.

So we asked about a couple of situations. First, lower-risk localized breast cancer and whether or not people have had situations like that where they’ve stopped therapy and had the patient try to become pregnant. And I think with the POSITIVE data, pretty much everybody. And I think at this point, even in general practice, it’s now a very common issue.

But some of the specifics from the trial that Erica is going to talk about, it was interesting to ask in terms of what people are actually doing. How long would they keep the patient on hormonal therapy before they would discontinue it? Most people are saying a couple of years. Komal Jhaveri, 5 years. Interesting, Kathy Miller, proceed to pregnancy with delayed hormonal therapy in a couple of patients. An interesting thought.

And then, how long would you feel comfortable in this situation, again, low-risk remaining off hormonal therapy? And everybody says 2 years. I guess also, I’d be curious to know what the pregnancy rate was. It was pretty high, I guess, in the POSITIVE trial. So Erica, so far, so good?

DR MAYER: Yeah. Yeah, that looks great.

DR LOVE: Okay. Well, here is where it gets interesting. Multiple positive nodes. I was kind of surprised. I guess the issue comes down to, again, I guess informed decision-making to the patient about the possibility of having metastatic disease and a pregnancy and a new child in that situation. Very difficult. But in general, people say they would consider it. I guess bring it up to the patient as a possibility.

A similar thought. Sara says she’d wait 3 or 4 years. Interesting thought also. And then, again, a couple years off, as well. I’ll come back to Seth. I was kind of surprised people would. On the other hand, I guess it’s the patient’s decision. But any thoughts about the POSITIVE strategy in people with high-risk disease?

DR WANDER: Yeah, I agree with the consensus from what you demonstrated there. I can think of all 3 scenarios occurring in my own clinic. I’ve had a number of patients, small number but very low-risk disease who might be closer to 40 years old who maybe haven’t had a child yet or really would like to have a child who would like to delay initiation of hormonal therapy for pregnancy. I think that’s a really important and sort of difficult informed consent decision because, of course, there, you’re not getting the 2 years under your belt that you would like to get. In the other kind of lower-risk scenario, I think based on the data that you’re alluding to and the data that Ann has shown, trying to get 2 years under your belt and then take a break for a year or 2 to go to pregnancy and then come back on hormonal therapy is something we do fairly routinely. I think the last scenario you showed is the most difficult, where you have the higher-risk patient who maybe has multiple positive lymph nodes. And again, this is patient-centered decision-making, risk versus benefit, thinking about how much treatment you can get on board. Ideally, the closer you can get to the 5 years in that scenario, I think would be better.

But you also have to think about I’m thinking of a patient, I didn’t use this as a case because of the topic that I have later, but I’m thinking of a patient that I take care of who she had a Grade 3 ER-positive locally advanced tumor with at least a couple of positive lymph nodes. She got preoperative ACT, had a complete response. This was HER2-negative. She’s young, she has 1 child. They already had banked eggs previously and are thinking strongly about taking a break for pregnancy. She’s going to do her 2 years on ovarian suppression, AI and abemaciclib based on monarchE. And then the question becomes after the 2 years, now with the CDK inhibitor, additional risk reduction, how do we feel in this patient who fits the high-risk profile but who had a path CR? So I don’t want to derail the conversation, but I think that fits in really specifically to that last scenario that you were just alluding to.

DR LOVE: So Virginia, part of the issue, and important part of the issue here, obviously, is the health of the patient. But to me, another issue is the future life of the child. I don’t know if you’ve had patients who attempted and conceived while having metastatic disease. But any thoughts about this situation and I guess the scenario of a person being born who is going to go through the death of their parent? Not that different than the idea of somebody, an older person who wants to have a child, in a way. Any thoughts, Virginia?

DR KAKLAMANI: This is difficult and our bias comes in, but we have to suppress it because this is the patient’s wishes. And so to me, what I typically do is I try to be as honest as I can about the risk of recurrence. But I don’t overstate it. I don’t discuss it ad nauseam because these women are very motivated to go on with their lives. And I think as long as you feel that they’re understanding of the potential risk, then it’s okay.

I’m reminded of a patient I saw years ago, 16 years ago, who was diagnosed with breast cancer right around delivery. She was having back pain when she was pregnant. Of course, she thought that this was pregnancy related. Her husband is a physician. And right before she gave birth, she was found to have metastatic breast cancer. HER2-positive, ER-positive as well. Not only is she still alive and doing well with HER2-positive metastatic disease and brain metastases, her son is doing amazingly well, getting ready to go to one of the premier colleges. I think, Erica, he’ll be joining you over there.

DR LOVE: Wow.

DR KAKLAMANI: So these are things that you think about. And had you told me that 16 years ago, I would have said that there’s no way. And now, this is one of the scenarios that help me suppress my bias.

DR LOVE: Interesting.

DR MAYER: I think that’s a great point about our bias versus the patient’s needs and goals. Because I actually had a dear patient pass away recently who chose to have a baby after her diagnosis of metastatic disease with a surrogate. And full disclosure, I felt uncomfortable a little bit at the time thinking, do you really know what’s going on with your health? But this was like 10 years ago. And with the advent of new therapies for metastatic disease, we got a decade of therapy. Moreover, her greatest accomplishment in her life, as she told me in our last few visits, was being a mom and having that opportunity and being able to raise a child. And she took such great comfort from that. And I thought, you know, it’s not my decision. It’s her decision and I respect it.

DR LOVE: Yeah, this is really getting me warmed up for ONS because we spend a lot of time, a lot more time with it than with the docs on these kind of issues. I really enjoy it.

One final question back to Bill about, you know, I pointed out that situation where Sara waits longer. What about that strategy? Your patient had a 10-year history. She was only 25. I guess if she had waited 5 or 7 years, she still could have conceived. Any thoughts about as the risk increases, delaying the time you interrupt their hormonal therapy?

DR GRADISHAR: So if the question is, would we in a higher-risk patient push them to delay getting pregnant or trying to get pregnant?

DR LOVE: Yeah.

DR GRADISHAR: Yeah, I think, as Seth was saying, as we approach what we view as the optimal duration of endocrine therapy, I think our level of comfort with encouraging someone to go forward with a pregnancy goes up. We just feel more comfortable with it. And for a lot of all the reasons that Virginia and Erica were talking about. We want to make sure the patient is as much out of the woods, so to speak, as we can be. And recognizing that in ER-positive disease, you can get late recurrences. But still, the farther down the road you are, the better.

DR LOVE: Alright. Well, let’s go back and take a look at some data. Erica put together a great presentation here looking at ovarian suppression to preserve function and also to allow pregnancy.

DR MAYER: Super. Thanks so much. So I was going to talk about 3 topics. The risk of infertility when we give cytotoxic chemotherapy, the role of ovarian suppression during chemo to help maintain fertility, and as we’ve been discussing, the safety of pregnancy after a breast cancer diagnosis.

So one of my dear colleagues, Phil Poorvu, had a very nicely publication a few years ago really summarizing risks of treatment related amenorrhea with our common breast cancer treatments. There’s a couple trends that are important in this slide. First of all, we can see that the rates of amenorrhea at either 1 year, on top, or 2 years, on the bottom, are variable based on the regimen that a patient may receive. And in general, the longer duration regimens such as ACT or TCHP are more likely to lead to temporary or permanent amenorrhea. On the flip side, a lighter regimen like TH with weekly paclitaxel is minimally likely to cause amenorrhea, only about 10% at 1 year out, so very minimal impact. And these rates also vary based on a woman’s age. For our youngest patients who are 30 and less, the rates of permanent amenorrhea tend to be quite low. Although as women enter their 30s and up to age 40 in this analysis, the rates increase. So when we’re thinking in that first step, what is the risk of infertility with chemotherapy for an individual patient? We want to be thinking about what is the proposed chemotherapy regimen, and also their age and how that impacts her risk.

This is similar data from a different cohort. This is 1,600 women. And we can look at early, late or very late as shown by the colors in the bar graph. And I think what’s very interesting here is you can see in the women less than 40, the vast majority will recover menstrual function either early or late, but we do see pretty good rates of recovery. But there’s a hinge point here at age 40. And patients who are older than 40, very few are regaining menstrual function. And so when we’re thinking about what our risks are for individual patients, we can think about the sort of 35 to 40 years old as really where that hinge point begins.

And so this is so important for our patients because many women are delaying pregnancy in our modern times including many of our friends and family and colleagues. And a breast cancer diagnosis, particularly in one’s 30s, can really impact fertility and family planning. It’s so important for us to discuss this with our patients in their very first visits. We’ve done surveys through the Young Women’s Breast Cancer Study asking patients about their thoughts about fertility. And we learned that about one-third of patients at the time they’re diagnosed with breast cancer, these are women less than 40, they want to have more children. And at least half the patients who walk through the door are concerned about risks of infertility. And if we don’t ask, we may not actually hear these risks from patients. So it’s very important that this is part of the initial conversations. And I think something that has become very much part of our routine practice is a referral to reproductive endocrinology for patients who are interested in fertility preservation. And I think many cancer centers around the country have this kind of baked into the way that they see the youngest patients.

We’ve had guidelines from ASCO that were initially published almost 20 years ago and they’ve been updated a few times with recommendations on fertility preservation. And this goes in several steps. Assessing the risk for infertility, communicating that to a patient, talking with the patient about fertility preservation options, and then referring patients. And we can see that the modalities that we can use for fertility preservation have evolved over time including things that must be done by reproductive endocrinology such as embryo or egg preservation. There’s some very cutting-edge work going on now looking at removal of ovarian tissue itself and preserving that. And then most recently, in 2018, we have the advent of ovarian suppression. So this is a tool that we as medical oncologists can do ourselves in clinic with our patients.

So why does this work? So temporarily providing ovarian suppression with a GnRH agonist will reduce ovulation. It’s basically allowing the ovaries to sleep during the treatment. It’s possible this may reduce apoptosis. It may increase germ cells. But we do know from a variety of studies that this is an effective tool to use to help maintain fertility. Importantly though, this doesn’t replace cryopreservation. So for a patient who is highly motivated for fertility preservation, we certainly can do this. It’s very easy for us to do in clinic. But this doesn’t mean we shouldn’t also be referring them for reproductive endocrinology consultation.

There have been a variety of studies that have prospectively evaluated the role of concurrent GnRH agonist during chemotherapy versus not. Some of the largest include the PROMISE-GIM6 study, that’s an Italian study led by Mateo Lambertini, and the POEMS study that was led by Halle Moore. And in these studies, the GnRH agonist used could be either triptorelin or goserelin. In my clinic, I use leuprolide. And in general though, what’s important is that it’s supposed to be started before you start the chemotherapy. It takes a little time for these drugs to kick in. And so in these trials, the start time was at least a week or even 2 weeks before the initiation of chemotherapy. That’s ideal. Sometimes, it doesn’t work out that way. But that’s what is recommended. And then it’s continued through the last dose of chemotherapy. And then, at least for hormone receptor-negative disease, it could be stopped. For hormone receptor-positive, then we merge into Bill’s consideration of, do we continue ovarian suppression?

