Introduction

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice, and welcome to Inside the Issue as today we explore the current role of ovarian suppression/ablation in the management of breast cancer. We have a great faculty, Dr Kathy Miller from Indiana University and Dr Ann Partridge from the Dana-Farber Cancer Center and we have these other docs who participated in the survey that we’re going to show you.

We know a lot of people end up listening to our webinars and if you’re into podcasts, check out or Oncology Today series, including a recent program with Dr Curigliano on HER2-positive metastatic breast cancer.

We do webinars all the time. Next week we’re heading out to the GU Cancer Symposium. So, for those of you who are in the San Francisco area, come on over. We’re doing 3 satellites there, but it’s also going to be online, live, on Zoom — a little bit late for the Eastern people. But Wednesday night we’ll be starting out with Renal Cell Cancer, Thursday night, prostate cancer, and Friday night, urothelial bladder cancer.

And then on that Saturday, the next day, we’ll be working with the North Carolina and South Carolina Oncology Associations doing a daylong multitumor meeting. We have 15 investigators coming to Charlotte. As you can see, we have a great faculty. We’re going to cover most of the common solid and hematologic cancers. It’ll be a great day.

And then the following Wednesday we’re starting our series on the management of colorectal cancer. A lot going on there, including HER2-positive colorectal cancer finally, relevant to what we’re talking about today.

And then on Thursday, the 23^rd, we’re going to be doing an interesting split symposium, first Dr Patel from MD Anderson is going to enlighten us about tumor treating fields. I’ve been always trying to figure out how that works, but hopefully he’ll be able to explain it. And then Dr Konecny will update us on PARP inhibitors.

But today we’re really here to talk about premenopausal breast cancer, about a third of breast cancer overall. And as we do a lot of times, I worked with both of the faculty separately over the last couple of weeks to record a presentation and an interview, and that’s really part of this program. The links are in the chatroom, but also, we’ll be sending out an email after tonight’s program for all 3 of these. Ideally, you watch both presentations; they really carefully go through all the data, and then check out whatever is going to happen here tonight which I imagine is going to be pretty interesting.

So one of the things that both of our faculty did as part of their presentation is present some cases and we picked 4 of the cases to talk about today. And that’s really going to form the agenda, the meeting. We’re basically going to make rounds.

But before we get started, I just want to kind of provide a little bit of an overview of, after talking to both of you, thinking about it, reading about it, what are some of the common issues that come up in this topic that we’re going to talk about tonight. And, Ann, this first one is the one that really surprised me. The more I looked into this question of who should get adjuvant tamoxifen alone, the more complicated it became. I became aware of some of the online tools. There’s new survival data from SOFT and TEXT. Now we have Oncotype to potentially —- we’re going to include in the equation.

And we’re going to start out in a second, Ann, with a patient where this was an issue, a patient with a node-negative tumor.

But I’m curious, in general, how you think through the issue. Obviously, people understand low risk, less benefit, maybe avoid side effects of ovarian suppression. But generally speaking, how do you, for practical purposes, Ann, decide whether you’re going to use tamoxifen or not?

DR PARTRIDGE: I typically, if I’m choosing whether I’m going to use ovarian function suppression or not, or tamoxifen alone, and, of course, the partner of ovarian function suppression is another consideration, it’s really about the risk of the disease and then it’s the preferences of the patient. And it’s easy at the extremes. I think a small node-negative, highly hormone-sensitive tumor, if you’re sending a genomic test and it’s low risk and the person’s premenopausal, you can feel pretty comfortable using tamoxifen alone. In someone you wouldn’t otherwise give chemotherapy to, that’s really easy.

I think when it comes to being very young or someone with higher risk, that’s when you really start to think about using ovarian function suppression and weighing that in — are the benefits worth it.

We know from the original SOFT data, that people do seem to get risk reduction across the board — the hazards are .76, generally — but that’s tiny when it comes to lower-risk, premenopausal and not so young patients.

DR LOVE: So, Kathy, I think we could just leave this slide up the whole hour and let the chatroom — they’re already pumping a bunch of questions. So in addition to answer the question I just put out there to Ann, maybe take a shot at this important question from Lisa in the chatroom, what about adjuvant endocrine therapy in male breast cancer patients? What patients get tamoxifen alone? What do we know about disease-free survival and overall survival benefits in men?

DR MILLER: So we have very little direct data in men. Most of the treatment in men is really extrapolated from women. I think the largest single study of breast cancer in men that I’ve seen published had all of 24 patients. So the best adjuvant data in a very small series of patients is with tamoxifen. That is usually my recommendation to men with tamoxifen. There is data using the aromatase inhibitors in the metastatic setting. They certainly do have activity, but those studies gave them with a GnRH agonist to decrease the testosterone levels. Otherwise, I think there was concern that there just was going to be so much testosterone available for peripheral conversion that you may not really reduce the estrogen levels sufficiently with an aromatase inhibitor alone.

So in men, when you think about a GnRH agonist with an aromatase inhibitor, the potential toxicities get ramped up pretty substantially, very similar as they do to women when you add an GnRH agonist.

So in the adjuvant setting, I’m focusing in my men on tamoxifen. I don’t think I’ve given other hormone therapy options in the adjuvant setting to any men that I can think of.

DR LOVE: So, Ann, Emily in the chatroom has a 46-year-old premenopausal woman, Stage I hormone receptor-positive breast cancer, on anastrozole and goserelin. Wants to know would you add zoledronic acid?

And Nikolaos wants to know, if you have a patient — it sounds like he has a patient with endometrial hyperplasia requiring DNC, how worried are you about endometrial cancer with tamoxifen?

DR PARTRIDGE: Okay, so let’s start with the zoledronic acid. We know from the overview and originally from the ABCSG-12 trial, that zoledronic acid does appear to have a small statistically significant improvement for patients who are getting it — who have been either, are postmenopausal or are made postmenopausal. Three years is probably good enough, 2 to 3 years we’ve seen from recent data.

So I do think about it in my young patients whom I’m suppressing their ovaries in particular, to add benefit both for the bone health as well as potentially the breast cancer health. Although, I will say I don’t do it that constantly because a lot of patients don’t want those drugs. And especially if you’re dealing with a very young patient, who might be having a baby in the not-to-distant future, then it becomes a little problematic around kind of when do you time it? And is it safe enough because we don’t have a lot of data in that setting?

DR LOVE: Another great question, Kathy, from Charles. Once ovarian suppression is started, do you, in older women, test for ovarian function to see if they’re going through natural menopause so you can stop the ovarian suppression?

DR MILLER: So here’s the challenge, you can’t do that. if you have fully suppressed the ovaries, those blood tests that you’ll do to look at FSH levels will be tricky because the ovarian function suppression works by decreasing FSH levels. So those will still look premenopausal, but their estradiol levels, if you’ve suppressed function, should be in the postmenopausal range. And you have no way of knowing is that because you have successfully medicated them, or because their ovaries have now given up and would no longer be functioning even without that suppressive medication.

What that means is that at some point, you and the patient are going to have kind of take a leap of faith, assume that through passage of time and age, their ovaries are done. If they’re going to remain on an aromatase inhibitor, I think that then obligates you to caution her certainly if suddenly her menopausal symptoms are completely gone. If she has any vaginal bleeding or menses, she needs to let you know immediately. And I actually check hormone levels several times in those women after stopping their ovarian function suppression. In some of my patients who’ve been on the ovarian function suppression and an aromatase inhibitor for 5 years, we’ve actually switched them to tamoxifen so that we can stop the ovarian function suppression without concern that if they have residual ovarian function they’re no longer on hormone therapy.

DR LOVE: So audience, I’ve got to say this happens a lot when we really dive deeply into topics. I was really surprised by what I’ve been finding here. I do not think it that easy to figure this — answer this question out. But let’s just see, maybe I’m wrong. But I don’t think the literature is that clear. I’m not sure literature is clear at all about how you factor in Recurrence Score. So we just ask people what they do, and I’m going to show you in a second what they do.

Case: A woman in her mid 20s with T1cN0M0, ER/PR-positive, HER2-negative breast cancer, Recurrence Score^® (RS) of 26 — Dr Partridge

DR LOVE: We’re going to present Ann’s case in a second, but audience, here’s a question we’d like you to answer, a poll question. This is based on Ann’s case. You have a 25-year-old premenopausal patient with a T1cN0, so node-negative. Actually the tumor was 1.6 centimeters, Ann just told me. ER-/PR-positive, HER2-negative, Recurrence Score of 26.

So regardless of whether you’d use chemotherapy or not, what kind of hormonal therapy would you use in this situation?

So I want to just go back and actually go through the case. So, Ann, this is a25-year-old woman. Can you tell us a little bit about she presented? How you thought through the case? And maybe we can just talk a little bit about what happened?

DR PARTRIDGE: Sure. So this is a very young woman who palpated a mass. She recently married and palpated a mass in the shower in her right breast. And she was wise and brought it to pretty prompt medical attention; she actually had a family history of breast cancer in her mother. And she, fortunately, got very prompt attention and she was found to have a 1.6-cm Grade 3 tumor, both clinically and ultimately, the decision was to take her to surgery first because she had no appreciable lymph node involvement and it was operable with a lumpectomy.