And so there’s been a meta-analysis that’s looked at all of these studies to see how effective this strategy is. If we consider the figures to the right, we can see that the use of concurrent GnRH agonist significantly reduces the chance of chemotherapy-induced premature ovarian insufficiency. It reduces the rate from, in the meta-analysis 30%, in the control arm to 14% in the treatment arm. So that’s like a 60% reduction in the risk of amenorrhea. And that’s really quite substantial and amazing that we can accomplish this in our clinics pretty easily. In the subgroup analysis, this appears to work in all of the subgroups including younger versus somewhat older women, ER-negative versus ER-positive, regardless of chemotherapy regimen, shorter versus longer chemotherapy. So this is a tool that’s available for all of our patients. Pregnancy rate was practically doubled in the patients who received GnRH agonist, up to 10% versus 5% with control in our younger patients. And I really like the use of pregnancy rate as one of the primary endpoints of these studies. That’s a much more tangible endpoint than return of menses, particularly when we’re thinking about this for fertility preservation.

And we’ve just seen some longer-term follow-up from the Italian PROMISE-GIM6 study at 12 years. I think this is important if we’re concerned in any way that this sort of concurrent use of an endocrine maneuver and chemotherapy, if this could have any adverse outcomes for patients in terms of breast cancer-free survival. And we can see overall survival for all patients including hormone receptor-positive and hormone receptor-negative is fairly identical. So I think we can feel pretty confident that this maneuver is not exposing patients to any decrement in efficacy of their other aspects of breast cancer treatment.

Now I had originally planned to talk about some of the side effects of treatment but actually, I think Virginia is going to cover this in detail. I would just point out that we know that ovarian suppression can cause vasomotor side effects, insomnia, long-term exposure can cause osteoporosis. These are a little bit more relevant for long-term exposure than the short-term that’s used for ovarian suppression.

We do know these can improve with time for patients who are on these therapies long-term, both in terms of specific PRO reports of toxicities as well as global quality of life.

And then this brings us to another important topic which we were discussing. And I love how our first case really leads into this. But the question we all face in clinic, is it safe to get pregnant after a breast cancer diagnosis? And it’s interesting that so many of our questions in medical oncology we answer through very elegant randomized clinical trials. But this is a really important question that you cannot answer through a randomized trial. We cannot randomize our patients to pregnancy versus not. But we do have the benefit of decades of publication of cohort studies looking at patients who chose to get pregnant and comparing them to carefully selected controls to try to determine if there’s any apparent adverse outcome from choosing to get pregnant. As you look across these studies, I think it’s interesting to see the first one was from 30 years ago. And this was a small study, just 23 patients. And the most recent study from 2022, almost 1,000 patients. So over time, we are getting better and better at studying and trying to answer this question. But reassuringly, what we see from this is that there is no signal that in these patients who chose to get pregnant that they’re having an adverse outcome compared to those who did not.

And the very interesting observation that comes out of this is that for the hormone receptor-negative patients on the right, it’s almost as if there’s a protective effect of pregnancy. Those patients actually have a significantly improved outcome compared to those who didn’t. Now some have proposed maybe there’s something about getting pregnant that treats the breast cancer. I’m not sure if that’s the case but perhaps it’s a little bit more what’s called healthy mother bias, that the patients who choose to get pregnant on some level, they and their providers feel comfortable with them moving forward with this decision versus patients who choose not to. For hormone receptor-positive, there does not appear to be any benefit or decrement. It’s no difference. However, I will add that many of these patients had actually finished their planned 5 years of adjuvant endocrine therapy. And that’s quite different than our modern use of endocrine therapy where we have patients on for 5, 7, 10 years.

And so this is the background that led to the development of the POSITIVE study, a study that was led by my colleague, Ann Partridge, as part of the IBCSG. This was a really important global study that enrolled premenopausal patients who very importantly wanted to be pregnant. They had to be 42 years or less. And importantly, the time period of eligibility was patients who had been on adjuvant endocrine therapy for at least 18 months, but no more than 30 months. And they could have Stage I to III breast cancer, and no clinical evidence of recurrence.

This is the procedures for the study. And I think this figure is really nice to remember because it really provides a lovely framework for how we can approach this with patients. Patients who were eligible and who enrolled in this study were allowed a 2-year break to attempt pregnancy, conceive, deliver and breastfeed. This also includes a mandatory 3-month washout from the prior endocrine therapy. If they did not get pregnant in a year, it was recommended to have a fertility assessment. Once the 2 years were done, the patients were strongly recommended to resume their adjuvant endocrine therapy and then went into long-term follow-up.

So of the 500 or so patients who enrolled in the study, at least 74%, so, like, three quarters of patients, were able to get pregnant. And of those pregnancies, close to 90% resulted in a live birth. So about 64%, two thirds of patients who entered the trial, had a pregnancy that resulted in birth, 317 babies. I don’t think there’s any other breast cancer study that has either this kind of endpoint or when you think about 317 babies of breast cancer survivors, it’s like the happiest endpoint ever. So overall, this was a highly successful maneuver.

Additionally, the POSITIVE investigators tried to study, is this a safe thing to do? And this was a single arm study. There was no control arm. But they used matched patients from SOFT and TEXT, so a pretty contemporary group of young patients. And at least at 3 years, there was no significant difference. I think we’d all acknowledge that hormone receptor-positive breast cancer has a long natural history and that longer-term follow-up is needed to really understand this better. But at least in the short-term, I think we can feel quite good about the results from this study.

More recently, at San Antonio, we had a nice update from POSITIVE that was specifically looking at patients who had undergone embryo or egg cryopreservation, and looked at the patients who used assisted reproductive technology including ovarian stimulation to get pregnant. There was 179 patients in the group who did and 318 who didn’t. And when they compared outcomes in terms of breast cancer recurrence, there were no significant differences. So this also provides some help for our patients. If they need to use IVF to get pregnant using their preserved eggs or embryos, this also appears to be a safe and feasible thing to do. So I think we’re going to expect to see much more coming out of POSITIVE looking at all of the nooks and crannies of the study. But really, one of the most remarkable studies that we’ve had in breast cancer in the past few years.

DR LOVE: I just wanted to pick up on the issue, you know, Seth, we did a great session together. We went through a lot of the endocrine biology of breast cancer which was very informative to me. I’m still thinking about it. But I am curious too what your thoughts are on the endocrinology of pregnancy, Seth, and how that fits into your vision of breast cancer biology, recurrence risk, et cetera. In the past, high-dose estrogens were used, high-dose progestins. Any biologic rationale whereby in some way the endocrinology of pregnancy would be actually beneficial, Seth?

DR WANDER: Yeah. Thanks, Neil. I think it’s a really interesting question. And the data that Erica just alluded to is also really fascinating, particularly the hormone receptor-positive versus -negative and the impact of pregnancy. I think you’re right in the sense that there may be some selection biases to kind of who those patients are that go on to get pregnant, particularly in the ER-negative group. For the ER-positive group, big picture, we’ve always thought about in medical school and kind of early on in fellowship, you learn these epidemiologic risk factors for breast cancer, right? And sort of early menarche, late menopause, nulliparity means longer or larger lifelong estrogen exposure increases risk. And obviously, the more pregnancies you have, the more time you’re pregnant, the lower the estrogen state for most of that pregnancy. So perhaps it’s similar from a biologic perspective to kind of estrogen deprivation. If you’ve had multiple pregnancies, for most of those pregnancies after the first number of weeks, it becomes a low estrogen state.

I think the kind of more nuanced and interesting question is at the level of sort of molecular biology or signal transduction. What’s happening to those microscopic cancer cells during pregnancy? Is it simply that like ovarian suppression or like aromatase inhibitor, you’re taking away total body estrogen and you’re depriving those cells of the signal that they need? Or is there likely some more complicated endocrine milieu that’s altering the wiring of those cells and perhaps promoting dormancy or promoting apoptosis or slowing outgrowth or spread or something like that? And I think we don’t really know the answer to that question.

From a lot of really interesting biology done in xenograft models, we know that even very small breast cancers, if you extrapolate for mice that can form breast tumors in the mammary fat pad spontaneously and then you look at the bone marrows of those mice when the tumors are very small, they haven’t spread to regional lymph nodes, you can find individual cancer cells that have escaped those tumors if you were to extrapolate to sort of a human much earlier than we would otherwise anticipate. And what allows those tumors cells to spread? What allows them to survive? First, probably in the bone marrow and then go on to someplace else. And how something like pregnancy or some of the other maneuvers we’re talking about impact that, I think is still a really open question in terms of the relevant biology. But it is interesting and I think it starts with an understanding of total estrogen lifetime exposure. And then eventually, it needs to get to the point of understanding what’s happening within the cellular machinery both during, before and after pregnancy.

DR LOVE: I was just flashing on some of the conversations I’ve had over the years with Rowan Chlebowski about the Women’s Health Initiative and postmenopausal hormone replacement and that whole scenario, the biology there that they hopefully learned a lot about.

Case: A woman in her early 30s with HR-positive, HER2-positive (IHC 3+) IDC recommended to receive perioperative TCHP who is interested in fertility preservation

DR LOVE: Alright. Let’s get back to clinical reality here. A 33-year-old woman. What happened with her, Erica?

DR MAYER: So this was a woman I met pretty recently, 33 years old. She presented to her gynecologist with a right breast mass, which was 4 cm on imaging. She had at least 2 abnormal axillary nodes. So she had breast and ax biopsied, and she was found to have invasive breast cancer, Grade 3. ER-positive, PR-positive, HER2 3+. MRI confirmed that she has locally advanced disease. So she’s been recommended to receive preoperative TCHP chemotherapy.

And so I have a very specific question on the next slide but I guess I’d put out there, how would people approach fertility preservation in this setting? I will say that she has a boyfriend, but not married, a boyfriend.

DR LOVE: So Bill, it’s another HER2-positive patient going to get preoperative chemo HER2 therapy. Any thoughts about Erica’s question concerning endocrine treatment?

DR GRADISHAR: Well, we would typically have someone like this see the onco fertility folks which is not an effort to not answer the question. But the 2 things that we would be thinking about is obviously, giving her a GnRH agonist, trying to make the ovaries quiescent. And then the other issue that would be potentially addressed is egg harvesting. So those would be the things that we would consider.

DR LOVE: Erica?

DR MAYER: Yeah. So that’s exactly what we were thinking. So she’s interested in fertility. And it’s interesting about the egg harvesting versus embryo as I’ve had issues over the years with patients who choose to do egg versus embryo and if their relationship remains stable or falls apart in the years after diagnosis, that creates really complex ethical topics.

DR LOVE: Wow.

DR MAYER: But anyway. So this patient, we refer her to onco fertility and she does her cycle of IVF and she preserves eggs. And we’re going to give GnRH. And a very technical question. When would we want to start this?

DR LOVE: Virginia?

DR KAKLAMANI: Erica, as you mentioned, on the studies, at least 1 to 2 weeks before chemotherapy. And I try to shoot for the 2 weeks. Now this is a case that you’re already delaying chemotherapy for onco fertility even though our colleagues are just absolutely amazing at doing what they’re doing in a couple of weeks. But still, by the time you send them to see them, that’s another week, right? And then at some point, you have to put in a port, you have to do an echocardiogram, and this might delay treatment as well. So those are all very day-to-day issues. But I would try to do a couple of weeks if I had the luxury to do that.

DR MAYER: Yeah.

DR LOVE: And, of course, again, patient involvement in the decision is also probably helpful where it’s challenging.

Case: A woman in her mid 30s presenting with ER-positive, HER2-negative breast cancer during early pregnancy who received preoperative TAC and had pathologic complete response at surgery

DR LOVE: How about your other case here, the 35-year-old lady?

DR MAYER: So this is a patient from a few years ago who came to me at age 35. She had a clinical T2N0 breast cancer, high-grade, ER-positive, PR-negative, HER2-negative, and she was pregnant. Her tumor was 4.7 cm on imaging. She was pretty early on in the pregnancy. And we gave her preoperative ACT chemotherapy. Then, she had surgery. And thankfully, had a pathologic complete response and had a healthy baby. So she was initiated on ovarian suppression and aromatase inhibitor. After a couple of years, of adjuvant endocrine therapy, she came in and she wanted to talk about, what is the safety of getting pregnant? How can I get pregnant? I’m ready. And so I wanted to talk a little bit about navigating that conversation with her.

DR LOVE: Could I also ask how often you see patients get a path CR from a 4.7-cm ER-positive, HER2-negative tumor?

DR MAYER: Not often. But this is that high-grade luminal B type of ER-positive breast cancer. So yeah, this was surprising and a happy surprise, but not the typical thing we would see with like a luminal A, ER-positive breast cancer.

DR LOVE: So Seth, any thoughts about the questions here?

DR WANDER: Yeah, this was reminding me of the patient I was thinking of earlier who had a locally advanced Grade 3 tumor. And I agree with Erica, it probably comes down to the intrinsic subtype and the fact that, the fact that she has a path CR, I’m thinking about my own patient, makes me feel a little more comfortable about potentially taking this break. I still think we are living in the paradigm from the POSITIVE trial and from some of the data that Erica just went through and some of the questions we looked at earlier. Remind me, Erica, how long has this patient now been on?

DR MAYER: 2 years.

DR WANDER: Okay. So I would feel a little more comfortable now that she’s kind of 2 years in, we have data from the POSITIVE trial, she had a path CR, thinking about taking the break. But again, it’s still a patient centric decision. It’s still really important to have these discussions about understanding risk versus benefit, understanding the fact that recurrence risk could theoretically be higher, particularly for patients with higher-risk disease. Though here, you had a patient without positive lymph nodes who had a complete response to chemotherapy who got 2 years under her belt. So for those reasons, I think I would feel fairly comfortable if she understood all of the caveats that we’ve been discussing today, thinking about taking the break for 1 to 2 years and then trying to come back on and finish the 5, maybe even up to 7-plus years of treatment.

DR MAYER: Yeah. And then another feature here is because she presented when she was pregnant, she did not have the opportunity to bank eggs or embryos. So now, she’s 37 and time is ticking and she’s well aware that her eggs are getting older. So she’s been putting pressure on me, you know, like I’m worried, I don’t want to wait until I’m 40 years old to be pregnant. And I think sometimes knowing if you have those kind of young eggs preserved colors a little bit patients’ ability to kind of wait versus feeling like they want to move forward with things.

DR WANDER: So Erica, with that in mind, if it had been a year, if it wasn’t 2 years, how would you feel about it?

DR MAYER: I feel like as we are data-driven providers, I have to sort of look to the data that guides us. And I think we saw that in the survey of our colleagues that 2 years tends to be the number that most people feel pretty comfortable with. That being said, as we know, patients are going to do what they’re going to do. And sometimes, people will try to get pregnant sooner. But an important thing is that when they are trying to get pregnant and if they do it outside of our recommendations, we have to at least make sure that they’re doing the appropriate washouts. And so in advising her, for this patient, at 2 years, I’m going to be saying it’s okay to get pregnant but I really think we have to make it very clear that they need a 3-month washout on their therapy. And with ovarian suppression, you need at least 3 months, if not longer, to see resumption of ovarian function, depending on how long people have been on it. But I think for those patients who want to accelerate the timeline, they at least need to make sure that they’re following the washout guidelines.

DR WANDER: I’ve found in my own experience that it’s been really helpful to begin these conversations very early. I’m thinking of the last few patients that I’ve run into this with. And we’ve begun discussions about even thinking about trials of fertility shortly after the initial diagnosis and maybe completing chemotherapy. Obviously, the egg banking point comes up immediately. But I find that sort of drawing this discussion out over a prolonged period of time helps the patient and the partner start with the family planning and work with the reproductive endocrinologist if they’ve already banked eggs and things like that. And it’s a lot less stressful if you’re looking way down the road like 6, 12, 18+ months saying okay, this is the date that we’re thinking about taking the break, and it’s not kind of a last-minute thing. And it sounds like in this case, you had, the patient had the opportunity to kind of plan ahead knowing what she was interested in doing.

DR LOVE: We’re going to move on in a second, but I just want to finish out this section. If you maybe could just paint a little bit more of a picture of this woman so we can get a better feel for what her values were, how important it was for her to get pregnant, maybe what her occupation was, kind of what the picture was.

DR MAYER: Yeah. This woman is, she’s really delightful. She works at the Boston Museum of Science as a science educator. And so she loves her job and she loves teaching kids. And she got pregnant, her first pregnancy at age 35, which, in our world of professional women, is not that old but in the world of gynecology, Ob/Gyn, it’s a little old. And so being well aware of the fact that she was already starting with a later pregnancy and then time is ticking, I think was part of why she was, I wouldn’t say putting pressure on, but really wanted to talk about this extensively. But I think Seth’s point about bringing this up early and having multiple conversations is good. And sometimes, you just don’t have time in your regular visit so you have another visit just to talk about this topic because it’s really important for people. And I don’t want to have someone feel like they’re short-changed and not really taking the time to listen.

DR LOVE: So I wonder what this woman’s scientific background is. Did she actually go through the literature? Was she familiar with the numbers? Did she have a good feel for what the deal was?

DR MAYER: One of the wonderful things about practicing in Boston is we are surrounded by universities and biotech. So patients routinely bring in the numbers and the papers and everything, which I love. And so yes, so she had looked at a lot of the papers herself. And we read the POSITIVE paper together in clinic.

DR LOVE: Wow, wow. Cool. I like it.

Tolerability and Toxicity of OFS — Dr Kaklamani

DR LOVE: Alright. Tolerability/toxicity. And you know I think one of the things we like to think about in our work in general is we engage obviously in very high-level discussions, but also we keep in mind that a significant fraction of our audience is within 10 years of starting oncology. And in fact, we get a lot of use by fellows. So keep them in mind with these issues that maybe an experienced oncologist has a lot of experience with, but a fellow might not. I just want to chat a little bit, again, before we sort of get into data in terms of what you all do in your practice. I’ll start out with you, Bill. This is a question we asked in terms of vaginal dryness and dyspareunia, most people are using lubricants and moisturizers. What’s your experience with it, though, Bill, in terms of how effective lubricants are? What about using, do you ever consider, and we ask this later, postmenopausal hormone replacement? And anything else you want to say about this clinical issue?

DR GRADISHAR: Well, we usually discuss any of a number of the different lubricants and emollients. And some patients, as you well know, don’t like them. They don’t like applying them or using them. Others don’t seem to have an issue with them. And equally important, they’re not always successful for everybody in terms of making the experience more pleasurable than it was. So I think it’s a mixed bag. We certainly start with that though. Those are the things we start with. And I know one of the comments, at least on the prior slide, was laser therapy. We haven’t really embraced that fully. I think the data is a little bit more lacking there, but I know some providers do do that.

DR MAYER: It seems to only be our friends who are providing care in California.

DR LOVE: What is it, laser treatment? What do they do there?

DR MAYER: It’s a machine that does, I think it’s supposed to stimulate tissue regrowth. But I agree with Bill, I think the data has been very controversial. But there are some economic implications to purchasing and using these lasers.

DR LOVE: Interesting.

DR WANDER: I agree, we’re not routinely using that either.

DR GRADISHAR: And I don’t think it’s covered by insurance.

DR LOVE: I’ve never heard about it. Virginia, any thoughts about this question, are there situations where you would use hormone replacement therapy in a patient with a history of breast cancer? Most people say no, but there are some suggestions. BRCA cancer previvors. Anyhow. Virginia, any thoughts?

DR KAKLAMANI: I think in my triple-negative breast cancer patients, I’d feel more comfortable even though that is even an area that we haven’t studied well. We know that these patients may potentially have a higher risk of developing another cancer, and might be ER-positive, who knows? I had a patient the other day who is triple-negative asking me about getting oral contraceptives for contraception because she finished her treatment, she had a complete response. And that very simple question led to a 10-minute discussion on the fact that even that we don’t have data on. So I typically don’t recommend any hormone replacement therapy unless a patient has triple-negative breast cancer and they’re pushing quite a bit.

DR LOVE: So Erica, what’s the thinking of a BRCA carrier previvor? Oh, they don’t have breast cancer.

DR MAYER: It would be —

DR LOVE: So these are BRCA carriers who — yeah.

DR MAYER: Who’ve had their prophylactic oophorectomy. So they’ve become menopausal. And now, the recommendations are to consider doing that at age 35. So it would be those people. But in a BRCA carrier with a history of breast cancer, then I think that becomes more controversial.

DR KAKLAMANI: And the other issue is that you’re doing an oophorectomy and decreasing the breast cancer risk. If you give hormone replacement therapy, you’re probably not decreasing the breast cancer risk anymore as much. But I think even in that case where patients have not had a bilateral mastectomy, it may be worth considering giving HRT because subjecting a 35-year-old to permanent menopause is not pleasant either.

DR LOVE: So Seth, any other thoughts about complementary strategies that might be utilized? I was just flashing on, you know, at your institution, Jennifer Temel did a study that showed survival benefit of palliative therapy in people who’d just been diagnosed. I remember Tom Lynch who was the head of the MGH program at that point said if this were a drug, we would be giving it.

DR WANDER: Yes.

DR LOVE: And I guess my question is, are there any complementary strategies that really, there may be really good data on some of these strategies?

DR WANDER: Absolutely.

DR LOVE: I just would love to see more on that. But what do we know about it right now, Seth?

DR WANDER: Yeah. I think this is a hugely important topic that, as everybody has alluded to, comes up in clinic constantly. We’re having very long discussions about different forms of hormone replacement. And in my own practice, I really try to shy away almost in virtually all scenarios of systemic hormone replacement. That’s like nails on a chalkboard to a breast oncologist, right? Any form of systemic supplemental estrogen. I think it’s a bit less controversial when you’re looking at topical estrogen. We talked a little bit about trying to maximize nonhormonal topical vaginal estrogens. And then if you need estrogen-based topical agents, we typically say to use the smallest possible duration — smallest possible amount for the shortest possible duration to alleviate symptoms.