And so she went to surgery and it ended up being a 1.6 centimeters, hormone sensitive, HER2/neu-negative. It remained Grade 3. And then a genomic test was sent, as you can see.

DR LOVE: So this is one of the online tools that we have to calculate a number. I’m not sure exactly how to apply the number, but it’s an interesting site to visit. We just talked a little bit about the issue of monitoring. And before we get back to your case — this is, I guess, your internal way at Dana-Farber that you monitor patients on LHRH agonists? Kathy, I don’t know if you do it the same way. But Ann, can you explain how you approach monitoring these patients?

DR PARTRIDGE: Sure. So if the choice is to give someone ovarian suppression, which we kind of did in that patient — we’ll get back to her — we want to see them looking postmenopausal, and then we start the AI, although we don’t always check it before we start because we assume the LHRH agonist is going to work. But when we monitor, and we especially have started monitoring our very young patients more frequently, our normal for postmenopausal is less than 20 — excuse me — less than 10. If they’re less than 20, but between 10 and 20, we’re a little more likely to let them ride it out a little longer and wait another couple of months and then recheck it, especially if they’re on tamoxifen because sometimes we partner it with tamoxifen. And if they’re on an AI and they’re higher than 20, we’ll sometimes put them on to tamoxifen with the ovarian suppression until we get them suppressed.

So we’ve recently talked about this as a group. There’s no wrong answer here, which means there’s no right answer here. But increasingly, we’ve decided we need to follow them because you don’t want someone living on ovarian suppression, on an AI, with constant breakthrough. And especially in a very young person, clinically you can see that.

DR LOVE: So Kathy, how would you think through hormonal therapy in this patient?

DR MILLER: So this patient has 2 factors that would really concern me about her risk. Just from her standard pathology, this is a Grade 3 tumor, Her Oncotype score is consistent with that biologic risk. And she is a very young woman. So those are factors that in the most recent 12-year analysis of the SOFT and TEXT trial, suggested a not trivial improvement in overall survival, an absolute improvement in overall survival of somewhere between 3% to 5%.

So my preference for her would be ovarian function suppression with an aromatase inhibitor then added once her ovaries have been suppressed.

Now, you do need to think about the toxicities with this very young woman of menopausal symptoms in the short- and intermediate term. Her long-term risk of bone health and compromise. Potential long-term risk of cardiovascular disease. And all of the quality-of-life effects that this brings.

So, while that would be our initial preference, or she’s really struggling with toxicities, we’ve maximized all of the non-hormonal options to try to mitigate her symptoms and this is just not tolerable, then we have options to back off to function suppression with tamoxifen. Stopping the function suppression and going with tamoxifen alone. But our start and our goal would be to get her to ovarian function suppression and an AI.

DR LOVE: So the majority of the audience goes for ovarian suppression plus an AI. Eight percent of the audience says tamoxifen alone.

What happened with this patient, Ann?

DR PARTRIDGE: So this young woman had actually been using the ovarian suppression as fertility and prevention of premature menopause, and so she was already on the ovarian suppression through her chemotherapy. And not that we’re assured that she would need it and, as we all know, there’s only a small incremental benefit with regard to preservation of menses especially in a young person — you’d expect that she would have, if she weren’t going to ovarian suppression her menses would still be functioning with just TC. But she was already on it, which is, I think, perhaps what was also contributing to her feeling so badly when she came back to see us.

So we kept her on it with a plan to give her hormonal therapy. We wanted to give her letrozole and she just wasn’t ready to start it. And so we were getting her through radiation, and we’re actually seeing her back in a month, but we’re keeping her on the OS right now. and then we’re going to kind of try and do it incrementally because emotionally, she couldn’t take one more thing at that time. She will, and she says she will. We just decided to stagger it a little bit for her overall health and well-being.

DR LOVE: So Kathy, maybe you can a look at how our faculty responded to some variables in how they approach therapy. So we started out with a real small tumor, 0.5-cm and Recurrence Score that’s low. Everybody says tamoxifen. But even for a small tumor, a couple of people would go with ovarian suppression if the Recurrence Score was 20.

We go up to 1-cm and you bring up the issue of ovarian suppression and ablation. Everybody else says tamoxifen. But again, when we increase the risk and it gets into the intermediate score where all these questions come up.

Any comments about it? Here’s what happens when you get up to 1.5-cm. Again, people seemed to, except for you Kathy, base their approach on Recurrence Score. Two centimeter now, even in a low Recurrence Score patient we’re starting to see people move over to ovarian suppression, usually with an AI, but also tamoxifen. And then 2.5 cm.