I think, Neil, your question here is in addition to that, what other sort of nonpharmacologic lifestyle things. Of course, we have options and I’m sure we’ll hear about this from Virginia in a minute about SNRI therapy or gabapentin or oxybutynin, supportive maneuvers principally for hot flashes and things like that. We tend to use, we have kind of a wellness program, a survivorship and sort of mind/body opportunities with graded exercise programs we’ve had a lot of success with. And one of the problems here is when it gets really cold out, people aren’t active and outside like they are down in Miami, and can be all year. So trying to help patients develop programs where they can stay active can help with hot flashes and anxiety and other symptoms. And acupuncture, I’ve had a lot of success with acupuncture. We have a great acupuncture program and patients really like either acupuncture or acupressure as an opportunity to address a lot of these symptoms including hot flashes, but not just hot flashes. And I’m sure we’ll be able to talk a little bit about that in the next few minutes as well.

So I agree with all of these, exercise, CBT, acupuncture. These are tried and true nonpharmacologic methods that a lot of my patients have used and we have programs in place to help them with that.

DR LOVE: So before we go on to the next topic, just to come back to you, Erica. Again, the issue of diet and exercise. And some of your people in colon have looked at this in terms of actually diet and exercise affecting recurrence. What about in breast cancer? Is it more than feeling good? Any reason to think some kind of metabolic strategy might actually slow recurrence rates, Erica?

DR MAYER: I think this is going to be the next big wave for us in breast cancer. There’s a very large study through the Alliance called BWEL that’s led by my colleague, Jennifer Ligibel, that’s a very large prospective randomized trial in which patients were randomized to a structured exercise intervention with coaches versus observation. She’s already shown data from the study showing that patients who do the exercise are losing weight which is, of course, really important and great. And we are waiting for results from the study when it’s mature to see if we’re actually going to see an endpoint on breast cancer outcomes. Which if that is a positive study, I think will hopefully dramatically change how we are able to discuss and coach our patients. And it’d be wonderful, like Tom Lynch said, if we could turn exercise into a pharmacologic agent that we could prescribe to people. So I think that’s tremendously helpful.

I think another really interesting area is the use of weight loss medicines which have become very prevalent in our culture and very effective. And if we can lose weight by exercise versus if we can lose weight by taking a medicine, does that have an impact on breast cancer outcome and does it matter how you get there? If you do exercise and you create the hormonal milieu that happens after exercise, is that crucial? Or is it just about weight loss? So I think in the next 10 years, we’re going to see a lot of really interesting work that’s going to be delving into both of those topics.

DR LOVE: Alright. So we’re going to pick up now and Virginia is going to cover some of the data looking at tolerability/toxicity.

DR KAKLAMANI: Thanks for having me, Neil. So here is just a general slide on all of these adverse events that we all know are associated with ovarian suppression. And some of these are things that we don’t spend as much time talking about such as alopecia, hair thinning, but definitely bothersome for our patients. We know that patients are going to gain weight. This comes with the addition of metabolic syndrome. Metabolic syndrome is also associated with increased risk of breast cancer, potentially recurrence, so a lot of other topics that become extremely important. Ocular toxicity, a lot of our patients are complaining about that. And sending them to an ophthalmologist may not really solve all of their problems. So these are things that we address in clinic every day or we try to address in clinic every day.

So there’s a couple ways of looking at this. One is the short-term and the other one is the long-term toxicity. So this is some data from the OPTION trial that looked at GnRH in patients receiving chemotherapy. And so these are the short-term toxicities associated with chemotherapy and ovarian suppression. And as you can see, also as expected, there’s an increased risk of hot flashes. There’s also an increased risk of joint pains. And that is comparing the chemo arm to the chemo plus goserelin arm. So this is above what chemotherapy would do. And then also some headaches, mood swings that the patients are going to have. And several of the gynecologic symptoms that we’ve already discussed today including loss of interest in sex.

So from this TEXT and SOFT trial, Erica mentioned some of these, but I summarized these in these tables of the different arms and what the toxicities were. And when we look at hot flashes, for example, there’s an increase in hot flashes by adding ovarian suppression to either tamoxifen or exemestane. When we look at insomnia, again, it gets worse compared to just tamoxifen single agent. Musculoskeletal issues, osteoporosis, significantly higher, especially if we add exemestane and not tamoxifen to ovarian suppression. What was interesting to me, and probably suggesting we’re doing a poor job grading this, is decreased libido where there didn’t seem to be any difference between tamoxifen, OFS and tamoxifen, OFS and exemestane. And I think we all know in clinic that that’s probably not true.

And then as far as rate of discontinuation which, as we all know, if you don’t take a drug, it’s not going to work. There were differences between the different arms, especially if you’re adding exemestane to ovarian suppression. The endocrine therapy discontinuation rate was higher. And then as far as the discontinuation rate of GnRH, around 20% of patients discontinued ovarian suppression on the SOFT trial.

So looking at now data in individuals that are not breast cancer patients and what the effect of an oophorectomy is. And this is from a population-based study. And as you can see in this cohort, women that were under the age of 45 that had an oophorectomy had an increase in many conditions including mortality compared to patients that were 46 to 49 and went through the exact same procedure. And so the next table, which is extremely complicated but I’ll try to guide you all through, looked at specific conditions. So looking at depression. Whether you were under the age of 45 or 46 through 49, there was no difference. There was an increase in depression just by having an oophorectomy. And I think we all see this in clinical practice. Hyperlipidemia, again, especially in the women under the age of 45, and this is the blue line. The women between 46 and 49 is the burgundy line. But the hyperlipidemia is an issue as well. Coronary artery disease, especially in the younger women. It didn’t seem to be an issue in the women between 46 and 49. But in the younger patients that are going through menopause early, that was an increased risk. Congestive heart failure as well. Arthritis here. And, Neil, your question about asthma and COPD, you can see those there that are increased, especially in the women under the age of 45 that become postmenopausal because of an oophorectomy. And osteoporosis as we all know as well.

Now from the Nurse’s Health Study, similar data again looking at women that received or did not receive estrogen therapy after having an oophorectomy. And these are the women under the age of 50 that had a bilateral salpingo-oophorectomy, so not the whole patient population. And you can see that all-cause mortality was higher in women that had the oophorectomy. We also looked at coronary heart disease, and that was higher as well. And then finally, cardiovascular disease in general, not just coronary artery disease being higher.

So what are the issues? Vasomotor symptoms. And we saw some of the answers to these such as behavioral modifications. Here in Texas, I have to tell my patients that avoiding spicy food is probably good for you if it comes to hot flashes. And they look at me saying, well I’m not going to do that. Acupuncture can help, physical activity, pharmacologic maneuvers. And the most recently approved drug, which I’m going to probably butcher, fezolinetant, has been shown to be effective although the data is not from breast cancer patients.

But this is the data. So these are 2 pivotal trials that were done with fezolinetant. And what they showed was that women didn’t just have a reduction in the number, but also the severity of hot flashes by taking this medication. And both of these studies did a crossover, again, showing that the women that were on the placebo that then were switched to fezolinetant had improved outcomes. And this is something that I’ve started using in clinic and have been very successful and finally have patients coming in and saying, oh my God, I feel some much better now that I’m taking this medicine.

And when looking at the treatment-related AEs, it seems to be a relatively easy drug to take. There didn’t seem to be, this was the third study that we don’t have the efficacy data yet, but this is the toxicity data. You can see that there were few adverse events and mostly Grade 1 and Grade 2. And it didn’t seem to make any difference whether patients were on the placebo or the drug. So it’s a pretty safe pharmacologic option but, again, has not been studied in patients with breast cancer.

And I think what we all struggle with is these gynecologic issues with vulvovaginal atrophy as well as sexual dysfunction and so forth. And this is just a summary of what we can do. And a lot of debate as to whether we can use low-dose vaginal estrogen or not. We don’t have safety data. I personally use that in my practice after I’ve tried all the moisturizers and so forth and haven’t had much success with that. But it would be nice to get some safety data because patients are going to ask. I thought I’m not supposed to take estrogen ever again and now you’re giving me estrogen to take.

And bone health becomes an issue for these patients. We want to be doing bone density scans every 2 years or so. And based on what their bone density score is, and I typically use the level of -2.0. If the T score is better than -2.0, then I typically just recommend calcium and vitamin D. But if it’s worse than -2.0, then I will recommend either oral bisphosphonates or IV bisphosphonates that may also have an improvement in breast cancer outcomes.

DR LOVE: So before you go through your cases, just a couple of questions. You mentioned ocular issues. What kind of ocular issues, Virginia?

DR KAKLAMANI: First of all, there’s cataracts. And tamoxifen has also been shown to not necessarily cause cataracts, but it increases the rate of the progression of cataracts. But patients will talk about blurry vision. And the easiest thing for me to do is, oh go see the ophthalmologist who typically gives them a better prescription of glasses, and this may or may not work. But I haven’t really seen a lot of work looking at that. And as we’re engaging ophthalmologists more and more to oncology with all of our new drugs and the ocular complications, this might be a good time to actually address this.

DR LOVE: Yeah, that’s why I noticed it, because we talk about ophthalmic issues all the time in almost every part of oncology with ADCs and all.

Case: A woman in her mid 30s, uninterested in fertility preservation, who received chemotherapy and TAC followed by tamoxifen and abemaciclib for ER-positive, HER2-negative breast cancer

DR LOVE: Alright, how about some cases here? We have a 35-year-old woman. What happened with her?

DR KAKLAMANI: Yeah. So she was found to have a 2-cm ER-positive, HER2-negative breast cancer, 1 positive lymph node. Had surgery and then she underwent chemotherapy with an anthracycline and a taxane. She did not want to have any more children. Her genetic testing was negative. One of the other good things about living in Texas is the fact that all of our patients typically have children in their teens and early 20s as opposed to the north part of the country where they wait until they’re a little older. So she became amenorrheic after her chemotherapy. But because of the uncertainty of whether she was going to be completely postmenopausal or not, we started her on tamoxifen and abemaciclib. And now after 6 months, she started menstruating again.

So the question here was, should we be giving this patient ovarian suppression or not? Or do we feel, and I think Seth commented a little bit about this before, do we feel comfortable with the CDK4/6 inhibitor that we might be improving her outcomes enough to not need to now put her on ovarian suppression?

DR LOVE: Seth?

DR WANDER: Yeah. Thanks, Virginia. And actually, I was going to turn this to Bill in a second because there’s a tangential question here that’s of interest which is tamoxifen and abemaciclib versus whether all patients need to be on ovarian suppression, an AI and abemaciclib. And if you look at monarchE, they did allow either. A subset of those patients were on tamoxifen. Of course, you have this theoretical sort of compound risk of thrombosis. Both tamoxifen and abemaciclib have low rates of thrombosis. And for abemaciclib, the data both from the clinical trial and some real-world data that our team put together at MGH is primarily in the metastatic setting where the patient has active cancer that may be contributing to DVT risk.

But Bill and I were at an event in Chicago about a year ago or year and a half ago, and I was really interested when this question came up. And I was asking Bill and the other panelists about their preferences related to whether you offer tamoxifen with abemaciclib, you know, based on the monarchE data and based on the compound thrombosis risk. And actually, we had different responses from folks on the panel.

I have done this. I have offered tamoxifen with abemaciclib in specific situations, again, having a patient centric discussion, making sure they haven’t had a history of stroke or DVT, making sure they’re not active smokers or have other risk factors. For patients who can’t tolerate for all the reasons that Virginia was alluding to, OS and AI, or for patients who really don’t want to be on ovarian suppression because they’re thinking about future fertility and they want to know what their menstrual cycles are doing, I have use tamoxifen with abemaciclib. But I’m curious for the other 3. I think I know what Bill is going to say because I remember what he said the last time. But I’m curious what you all think about offering tamoxifen and how often you’re using tamoxifen with abemaciclib because that does impact the decision-making here.

DR LOVE: Bill, any thoughts? When I think about tamoxifen, I think about low risk. And when I think about abema, I think about high risk. But this woman has 1 node. But any thoughts about the general question, Bill?

DR GRADISHAR: Well, I think that for most patients, we do use an AI. But I think Seth articulated both sides of the argument very well. There are patients where tamoxifen may be a better choice or at least an equal choice for all the things that Virginia was talking about as well. So for the vast majority of patients, I’m using an AI but I could see a circumstance where you were worried about clot or whatever and tamoxifen could be the choice that’s utilized. But I don’t have much more to add compared to what Seth already elaborated on.

Case: A premenopausal woman in her late 40s with a 3.6-cm breast tumor and a Recurrence Score^® (RS) of 26 who becomes amenorrheic with chemotherapy and TC

DR LOVE: How about your second case, this 48-year-old lady?

DR KAKLAMANI: So she’s 48, premenopausal but obviously close to getting into menopause. Was found to have a 3.6-cm breast cancer. Her Oncotype DX score was 26. So she received chemotherapy with TC, which, based on the data that Erica showed us, doesn’t necessarily put you into menopause at a very high rate, but she’s 48 years old. And so she becomes amenorrheic.

And here, the question was, what do we do now? Do we give her tamoxifen or do we give her OFS? And if we give her OFS, we’d probably subject her to OFS for around 5 years which she may not even need. Or what else should we be giving? So this is something that comes up in clinic all the time, these women that are kind of perimenopausal or close to becoming perimenopausal and trying to figure out what the best endocrine therapy treatment would be.

DR LOVE: Erica, any thoughts?

DR MAYER: Yeah. So for this patient, she has Stage II disease. I would describe this as being higher-risk based on the genomic score. And one of the first reactions to that was to offer adjuvant chemotherapy. In line with that thinking, my preference would be for her to initiate an aromatase inhibitor. And I think there’s 2 paths you can go down. One would be start AI and just give a GnRH agonist to just make sure that she stays amenorrheic. Or give her an AI and monitor. And that’s actually something that I tend to do, is I will just check labs every 6 weeks to begin and then I space it out. I’m looking for estradiol levels. And exactly as Virginia said, to get TC at age 48, she’s probably in permanent amenorrhea. But I would like at least a couple years of close monitoring before I would feel more confident about that.

DR LOVE: So Virginia, what’s the follow-up to this case? And also, the follow-up to your 35-year-old woman who started menstruating?

DR KAKLAMANI: So the 35-year-old woman, I talked to her about ovarian suppression and she agreed to do that. And so I gave her OFS and switched her to an aromatase inhibitor. I will typically give an AI if I give OFS too because if we’re going to get the benefit of OFS, we might as well also get the benefit of the AI.

This patient, what I typically do, I don’t check estrogen levels as frequently as Erica does, so I put them on tamoxifen initially and then check estradiol levels at 6 months. If they’re postmenopausal, then I’ll check them at a year and if they’re again postmenopausal, I’ll switch them then from tamoxifen to the AI. If I see that the levels are not postmenopausal, then at whatever timepoint it is, I will give them OFS and then give them the AI then.

Other Practical Considerations in the Application of OFS — Dr Wander

DR LOVE: So we’re going to move on, and Seth is going to present some additional data. But again, I just want to kind of start out with some discussion clinically. Seth, can you talk a little bit about this question of, and this kind of relates to the 2 cases that Virginia just presented, not just the assays but how you do the assays, how you interpret them? And what is AMH?

DR WANDER: Right. I think they are referring to antimullerian hormone, which we don’t typically use. We’ll show this in a couple of slides here. But in terms of monitoring menopausal status, we have to think a little bit about where we are in terms of patient age, whether they just got chemotherapy, what medications they’re on because that can impact some of the levels here. To Erica’s point, if I have a patient who is in her late 40s, perimenopausal or early 50s and we just gave chemo, even if it was relatively light chemo, I would also use the same approach and think about just monitoring clinical status if there’s any spotting or menstrual bleeding and then check FSH. We usually do FSH, LH and estradiol at some interval somewhere between 6 and 12 weeks depending on, again, the patient’s symptoms and where they’re at. And it looks like most of the folks here agree that they’re at least checking estradiol as the key readout. Because ultimately, that’s the most important thing, right? Regardless of where the FSH and the LH are. And they can be in transition as a patient is moving from perimenopause into menopause. The practical thing that matters is what the estradiol level is because that’s the thing that’s going to impact the function of your aromatase inhibitor, tamoxifen, et cetera.

DR LOVE: So another practical issue that I guess Seth is going to comment on but, again, just, and I think actually Erica talked about this, Virginia, is in patients who want to maintain fertility. Where you’re going to use a GnRH analog, when do you start it? Do you start it at the same time as chemo? I think we talked about it a little bit earlier. Or do you start it prior to? What’s your usual practice, Virginia?

DR KAKLAMANI: I’ll try to start it a couple weeks prior to chemotherapy if I have the luxury to do that because that’s where most of the clinical data is pointing to. And the reason is you see that surge of estrogen during the first 2 weeks just because of how these GnRH agonists work. And so the hope is that you would do that prior to giving the cytotoxic therapy.

DR LOVE: Okay, let’s move on and we’ll have Seth present his talk on some additional practical issues.

DR WANDER: Thanks, Neil. And I really appreciate the invitation. I’ve learned so much from everybody today, so these are all really tough acts to follow here with the last talk, but my pleasure to wrap up today with kind of other practical considerations.

We’ll talk about 4 things, and a couple things I’ll move through quickly because we saw data on a couple of these topics earlier. We’ll just circle back and touch upon defining and assessing menopausal status in patients with breast cancer. We’ll talk a little bit about the optimal timing of ovarian suppression and how that relates to the state of the disease, the patient’s age, as well as fertility interest. We’ll talk about duration of ovarian suppression treatment. And then, we’ll talk a little bit about long and short-acting GnRH formulations. And I’ll have a couple of cases kind of spread throughout the talk here today.

So let’s start with just defining and assessing menopausal status. So we’ve heard a little bit today about some of the relevant endocrine pathways. And if you look at the NCCN guidelines, they’re fairly straightforward and they make intuitive sense as to some of the things we’re dealing with in clinical practice. So patients are defined as being menopausal if they’re over 60 years old or if they’ve had a prior bilateral oophorectomy. For patients under 60, you have to think a little bit about the state of their amenorrhea. So if they just recently had chemotherapy, then the guideline here would suggest continuing to monitor for any menstrual bleeding or, and/or following estradiol and FSH levels on serial measurements. And I typically do this over the course of about a year and I’ll do is again every several months. And if there’s any spotting or any bleeding, obviously, we’ll check the levels but that would be a clinical indication that we might need to think about either adding back in ovarian suppression. You have to be careful interpreting these labs for patients that have received some of these medications, particularly anybody who has received any recent ovarian suppression, anybody who has received recent chemotherapy because we can have a rebound in those numbers over time. So it doesn’t mean you can’t monitor it, it just means that you have to be aware of sort of what factors might be influencing the numbers at least in the short-term after diagnosis or after initial treatment.

And then I thought this was helpful just to show folks and they can go and look at this paper. This was actually a really nice consensus statement from the endocrinologists published in 2012 about defining the different reproductive stages over a woman’s lifespan. And this was broken down by a number of different factors including what’s happening to the menstrual cycles, what’s happening to the laboratory levels, including mullerian hormone and FSH, and then when you might start to expect to see vasomotor symptoms, et cetera. And the discussion that we’re having today is really focused on sort of the late reproductive phase and the menopausal transition, perimenopause into menopause. And so this table and this entire article is a really nice resource to think about what’s happening biologically and clinically in terms of symptomatology throughout the entire lifecycle here, both reproductive and menopausal.

And so let’s think a little bit about timing of ovarian suppression initiation and how that might relate to fertility. Erica gave a great overview of a lot of the data here which is somewhat controversial. I wanted to focus a little bit more in on this paper which was published in the New England Journal in 2015 by Dr Moore and colleagues. This was a study addressing the use of GnRH agonist during chemotherapy to improve fertility. They had almost 220 patients. These were hormone receptor-negative premenopausal patients who were receiving chemotherapy with or without goserelin. And the primary endpoint was the rate of ovarian failure at 2 years. Although to Erica’s point, I think a better endpoint is actually pregnancy rate, successful pregnancy rate which was one of the secondary endpoints. And what you can see here is that the patients who received the GnRH agonist did have higher rates of pregnancy and that reached statistical significance. They had a hazard ratio of over 2.4 in terms of likelihood of becoming pregnant. And obviously, more deliveries. And slightly fewer complications in terms of miscarriage and complications with delivery. Although, again, the numbers there were very small and not statistically significant.

There were some problems with this study and it’s a bit controversial. So some of the concerns related to this data, we didn’t have any insight in this population as to the use of reproductive endocrinology tools. So we weren’t sure within each group whether there was a balance between folks who were using IVF. It is also important to notice on this table that there were higher numbers of patients who attempted pregnancy in the group that receive GnRH agonist. And also really important is that preclinically, there’s a fairly large amount of data to suggest that the use of ovarian suppression doesn’t impact the chemotherapy getting into the oocytes and actually causing double-stranded breaks and DNA damage. So the data here, again, I think is a little bit controversial and we don’t really have a great understanding at the level of the intracellular compartment what’s happening with ovarian suppression to help improve sort of pregnancy chances later, especially because we know chemotherapy, regardless of whether you get ovarian suppression, can get into the oocyte and actually impact DNA health and other factors. So that’s something to consider.

So when we’re approaching this in the clinic, and we’ve already discussed many of these attributes today, we have some key questions. Why are we using GnRH agonist? Is it for fertility preservation or cancer risk reduction or both? What’s the patient’s current menopausal status? Are they in the full reproductive phase? Are they perimenopausal? Is chemotherapy likely to induce menopause? And thinking about the case that Virginia just shared with us for someone in her late 40s even getting doublet chemotherapy. What are the disease characteristics? We heard a lot from Bill about data in these higher-risk patient populations, node-positive versus node-negative. And should the GnRH initiation precede antiestrogen treatment? And I’ll show you a couple of cases like this. So, for example, might you start ovarian suppression during radiation treatment. And then would you go to tamoxifen or would you start the AI immediately? And again, the question here is probably related to how likely it is that the patient is going to quickly transition into menopause. How high risk the disease is. How quickly you want to get them onto antiestrogen therapy.