So I’d say there’s a little bit of heterogeneity in the faculty, which makes me think there’s probably a lot of heterogeneity out there in the community.

Kathy, any comments about, again, these data and the variation we’re seeing and how people thing this through. I mean I know it’s the art of oncology, but there’s data also.

DR MILLER: But I think this is not surprising. Because the data we have comes from the SOFT and TEXT trials. It comes from an older trial comparing ovarian function suppression to CMF. None of those trials included patients for whom we had the Oncotype data. So whether that should be incorporated into it, how we incorporate it into it, really requires an extrapolation. And I think what you’re also seeing is, as you increase the risk of recurrence, whether it’s because you’ve made the tumor a bit larger, or you’ve made it biologically a bit more aggressive by nudging the Oncotype score, you start to see the thresholds of risk at which we will start to consider different options.

I think this is difficult because you’re only getting the oncologist’s perspective. There is another person who’s perception of risk and benefit and toxicity is crucial here. So while I give you my best answer, that’s my answer as that’s my first option for hormone therapy as I walk in the room. It may change pretty quickly and pretty substantially after talking to that woman and sometimes in both directions. There are times that I’ve increased the intensity of hormone therapy because I have a very motivated patient who says if there is a very small incremental benefit, then I want to try that.

So I’m not surprised that there’s that difference. And I think the challenge you’re having is that the data we have always is a bit behind, because ER-positive disease has a really long natural history. So we want that 10-, and 12- and 15-year follow-up data. But that means the field has progressed and changed during that time. So then we have to stop and think about well, what does that data mean for the current treatment paradigms?

Ann mentioned it doesn’t encompass HER2. Didn’t encompass Oncotype score. It doesn’t take into account for higher-risk patients. Suppose they also got abemaciclib. Would this still add value?

DR PARTRIDGE: Could I had something to that. I think the other thing that a lot of people forget about is that while we all love the genomic expression/prediction tests, we know that they are just 1 piece of the puzzle. And it’s not black and white. And that size matters here, extent of disease, as well as grade when you’re talking about – we know from the initial studies, the validation trials initially that showed the benefits of at least the genomic — the Oncotype DLBCL test, grade and size were independent predictors of risk and prognosis. That doesn’t mean that chemo will add more, it just means that when you’re picking which endocrine therapy to give, those things should matter.

DR LOVE: So, also, you mentioned abemaciclib. You also have olaparib out there that would factor into the numbers in BRCA patients that has to be considered.

So a bunch of people, including Karen Green in the chatroom, want to get your slide from your Dana-Farber approach to monitoring. So audience, it’s in the chatroom. All the slides we’re showing tonight you can get in the chatroom. And when we send out the program it also will include that.

Ann, you mentioned that this woman was interested in future childbearing and you gave an LHRH while she got the TC chemotherapy. Can you talk about your overall approach to that issue? And your overall approach to women who are interested in future childbearing who are getting chemo? Do you usually offer ovarian suppression during chemo? Does it matter whether they’re ER-positive or not, or risk?

DR PARTRIDGE: Sure. Let me just add for that Dana-Farber algorithm, we’re actually updating that as a group this morning. So stay tuned. That was a hard-to-follow algorithm, so the devil was in the details. And I think we’re simplifying it. So stay tuned.

DR LOVE: Great. And send me the new one.

DR PARTRIDGE: Okay, I’ll send you the new one.

In terms of babies after breast cancer, I think that we are increasingly appreciating that more and more women are interested and that women do it, right. We’ve known for years that women do it. And we recently, lots of good retrospective data showing that women do it and that for the most part, when you control for tumor size and ER/PR status and treatment, women seem to do just as well if they’ve had a baby or not, but of course we worry about the non-randomized, the healthy mother bias, all those things. And so we just had the good fortune of being able to present the POSITIVE data, which was a kind of planned break or temporary interruption of endocrine therapy between 18 to 30 months into it. Try to get pregnant. Get pregnant. Have baby. Get back on, if you’re lucky enough. Try not to take more than 2 years off, at least based on the study. And the early data suggests safety in terms of similar risk of recurrence in 3-year follow-up.

So caveat, caveat. I think it’s something that we increasingly will use to support our patients. That’s how I do it now. Before that, I negotiated with each patient to try to kind of risk-based, get as much endocrine therapy as you can tolerate and tolerate your family planning being put on hold. Now at least we have POSITIVE to follow-up — or to use. But I think it’s really short-term data and that we just need to keep following these patients to help to inform our care. And make sure that it’s a temporary interruption, not a complete discontinuation.

DR LOVE: So just as you were about to talk, Abirami in the chatroom asked about, how many years is it safe to stop endocrine therapy? So we’ll take a look at what the faculty does, if we get to that slide.

We have a lot of great slides here. I’m not sure we’re going to get to all of them.

Kathy, what’s your approach to using ovarian suppression during chemotherapy to improve future fertility? In what situations will you do it? In what situations are you uncomfortable doing it?

DR MILLER: I’m not sure there are situations that I’m uncomfortable doing it. My main driver in doing it is, is this a woman who tells me fertility and trying to preserve future fertility is important to her. So we had the first randomized data from the POEMS trial years ago, in women with ER-negative disease, that had its most important endpoint being did you actually have a baby? And the women who had ovarian function suppression as an ovary preservation strategy were not only more likely to have menses return, they were more likely to get pregnant and have a baby.

We now have data from the POSITIVE trial that also gives us important data about the success of those pregnancy attempts, which is really helpful information to share with women and to help guide their decision-making.

I think we also have to keep in mind that preserving fertility doesn’t mean that that woman will choose to use that fertility. That’s a separate decision. And I’m not in the habit of arguing with women’s reproductive decisions, regardless of what they are. So if she tells me that this is important to her, I will try to preserve that as an option for her.

Now she had really high-risk disease, those conversations about using that fertility are very different. But it’s not because I can point her to data that says the pregnancy itself is going to increase her risk — it’s with the risk of recurrence that we know you have; how does bringing another child into the world and into your family fit into that risk? Is your partner on board for that risk and that potnential that they may be a single parent for a child or another child. Those are very complicated, personal decisions. I don’t think I should reduce the woman’s ability to have those conversations if she wants to have them.

DR LOVE: So, yes. What a challenging situation. Here’s an interesting comment, kind of surprises me, Ann, from, again, Dr Green who is asking about your suppression algorithm. Maybe this is why. She says, and I’ve not heard this, but you tell me, anecdotally, we found goserelin to be more effective at ovarian suppression than leuprolide. Is that true?

DR PARTRIDGE: I think that’s anectodal, and an interesting one. I have not seen any data to support that.

DR LOVE: Actually, it should be fairly straightforward to look at, right? I mean yo should be able to look at that.

DR PARTRIDGE: There have been some head-to-head comparisons where there’s no clear difference. But I can’t remember whether they did a head-to-head of goserelin to, or who was included in the mix. They all seem to get people suppressed on average.

DR LOVE: Yeah. I mean that was kind of my impression, that’s why it sort of surprised me.

Case: A woman in her late 20s with a 2.8-cm ER/PR-positive, HER2-positive Grade III intraductal carcinoma — Dr Miller

DR LOVE: Okay, let’s go onto to another case. Kathy, this is your patient, a 28-year-old woman. What happened with her?

DR MILLER: So this was an interesting route of diagnosis. So this was a 28-year-old woman whose breast cancer was identified during a physical examination as part of the fertility evaluation with a reproductive endocrinologist, who did a full physical examination of a woman that included examining the breasts. that identified a 1. — about a 1- to 1.5-cm mass on exam. It was over 2 cm on imaging. And by biopsy, it was ER-positive and HER2-positive.

She was very interested in fertility, so she began an LHRH agonist before beginning neoadjuvant chemotherapy with HER2-targeted treatment.

Tolerated that okay. I think struggled more with the ovarian suppression than the chemotherapy, that when they’re all going on at the same time it’s a little bit hard to know how much of the toxicity to apportion to different points of things.

At the time of her surgery, she had a pathologic complete response. So she finished the year of HER2-targeted therapy as planned. As we added an aromatase inhibitor to the ongoing ovarian function suppression, she really struggled with the toxicities of that. And she’s one of the women who we stopped the aromatase inhibitor, added tamoxifen as the ovarian function suppression dance partner, and she tolerated that combination quite well and was able to continue that.

About 3 years later, she said, I’m really tired of this. I started this whole path because I wanted to have a baby. I still want to have a baby. I’m now 32, about to turn 33. It’s time to do this. and I think over that passage of time and with such a great response, her fear of recurrence of her breast cancer was also not nearly as raw as it was when she was first diagnosed.

So she had very good questions. Is it safe for me to get pregnant if I stop the ovarian function suppression? Am I going to be able to get pregnant? And how do I do this?

Now she actually was one of the patients on the POSITIVE trial. So at that point, she had been on her ovarian — hormone therapy for between the 18- and 30 months. And enrolled in the POSITIVE trial so she could contribute to the data that would guide other women.

She did successfully become pregnant and delivered a healthy baby.