What about the appropriate duration of ovarian suppression? And this is something we talked a little bit about, but I want to show you a couple of additional studies here. So this was a study published in Breast Cancer in 2016. It was an open-label randomized pilot study with over 200 patients. Now as you can see here, one of the important things to notice is that almost all of these patients had relatively low-risk disease. Over 60% were Stage I and over 90% were either Stage I or Stage II. And they received GnRH agonist for either every 3 months for 2 years or every 3 months for 3 to 5 years, with tamoxifen. So the difference here was 2 years versus 3 to 5 years. And the primary endpoint was disease free survival and safety.

And what you can see here is that the DFS rates really did not differ at year 5 and year 7. So it was about 94% versus 92%. That’s the difference between the 2 versus 3 to 5 years. And really, even a little bit closer at year 7, less than a 1% difference. The overall survival rates were 100% at year 3 to 5 in both groups. But I would argue that even though this study does give us some confidence that using either 2 versus 3 to 5 years is okay, we really aren’t getting a lot of insight into that high-risk patient population that we’ve been talking about throughout the day. Remember, 90% of these patients were Stage I or Stage II. So we don’t really have a lot of confidence with this data in looking at your Stage III patients, your node-positive patients, the patients that you might be reaching for abemaciclib for the patients with potentially higher Oncotype scores. But certainly for the lower-risk patients, the duration 2 years versus 3 to 5 looks like it’s very similar.

And then this is data from the same paper which I thought was quite nice where they showed over time what happened in the 2 year group versus in the 3 to 5 year group as to serum estradiol level on the lefthand side and then bone health on the righthand side. And as might be expected, in the 2 year group, we saw the estradiol level come up when the patients came off of their ovarian suppression. And also not particularly surprising, in the 2 year group, the bone health was tracking a little bit better over time. You can see those lines start to separate as you get out into the 3 to 4-plus-year range. On the bottom side of that figure are the patients who were on bone modifying therapy. So if they were being treated with something like zoledronic acid, there wasn’t really a difference between the lines as we might expect. One of the reasons I think despite the rise in estradiol that you’re seeing similar outcomes here is because, A, we were using tamoxifen, so the tamoxifen is likely working for these patients regardless of what the estradiol level is and, number 2, these are the low-risk patients, right? So again, the patients with Stage I or Stage II disease.

Here's another look at the ASTRRA study that Bill showed us earlier so I’m not going to spend a ton of time on this. This was published in JCO with, I think, an update last year. Randomized Phase III, almost 1,500 premenopausal patients under 45 years of age. They all received chemotherapy, Stage I to III. They all received 5 years of tamoxifen. And they were randomized to receive ovarian suppression for 2 years or not with an improvement in DFS, as Bill showed us earlier, with a significant p-value and hazard ratio. The OS, we really didn’t see as much of a difference here with the hazard ratio crossing 1 on the righthand side.

And this was something that I was alluding to earlier that I thought was kind of interesting in the ASTRRA study. Overall, you see the hazard ratio here of 0.67. But when you start to break it down by subgroup, you actually see that the women in the 40 to 45 range got relatively more benefit. The hazard ratio is shifting over here to the left on the forest plot, again suggesting that maybe the best patients to think about the shorter duration of ovarian suppression may be the patients closer to perimenopause, coming into their mid 40s. The other interesting thing here is that in terms of HER2 status, and we’ve talked about a number of cases today, HER2-positive, the benefit of the ovarian suppression seemed to be more in either HER2-negative or unknown. And in the unknown group, we’d expect about 80% HER2-negative statistically. So again here, probably the ovarian suppression and the overall benefit on ASTRRA is being driven by the women in their kind of early to mid 40s and being driven primarily by the HER2-negative patients as opposed to the very young women or the HER2-positive patients.

Case: A woman in her early 50s with HR-positive, HER2 IHC 2+ invasive lobular carcinoma and a RS of 15 who declined chemotherapy and opted to stop adjuvant leuprolide after 1 year

DR WANDER: So I just wanted to start with this first case. This is a real patient that I‘ve been taking care of now for about 4 years. A 50-year-old woman diagnosed with a right-sided breast cancer. She was perimenopausal with irregular cycles when we met about 4 years ago. On MRI, she had about a 1 cm lesion on the right at 0900, no abnormal adenopathy. The biopsy was lobular. We spoke a little bit about this earlier. Grade 2, strongly hormone receptor-positive and HER2-negative. So she went ahead with the excision. It was an invasive lobular cancer, 1.1 cm, Grade 2, 1 out of 2 sentinel lymph nodes had a macro metastatic deposit, so she was a postoperative pT1cN1a. Now we had had extensive discussions around this time related to Oncotype use. The patient was very, very hesitant to think about chemotherapy. But we talked about limitations related to the RxPONDER study. We talked about the RxPONDER and the TAILORx data in perimenopausal or premenopausal patients, and discussed that really the standard approach for a premenopausal patient or perimenopausal patient with node-positive disease is to offer chemo, but she was really adamant. I think an Oncotype had been sent by the surgical team. It came back in the low-risk range. Not particularly surprising for a strongly hormone receptor-positive lobular cancer. And in that context, having good discussions, reading all the papers in clinic for RxPONDER, opted to defer chemotherapy. So she went on with radiation and I started leuprolide monthly on her followed by letrozole because, again, we wanted to kind of maximize antiestrogen therapy for all the reasons we discussed earlier with a strongly hormone receptor-positive lobular node-positive breast cancer.

Now here’s where it gets interesting. So about a year after starting treatment, and now she’s about 52, she really felt strongly about stopping the ovarian suppression. She doesn’t want to be on medication. She didn’t like coming to clinic with any degree of regularity. And she had an identical twin, identical twin who was not on any medication who had become menopausal. Her identical twin’s menstrual cycles had stopped completely. So we were kind of tracking where her identical twin was and thinking about where she might be which was an interesting aspect of this case. So she had had no menstrual cycles or spotting while she was on ovarian suppression. Per her preference, I stopped the pill. And per Erica’s discussion earlier, we were tracking her labs. And I basically told her any spotting, any bleeding, or any big change in the labs and I really want to put you back on leuprolide for another 6 or 12 months. And so this was interesting. About 12 weeks in, here were her labs looking good. High FSH, high LH, low estradiol. And then about another 12 weeks later, she had this blip in the estradiol where it came up to about 40, the other labs stayed fairly high, FSH and LH. And I said uh oh, I’m a little bit worried right now. But she had no symptoms. She had no spotting. She really didn’t want to go back on leuprolide. I said we’ve really got to watch this and we’re going to check it again in another 8 weeks or so. When I checked her again 8 weeks later, it was back down to less than assay. And since then, it’s been less than assay and she’s had no spotting, no bleeding at all.

And so one of my questions for the group here is obviously, best approach to ovarian suppression in this age group, we’ve talked a fair amount about this. Whether folks are using 1 versus 3-month dosing, I’ll show you that data in a second. How long would you keep these patients on who are around 48, 50, 52, before you do something like we did here? Now this patient, as many patients do, was kind of dictating what she wanted to do and I was supporting her in any way that I could. And then what about this particular scenario where you have the blip in the estradiol? My hypothesis here is that she was right at the menopausal transition, we pulled the ovarian suppression off, her pituitary was pushing her ovaries as hard as it could to push out the last bit of estrogen. And we caught that kind of blip in the estradiol. And then after that, there was nothing else. It was sort of the last production of estrogen that she could have had when we came off the GnRH agonist.

DR LOVE: So Virginia, this will be a memory test to see if you can remember all the questions that Seth just raised. We’ll see how many you can remember and address. Any thoughts?

DR KAKLAMANI: So interestingly, I probably would have switched her to tamoxifen at that 6-month read. And we see this. Also, a reminder that our fertility colleagues use aromatase inhibitors to stimulate the ovaries and so we see it quite a bit and I’ve seen it on a couple patients where I check estradiol levels at 6 months, a year, everything looks nicely postmenopausal on tamoxifen, I’m all happy. I put them on the AI and 6 months later, they start menstruating. And then I realize that their ovarian function is still there. So I think that, to me, is the concern.

The other thing that can muddy the waters, and this is not the case, is patients that are overweight or obese, mostly obese, they may have a higher estradiol level and they may have postmenopausal levels of FSH, but an estradiol of 35, 40. And then what do you do? And those women may be in their mid 50s, late 50s sometimes. And then I don’t know what to do in these cases. I typically treat them as premenopausal just because I’d rather be safe than sorry. So this, to me, is an issue that makes these cases just so difficult.

DR WANDER: And, Virginia, you’re reminding me actually, we talk about tamoxifen. And we actually talked about that from the beginning and later. And she really didn’t like tamoxifen. She didn’t like the risk of uterine cancer even though it’s very small. She didn’t like the risk of blood clot. We did discuss that as an option, both on and off the ovarian suppression. But yeah, I definitely agree that that’s certainly a reasonable option if she wants to be off of that.

DR GRADISHAR: The other thing too, I think it goes without saying that in this age group and this scenario, you would also consider an oophorectomy. One and done. You’re done. If you take all the costs and everything, it’s probably giving her a shot every month or every 3 months. Doing an oophorectomy, you’re probably going to come out ahead just on all the issues.

DR WANDER: Yeah. Yeah, Bill, definitely. Yeah.

DR MAYER: One other sort of trick of the trade that I’ve had is I’ve had a number of patients who have that blip that happens. And on further questioning, there are some supplements that people take that can artifactually increase estradiol. I say artifactually because it’s not their own endogenous, but they’re providing some form of measurable estradiol. And once the patient stops that supplement, the number goes back. So there’s so many things that can cause that.

DR WANDER: Yeah. And just to follow up on that case, now it’s been 2 more years since then. She’s not had any menstrual cycles or spotting. She opted to stay on the aromatase inhibitor. We had discussed the monarchE data which came out after, a couple years after she was diagnosed. She didn’t quite fit the criteria. She wasn’t high enough risk and, again, she sort of wants fewer medications, not more. And so is just planning to stay on the letrozole for now.

DR LOVE: Before you go on, just to clarify something. I didn’t bring it up. We looked at it when we did this previous program, but just kind of curious. Virginia, in terms of choice of LHRH agonist. The feedback we’ve been getting is it’s mainly related to insurance coverage, et cetera, that most people consider them equivalent. Are there any differences whatsoever either theoretically or practically that you consider? And do you have a preference sort of outside of what you can access, Virginia?

DR KAKLAMANI: The mode of administration tends to be a little different. And so sometimes, patient preference becomes a key factor. But honestly, my pharmacy tells me please use this and I do. And at some point, we actually had to switch from one preparation to the other, and a couple of patients complained that they didn’t like the new preparation. We had to go back to the old one. But typically, it’s as you mentioned, more financially driven than anything else.