And we’ve seen, as Ann just alluded to, the initial early results of the POSITIVE trial. We’ve talked about the long natural history of ER-positive breast cancer. So these early results, while reassuring, are going to have to require ongoing follow-up and those women will still be followed.

But we did the pregnancy outcomes which I think are also helpful for patients. And I think actually were more positive than we might have expected. So we see of the women who attempted a pregnancy, roughly three quarters of them were able to become pregnant. The vast majority of those delivered a healthy baby. The likelihood of fetal complications, of maternal complications during pregnancy was quite low, and certainly similar to what you might have expected from an age-matched pregnancy — pregnant cohort. And two thirds of the women who wanted to breastfeed were able to breastfeed.

So I think this was helpful data to be able to share to patients in this, that the idea of getting pregnant after breast cancer is not a pipedream. That for women who are interested in that, most of them were able to accomplish pregnancy and deliver.

So she is continuing to do well. Is actually now back on her hormonal therapy. Given her toxicities, her period of time, we’ve elected that her ongoing hormone therapy is just going onto to tamoxifen alone and not going back to ovarian function suppression.

DR LOVE: So, Douglas in the chatroom wants to know were harvested eggs used?

DR MILLER: She did not use her harvested eggs. They are still sitting in wait.

DR LOVE: Interesting. So, really amazing. Almost three quarters of these women actually had pregnancies. And Ann, as soon as the program for San Antonio came out this year, I started hearing from oncologists in practice, “I want to see that presentation” and I think it was a really historic presentation. What an incredible effort, getting 500 women across the world to participate in this. Incredible. I love the initial comment you made about we want our patients not just to survive but to thrive.

Any other points you want to make about this study? And what you’re looking forward to see in the future?

DR PARTRIDGE: Sure. I think it is important, in light of the kind of positive outcomes about the babies, about 40% of the people in the trial indicated that they had used some form of assisted reproduction while on trial. We don’t know if pregnancy resulted in that and who among the people who didn’t get pregnant did that. So we need to do some more digging into those data. But it wasn’t all natural conception, although the majority looks like it was natural conception. So I think that’s important.

And again, I would emphasize that I’m very reassured and optimistic and think these are great findings, but as Kathy alluded to, I do think, especially in higher-risk patients, but even in lower-risk patients, which isn’t no risk, while we right now don’t it does harm to become pregnant, we had data to support that, I think people live with risk. And that these are real and hard conversations to have with people. And we’ll have to follow this cohort longer just to make sure that the pregnancy doesn’t have some later risk that becomes more evident.

DR LOVE: So more questions from the chatroom. So, Cynthia was to know would you consider to use tamoxifen instead of an AI in HER2-positive patients? I’m not sure where that comes from. But I was going to ask you anyhow, Kathy — is your approach to endocrine therapy fundamentally different in patients who are HER2-positive, Kathy, or pretty much the same?

DR MILLER: It’s really not different. I think the only way it’s different is, I make all of my therapeutic decisions starting with what’s the risk, residual risk, if I do nothing more than what has already been done? And for the HER2-positive patients, because there is such benefit in reducing their overall risk by inhibiting HER2, there’s less risk to work with for me. So the only way it may impact that is in some of those borderline cases where the residual risk starts to look so small that it would be harder to justify increasing the intensity of the endocrine therapy. But outside of that, no.

DR PARTRIDGE: I would just add that I totally agree with Kathy, as usual. For example, if you had somebody who might be a candidate for the APT regimen of Taxol/Herceptin or trastuzumab, excuse me, those patients in the seminal trial that suggested safety from that treatment, the premenopausal people, the vast majority only got tamoxifen and they did extraordinarily well. And so, I think that we want to use the data we have to inform this.

I think the person who put in the question was probably referring to the old SOFT/TEXT data that suggested maybe a better effect from tamoxifen in people with HER2-positive breast cancer. But it was a very small subset of people in those data and even the statistician said, please don’t pay attention to that at this point.

DR LOVE: Yeah, she referred to a HOBOE trial, which I just looked up, adjuvant triptorelin. Anyhow, maybe there is some data there.

Another question from the chatroom, Kathy — does lobular histology affect your decisions?

DR MILLER: Also no. In general, lobular cancers are much more likely to be estrogen receptor-positive and strongly so. Rarely will you see a lobular cancer that’s estrogen-negative unless they call it pleomorphic. Also, unless they call it pleomorphic, it’s unlikely that this woman is going to need chemotherapy or through an Oncotype or MammaPrint score would be arranged to justify chemotherapy.

So our knowledge of lobular impacts our assessment of risk. But once we’ve made that assessment of risk, the fact that it’s lobular versus ductal is not going to change the way I approach it from that point on.

DR LOVE: So just a little bit more from our survey. We were talking about HER2-positive disease. Ann, we put out this 28-year-old premenopausal woman, 2.8-cetimeter HER2-positive tumor, interested in preserving fertility. Gets neoadjuvant chemo, HER2. And then the question is, when would you initiate GnRH? And most people say with chemotherapy, as you would in a HER2-negative situation.

Also, the question about we just got into with the POSITIVE trial. We said would you do that in a patient a low-risk tumor? Everybody says, yes. I’m not sure they would have said it before.

We also asked with node-positivity, people have either done or would do in the right situation. Oops, I think I went the wrong way there.

And then getting back to this issue of the POSITIVE trial, we asked in a low-risk situation, how long would they need to be on hormonal therapy before you would consider it holding it in order for conception? Most people say 2 years. Dr Jhaveri says 5 years, which is kind of interesting.

Kathy, how do you think this through in terms of pregnancy and risk?

DR MILLER: So I’ll give you 2 nuanced answers — the POSITIVE trial required 18 to 30 months. And part of that was to exclude patients whose disease might have been ER-positive but really was not sensitive to hormone therapy and they had very rapid progression. Part of that was also to make certain that these were patients who were tolerating hormone therapy, so you really interrupting therapy that would otherwise be ongoing.

So that’s the best data that we have. So if you want the evidence-based answer, that’s it.

My real answer is I try to keep patients on hormone therapy until they tell me that they and their family are actually ready to start conceiving. So if that’s a bit less than 18 months, then it’s less than 18 months and I try to keep them on it as long as I can. If at 30 months they’re not ready to begin attempts at conception, but they are at 48 months, then we interrupt it when they’re ready.

DR LOVE: So Ann, actually — we’ve got so many questions coming in. I’ve never seen so many questions. I’m telling you; this is something. It’s one of the oldest forms of therapy in oncology and there’s a lot of questions about it. So here’s Christine, how long, once you stop tamoxifen, do you allow or recommend attempting pregnancy, Ann? How long do they have to be off it?

DR PARTRIDGE: So the study required 3 months for POSITIVE. Tamoxifen has a half-life of 7 days. So in theory, it should be out of one’s system by about 35 days. We were super-conservative and said, 3 months in order for it to washout and all for some heterogeneity and tissue levels maybe to washout because that, in theory, may be an issue.

The FDA has actually said, 9 months, based on some data in animals. There’s nothing that’s been validated about that in human beings. And obviously, the POSITIVE trial will go a long way to kind of debunking that, given we didn’t see a whole lot of birth defects, fortunately, so far in the 3-month setting. So I think in human beings as we’re doing it, I think the POSITIVE is providing good data to suggest that that 3-month window of washout was pretty reasonable.

DR LOVE: And we were talking about how long you people would feel comfortable allowing the woman to stay off hormonal therapy. Most people say about 2 years.

I’m curious, Kathy, how often do you run into people not wanting to go back on therapy because they feel so good once they stop?

DR MILLER: So I’ve not had that big of a problem with that and I’ve used this strategy with quite a number of patients now, but I think that’s also because by the time we are interrupting hormone therapy, if we’ve needed to reduce the intensity or adjust in response to their toxicities, we’ve already done that. So for a woman who’s been taking the drug for 2 or 3 years, we’re probably figured out to make it tolerable for her.

We have in a couple of other women who had been on ovarian function suppression, put them back on just tamoxifen, but that was also driven by they’d already had 3 or 4 years of ovarian function suppression. So we really at the point where we were comfortable not going back to kind of their full hormone therapy regardless.

DR LOVE: So Ann, getting back to your algorithm, Dr Green says, “I guess we just need to increase the Lupron dose in those patients that don’t get suppressed with the initial 3.75 mg” as you had on your slide.

Case: A woman in her mid 30s with a 3.5-cm ER/PR-negative, HER2-negative breast cancer with a BRCA2 mutation — Dr Partridge

DR LOVE: We’re going to go onto another case. We actually had a question about this scenario back when we were talking about olaparib/BRCA, for example. And Ann, you have a 35-year-old woman who has a 3-cm mass. What happened with her?

DR PARTRIDGE: So this young lady had a more risky breast cancer than the one that we were just talking about, and 3.5 cm. High grade. This woman is triple-negative. And she got genetic testing and had a BRCA2 pathogenic variant. She had some family history on her father’s side. She is otherwise healthy, and she, like Kathy’s patient, was trying to get pregnant. And we see this so often. It’s such a hard thing on these patients emotionally.

DR LOVE: How would you think through this situation?