DR LOVE: So Seth, let’s hear about long versus short-acting treatment.

DR WANDER: Great, thanks. And this is definitely a topic that comes up all the time for patients and particularly some of the patients we’ve thought about today who are very young and who you know are really going to be on treatment for the duration, this becomes a key issue. Because once the patient’s done with the radiation and done with the chemo, they don’t want to feel like they’re sick and they’re in clinic all the time getting treated, getting injections. So this is a really important topic.

So here’s a study from Breast Cancer Research and Treatment in 2011. This was from Japan. Multicenter, open-label randomized premenopausal early breast cancer. They had just under 200 patients. And they were randomized 1:1 to goserelin the 3-month dose versus the monthly dose. The primary endpoint here was noninferiority of the estradiol area under the curve over 6 months. The secondary endpoint was the E2 level itself, FSH level, menstrual cycle patterns, and safety. And again, one of the things I want to point out similar to the other study that we just looked at, these patients tended to be very low-risk. They had T1 tumors for the most part, a few with T2. Most of them were node-negative. And that’s one of the limitations of interpreting this data in the context of many of the patients that we are most enthusiastic about reaching for these medications for in general.

But with that in mind, as might be expected, there really wasn’t a difference. You saw a steep drop-off in the estradiol level in both arms that really were superimposable. And when you looked at — the other interesting thing for me, and again, I’m curious for the group’s thoughts on this, is symptoms. So anecdotally, in my own practice, I have had some younger patients who have told me that when they switch to the 3-month dose, I usually keep them on the monthly dose for at least 6 months or so to make sure that the symptoms are under control and that they’re doing well. But in the longer-term, some of them have told me in that first week or 2 after the 3-month dose, they feel the symptoms might be worse. More prominent hot flashes, et cetera. Although if you look at the data here from this study and the next one I’m going to show you, that was not borne out. If anything, it was actually the monthly dose that was causing patients slightly numerically higher rates of hot flashes and things like that. So there definitely as not a sign that the 3-month dose was causing more toxicity. If anything, for the most part, it was less toxicity with some of the symptoms that Virginia outlined previously.

Now here’s the second study in Breast Cancer published in 2016. This was, again, multicenter, open-label randomized Phase III. The difference here is this was advanced breast cancer. So these were patients with unresectable or metastatic hormone receptor-positive breast cancer. Over 220 patients, all of whom were receiving tamoxifen. And they were, again, 1:1 randomized to the 3-month dose of goserelin or the monthly dose. Now here, the primary endpoint was progression free survival, not estradiol level, but progression free survival over 6 months. And again, it was a noninferiority study. Secondary endpoints were overall response rate, E2 level itself, and safety. And what you can see here is, as expected, just like the prior study, the mean estradiol level dropped precipitously over the first couple of months and stayed low over the 6-month period regardless of whether you’re using the 3-month dose or the 1-month dose.

And then here, what you see is progression free survival rate at 6 months. Again, identical, and so it was felt to be noninferior. But again, I would highlight one of the big limitations of this study is you’re looking at a relatively short time period. They’re only looking at 24 weeks, 6 months of data. We know that the natural history of metastatic or locally advanced hormone receptor-positive breast cancer are in general over much longer time periods than that, particularly in endocrine sensitive disease early in the course of treatment. And so it’s not particularly surprising that at 6 months, there wouldn’t be a difference. It’s probable that it might not make a difference overall, but it would have been helpful, I think, here to have seen more follow-up, over 18 months, over 24 months, when patients might be expected to be experiencing more endocrine refractoriness or endocrine progression in the metastatic setting. But the estradiol levels dropped and stayed low. The response rates were similar. The PFS rate was essentially identical. And so that’s some indication, at least over a 6-month period, that these 2 strategies don’t really have any meaningful difference.

And again, here’s the toxicity data. Showing despite my anecdotal experience, and I’d like to hear what the others think, that the monthly dose, if anything, was slightly worse. That there really wasn’t a sign for more toxicity in the depo 3-month dose as we might intuitively expect.

And so I wanted to end on a case that I think pulls together a lot of the themes that we’ve been talking about from all of the talks today. But actually, before I do that, Neil, I’m curious. Does anybody else feel that there’s a subjective difference in toxicity in their own practices between the 3-month versus the monthly dosing? Because I was a little surprised by those 2 papers when I was getting this ready.

DR KAKLAMANI: I personally haven’t. The only thing that sometimes happens is at that 2 and a half to 3 months, people, women, especially the younger women may start feeling like maybe they’re going to start menstruating. And that tells me at 2 and a half months, they have to come to my office and get the hormonal levels checked.

DR WANDER: So the breakthrough, that breakthrough rate toward the end. I was worried. If the patient tells me the hot flashes get a lot better in the last 2 or 3 weeks, you say okay, that’s good but I’m actually a little worried about what your estradiol level is doing there.

DR MAYER: Yeah. Like Virginia, I have, I actually rarely use 3-month depo injections, but I certainly have patients who will say just towards the time when they come in, it feels to them like it’s wearing off. So my preference is to do monthly. And I think pretty soon, we’re going to have the ability for patients to do monthly injections at home which would dramatically improve convenience for them.

DR GRADISHAR: And we too typically do monthly rather than 3.

DR WANDER: Great.

Case: A woman in her early 40s with HR-positive, HER2 IHC 1+ breast cancer who has no interest in fertility preservation and significant residual disease at surgery

DR WANDER: So the last case here, a 40-year-old woman diagnosed with a left-sided breast cancer. She was premenopausal with regular menstrual cycles. G2P2. She had had an extended prior history of oral contraceptive use, none currently. No future interest in fertility. She had diagnostic breast imaging with a 5-cm lesion on the left plus clearly abnormal adenopathy on exam and on imaging. Staging scans were negative. Germline testing was negative, including BRCA. She had a core biopsy with a Grade 3 invasive ductal carcinoma, ER/PR strongly positive, HER2-negative. We gave her preoperative dose-dense ACT and then she had a bilateral mastectomy with residual invasive ductal carcinoma. There was a response. The tumor had shrunk from over 5 cm to about 3.5 cm with only 30% remaining cellularity. She did have 5 out of 10 regional lymph nodes that were positive, again, with treatment effect. So she was a ypT2N2. She got post-mastectomy radiation therapy. We started monthly leuprolide during radiation treatment for her and then subsequently initiated letrozole. She continued with the monthly ovarian suppression. We initiated abemaciclib after probably 6 to 8 weeks on the adjuvant AI after we had confirmed that she was tolerating it well. And then we subsequently initiated bone modifying therapy with zoledronic acid per some of our prior discussions.

So once we got, I sort of describe this to patients as getting to cruising altitude. We’re getting from 10,000 feet to 20,000 feet to 30,000 feet. We’re layering these things on one at a time as we get finished with the chemotherapy. Once we got to that cruising altitude for her, she was fairly stable. Occasional hot flashes, mild arthralgia, occasional loose stool. She was at that time on monthly leuprolide, letrozole, 150 twice daily of abemaciclib, and every 6 months zoledronic acid. She, after 6 months, wanted to consider transitioning to the longer-acting leuprolide dose. And that kind of allowed us to synchronize things where she’d come every 6 weeks to just get her lab check on the CDK inhibitor and then every other visit would get a shot so she wasn’t coming every 4 weeks. And then after about a year and a half of treatment, per Bill’s point, she’s sick of coming in to see us all the time and getting shots, so she had her ovaries out in that second year. And her plan has been to continue on extended duration letrozole. She completed 24 months recently of abemaciclib therapy. So I thought this case kind of pulled together a lot of the highest-risk features of many of the things we have talked about throughout the afternoon today.

And my questions for the group on the bottom. Just thinking about for this younger group, how are people integrating these treatments? Do they do it the way that I’ve done it here, kind of in a stepwise fashion where you’re doing one thing at a time and then seeing how they’re doing for a period of weeks? What are the thoughts on when to go for an oophorectomy? I always tell patients I like to start with something like leuprolide monthly for 3 to 6 months because we can stop it whereas once you go to surgery, you can’t obviously reverse that. And then, how are people integrating the CDK inhibitor? If you look at monarchE, they let people come in, I think, for up to about a year after their initial treatment. I tend to, again, I don’t want to throw everything in all at once because then, it’s hard to tease apart kind of what’s causing what in terms of side effects. But just curious for the group’s closing thoughts on what would be really one of the highest-risk type patients we would run into here.

DR LOVE: Erica?

DR MAYER: Yeah. So Seth, I totally agree. An N2 patient after preoperative chemotherapy is our high-risk patient where we really want to offer every single, as we might say, kitchen sink item available. I like your analogy of reaching cruising altitude. The one I tend to use is wading into the water, and that we just want to take it step by step. Adherence is so important here, so we want to make sure the patient can tolerate each step in the process before adding in another layer. Particularly, I think it’s so important to confirm adherence to oral endocrine therapy before we add something. I agree that, as Bill had brought up, this is a great patient to consider an oophorectomy. We never want her to be premenopausal again. But we don’t want to do it until we feel confirmation that she can tolerate the side effects and she’s used to it. So after a few months, I’ll bring up the topic and often have them have a consultation with gynecologic oncology to start thinking about it and thinking about when it’s going to make sense for them. But I do think given her risk, she needs all of these different modalities.

DR LOVE: Anything you want to add to that? You have this sort of practical conclusion here. Anything there you want to comment on, Seth?

DR WANDER: Yeah. Thanks. I just wanted to close by summarizing. In terms of defining and assessing menopausal status, we really need to look at both clinical features, how long they’ve had amenorrhea, what their age, prior menstrual history, and then thinking about laboratory assessments. We typically use estradiol and then FSH and LSH. Thinking about timing of ovarian suppression initiation. We have to think again about where they are clinically, age and menopausal status. What are our goals in integrating that ovarian suppression? What are the clinical risk features? And Erica gave a great overview of the relationship between using ovarian suppression and fertility preservation, and that’s something that we need to think about. And it’s a relatively easy and low-risk tool that we can use, but we have to understand the limitations of that data. Thinking about appropriate duration. This is really a personalized, very careful patient-centered decision-making. We need to think about clinical and laboratory monitoring for these patients. And then long versus short-acting. The data that I showed you suggests similar impact, but those studies were limited based on the cohorts that they used and based on the endpoints and the duration of follow-up. And this really depends a lot on age, preference, how long we’re going to use ovarian suppression, who might want to go for BSO versus who wants to stay on medication. And with that, I’ll conclude my section there. Thank you.

DR LOVE: Awesome. So there are just a couple more things I kind of wanted to run by you. Our crack scientific team saw this presentation, I guess a couple weeks ago at the national meeting.

Basically, it’s just looking at whether or not the impact of using a nonabdominal site makes a difference. I guess they had patients with prior abdominal surgery, scarring, et cetera where it made it difficult for abdominal injection. From what I can tell, and I was actually looking at the conference itself. There’s a lot of really great stuff you all present there in Orlando. But it looks like the bottom line is it didn’t matter whether it was in the abdomen or not. Seth, do you see this at all where people can’t get the injection in the abdomen?

DR WANDER: Yeah, it’s an interesting question. I would assume, again depending on the vehicle, that the bioavailability would be similar. But I haven’t run into this issue myself. We think about things like this with vaccination and lymph node swelling and lymphedema.

DR LOVE: Right.

DR WANDER: I think about alternative sites. I think it would be helpful if patients are uncomfortable with that or, let’s say, they’re taking some other thing that’s limiting your ability to inject in that area, it would be nice to have data suggesting that it’s okay to do it in other areas. I think it would make sense that it would be biologically.

DR KAKLAMANI: I have actually done this. And I did it because a patient had a flap, came to clinic, and the nurses tried to access her abdomen.

DR LOVE: Right.

DR KAKLAMANI: And she started screaming saying nobody is touching my abdomen. And so the nurses called me. And I said well do it in the leg. There’s subcutaneous tissue there. They said well that’s not what the package insert said. We’re not doing it. So I actually had to go back to the treatment room and do it myself, because the nurses would not want to do that. But a reminder that we do this with subcutaneous trastuzumab. And the data actually suggest even more bioavailability if it’s done in the leg than done in the abdomen.

DR LOVE: Interesting. So a couple other things. I’m going to come to Erica first for this next question. Just reflecting back on this decision and also thinking about some of the patients that we’ve talked about including patients who are very, very interested in details about this topic. We just spent 2 and a half hours talking about a pretty narrow topic, but there’s a lot of good content there. And I guess my question is, whether you’re aware of any efforts in terms of patient education that are particularly innovative or different. You talked about this diet study coming up. That’s going to create a huge need. What’s your sense right now what’s out there for patients? And what maybe could be better?

DR MAYER: I think it’s a really interesting question. And like so many of us, our patients are social media users and they’re on their phones. And they’re not necessarily looking for long form knowledge and lengthy things. Podcasts, that’s always of interest. But I think people like little bites. So a quick video on Instagram or TikTok that you can watch quickly while you’re on the train or listen to it. I think that’s kind of where humanity’s attention span is right now. But to be able to access those little nuggets of education I think is really nice.

And speaking of ovarian suppression, I think as we’ve just been discussing, this is such an incredibly powerful tool for treating breast cancer, but I don’t think necessarily that this is well-known outside of our niche. And when people get diagnosed with breast cancer, the first thing they’re thinking is chemo but that’s very infrequently given for hormone receptor-positive. So it would be great if we can find ways to educate patients about how effective and powerful ovarian suppression is. I would love patients to come into clinic saying, I hear this is really good treatment. Is this right for me? Because I think that would be a great way to start the conversation.

DR LOVE: Just one more topic. I just want to get your initial thoughts, if any, about a very interesting study that came out about a year ago in prostate cancer.

So Seth, your colleague, Matt Smith, we work with him all the time. And he shows a curve that he calls the pelican graph because it looks like a pelican with the treatment arm not relapsing and everybody else down here. And that was from a study that came out that I thought you all would be very interested in. So the treatment of really, early metastatic prostate cancer which is PSA-only disease. These men get primary therapy, radiation, surgery, and then their PSA comes up and their scans are all negative, but they have disease. Eventually, unless they die of something else, it’s going to progress at some point. It’s been very debated, as you might know, whether to even treat these people. They’re completely asymptomatic, but they have this, it’s kind of like an MRD thing. And for 30 years, they’ve used LHRH agonist, right? But with not very much data.

So they did a study last year they presented called the EMBARK trial. I don’t know if any of you have ever heard of it. But the EMBARK trial compared, which you see a lot of trials in prostate cancer, they’re like 10 years, at least, behind breast. They compared using an LHRH agonist to enzalutamide, the androgen blocker which has a lot of similarities to tamoxifen, believe it or not. Leads to increased testosterone levels, not decreased. Does that sound familiar? So they added that to the LHRH agonist, kind of like you would add an AI in breast cancer. And as they’re seeing in all the trials, they did better.

But they did something that nobody else did, ever. They had another arm that the FDA insisted on, which was enzalutamide alone. And enzalutamide was better than LHRH agonist. The same thing they’ve been using for 20 years. The combination was the best arm. And when I first saw that, it sounded kind of familiar. I know it’s a different disease. But any thoughts, Seth? Because I’ve been like, why aren’t you giving enzalutamide alone to these men? Maybe they’ll have better sexual function. They’re not tuned in at all. To me, the general oncologists are seeing the analogy to breast cancer, but they don’t because they don’t see breast cancer.

DR WANDER: Right.

DR LOVE: Any thoughts, Seth?

DR WANDER: I think it’s really interesting. And I also think this notion of PSA-only relapse and your comparison to MRD is accurate. And what we’re going to see with something like SERENA-6 and what we saw with PADA-1, which I think you and I talked about a few weeks ago, this idea that at a genomic molecular level, we can use circulating tumor DNA in the metastatic setting even to find early progressors in the absence of clinical or radiographic findings, and that intervening early with one of these strategies may prove to be more fruitful than waiting until the horse is out of the barn when there are millions of tumor cells and it’s clear on a scan. And that may be part of what you’re alluding to in the sense of this population where you don’t have radiographic progression and you don’t have clinical symptoms by attacking the tumor when the driving sort of problem is still subclonal and it’s still small.

I think the second part of your question is, well can we get away kind of with less toxic treatment that might be better than the traditional kind of option? And I think the answer to that is likely going to be yes too. In breast cancer, like with the dawn of enzalutamide and abiraterone, we have all these new next-generation antiestrogen drugs, new SERMs, new PROTACs, new next-generation oral SERDs. What GnRH may or may not add to that is a really interesting question for these younger patients based on the mechanism of some of these newer agents, particularly, for example, like lasofoxifene, a next-generation tamoxifen alternative. And I think we may see, like you’re saying, that the toxicity here is very manageable even without GnRH and that the efficacy is still there, particularly in the right population, maybe ESR1 mutant, small amount of progression picked up on ctDNA.

DR LOVE: So Erica, again, I’m just kind of curious about your thoughts here. It also kind of gets into the issue of the difference in the clinical experience and knowledge base of a general medical oncologists and a specialist. With the tumor agnostic approval of T-DXd, we’re out there talking about HER2 to GU, GI, everybody. And they don’t have a clue. Nothing. ILD, acute side effects. And the general oncologist knows all of this, so they have a different perspective. Again, just kind of curious what your thoughts are in terms of how, you know, a general medical oncologist looks at breast cancer and sees it in the context of everything else. Any thoughts about what I told you about prostate cancer, Erica?

DR MAYER: Yeah. I’m so amazed by how much knowledge my general oncology friends manage to keep in their heads at one time. Because we all live in our little silo of breast cancer and try to learn as much as we can from our colleagues, but it’s not the same as seeing all these patients and changing in each room that you go in what you’re thinking about. I think what interests me about that study is what you said about how the third arm is mandated by the FDA. And the FDA is really doing a very interesting job now with this program called Project Optimus that’s trying to make drug development be mindful of dosing and thinking about why do we pick certain doses. Why are we picking doses that are just below the dose that makes everyone sick? Can we get the same benefit from a lower dose? And forcing companies to add extra arms into studies or even do entire studies to do dose finding. And I think that’s incredibly helpful. The folks working at the FDA now are, they’re clinicians themselves, and I think they’ve been really mindful about what sort of ways do they interact with industry to make sure that decisions moving forward are patient centric. So I think a study like that that’s really demonstrating that you get a lot from a drug and you don’t necessarily need to use the old drug, that’s fascinating. And I’m glad that that kind of work is being done.

DR LOVE: And Bill, I’m just kind of curious too. Another thing that I’m hearing a lot through the FDA about is disparities. Actually, Erica, your colleague in myeloma, Paul Richardson, they presented some data from the big DETERMINATION transplant study. And they found that the African American patients don’t benefit and there may be even a biology behind it. Any thoughts about this issue of, again, new trials requiring disparity programs and how that is affecting clinical research right now, Bill?

DR GRADISHAR: Well, I think people have recognized for a long time that there are differences not only in outcome, but the effectiveness of therapy across different populations. We knew that with looking at Asian populations versus those in the US. If we look in the US, there’s differences potentially between African Americans and whites with respect to how a drug is metabolized. So I think it’s critically important. And it’s finally caught up that this is an issue that has to be emphasized. And the FDA, certainly all the companies, every single company that’s running a large trial, they have a whole group that’s fixated on DEI issues in terms of accrual to the trial and doing everything they can to enhance the number of people from under-represented populations to participate. So I think it’s finally come full-circle and we’re addressing this now.

DR LOVE: Any final comments, Virginia? Actually, I asked Dr Richardson, they somehow got 20% of patients in this Phase III trial were African American, how he did it, what the key was. And he said the key was to get African American oncologists interested in the trial which I thought was very interesting. Any final comment on this topic, Virginia?

DR KAKLAMANI: I think it’s also important to where you’re opening the clinical trial. If you open the trial in Asia, you’re going to have Asian patients. If you open the trial in San Antonio, we have 60% Hispanic patients. And one of the things that these companies are going to need to do a better job with is opening it in different sites, sites that they’re not used to working with. And also understanding that a lot of these women are going to need support. You can’t go to clinic 5 times a week because the study decided to do that because they have kids to take care of, they have family members to take care of. So you have to make it easy for them. Bring the study to them, not expect them to come in. And COVID helped a little bit with this, but we definitely need to do a better job because we’re not doing as good a job as we should.

DR LOVE: So final comment. When you said San Antonio I just flashed on Ruben Mesa who we’ve worked with so many times over the years. He just moved out of San Antonio. But, Erica, we did a program with Ruben a few weeks ago. And getting back to your diet and exercise thing, he had a paper. They did a paper on people with myelofibrosis, evaluating a strategy, I’m going to tell you what it is, to see whether it affected symptoms. It was just after 2 big ASH Phase III trials showed that adding a drug onto ruxolitinib did not improve the patient’s symptoms because ruxolitinib was so good. But Ruben had a trial where he showed an intervention that did work. A randomized trial. Not Phase III, it was small. Mediterranean diet. Low fat, low meat, a lot of vegetables. And literally, their symptom score, it dropped significantly where the new drugs didn’t do that. So that’s why I’m excited about diet, or part of it anyhow.

DR MAYER: Yeah, it’s great. I think that’s super interesting. Our patients, I think we all encourage them to eat a healthy diet although we also spend a lot of time counseling about not eating wacky diets, which is sometimes what we encounter. But I think the focus on exercise and weight loss is really where the field is going.

DR LOVE: Well, they actually believe that the diet is anti-inflammatory. I don’t know exactly what that means, but I guess to be continued.

DR KAKLAMANI: We have data. Actually, a long time ago, my dad’s a rheumatologist and we’re Greek, so we actually have data looking at rheumatoid arthritis and olive oil. And it is anti-inflammatory. So yes.

DR MAYER: Especially if you have it while you’re in Greece.

DR LOVE: Mediterranean — Mediterranean diet.

DR KAKLAMANI: That’s even better.