DR PARTRIDGE: So these are always heartbreaking. So first, we acknowledge their desires for fertility and that we will work with them as best we can to preserve fertility as an option. But, quite honestly, women who die from breast cancer don’t have babies. So in order to get her to fertility, we need to deal with the breast cancer.

So we would be talking about ovarian suppression prior to chemotherapy as an ovarian preservation strategy. We’d be talking with her reproductive endocrinologist, and looking at the timing to see if we can a cycle of oocyte harvest before starting chemotherapy, if that’s a level of reproductive assistance that she and her partner would accept and would want. And then proceeding with her therapy. And other than adding those fertility preservation things before we start her therapy I wouldn’t change her therapy at that point.

DR LOVE: So, what’s the follow-up here, Ann? What happened?

DR PARTRIDGE: So she got AC-TC with pembro. Prior to that though, because we knew we were going to give her that “kitchen sink” regimen and we have no idea what olaparib would do for her in terms of fertility — we have no data on that, and we knew we wanted to consider doing that. So she went on and banked eggs and embryo. She got a decent yield, as you can see there. And she got the leuprolide through treatment. And she had a nice response to therapy. But she had residual disease, so we did — and she is currently being treated with olaparib.

I think that was her. Yeah. Yeah.

DR LOVE: Right.

So a couple of more questions from the chatroom. Kathy, your investigator colleague, Frankie Holmes is actually watching. She says, just to be clear, to preserve fertility I start the GnRH at least 2 weeks before I start chemo. I thought that was the recommendation, not at the same time? Is that what you do, Kathy?

DR MILLER: So I start it at least a week before. We try for 2 weeks before. Timing and patient anxiety doesn’t always get us 2 weeks. But we always start at least a week before.

DR PARTRIDGE: I will confess, we try and do that but we don’t always make it happen. We still do it because it’s not clear that it wouldn’t work doing it at the same time.

DR LOVE: So, here’s a couple of more questions that we put out to the faculty, now we have a 35-year woman, with multiple, positive nodes. Not interested in future childbearing. And the question is, what about oophorectomy? Surgery, as opposed to LHRG agonist?

So Ann, in general, how do you think through this issue of when to bring up surgery? Obviously, you have a BRCA patient, that’s a different story because now you have a prevention issue as well in the ovaries. But what’s your approach?

DR PARTRIDGE: So I’m increasingly impressed with the long-term late effect concerns of very premature menopause, when you don’t otherwise need it for prevention of ovarian cancer. And as you heard from Kathy, in the second 5 years we don’t know what to do for these patients. So even if you’re giving someone OS/AI up-front because they have a high-risk cancer, there are no good data for what to do in a patient like that in the second 5 years.

I tend to go to tamoxifen in those patients, unless they love being on ovarian suppression and their AI, which some do and many don’t, and I think we let their ovaries come back because it’s good for their hearts and their bones and their brains. And it’s maybe going to help prevent something worse long-term. And I think, in the absence of data, if they can tolerate getting the shots, I tend to be more in favor of using the shots. But if they have a strong preference or they can’t get into get the shots, it’s not wrong to do ablation with surgery.

DR LOVE: So, Karen Green again says, you don’t always have the luxury of time for Frankie’s approach; sometimes you have to start same day.

Here’s the faculty’s approach to duration of adjuvant endocrine therapy in a 35-year-old woman getting ovarian suppression. Everybody says 5 years. Do we have any data, Kathy, on going beyond 5 years? And any speculations about what that would show?

DR MILLER: So I’m not aware of any data looking at ovarian function suppression beyond 5 years. We know that the risk extends beyond 5 years. We also know that the benefits of 5 years of hormone therapy extend beyond 5 years. And we know that continuing hormone therapy at least with tamoxifen or with an AI in women who are naturally postmenopausal beyond 5 years, also has some benefit.

The challenge is that the benefit of that additional 5 years, when you lump everybody together, is quite small. So that also is not a simple question.

I suspect, without data, that in really, really high-risk women, there may be some benefit of continuing the ovarian suppression for a bit longer time as well, but that does become a real challenge of then balancing, what can I extrapolate that benefit might be? What am I doing to her heart and her bones and her mental health and all of those things by the ongoing ovarian function suppression.

So, other than in some of my patients who’ve elected oophorectomy, because I’m not going to put the ovaries back, and I’m not going to give her supplemental estrogen, so except in those women, I have not continued the ovarian function suppression beyond 5 years.

DR LOVE: So Ann, Dr Mallidi in the chatroom wants to know, for practical purposes, exactly how you put somebody on LHRH agonist plus an AI? She said, do you start the Lupron, check estradiol and then put the AI on? And like, what’s the timing? How exactly do you do it, Ann?

DR PARTRIDGE: So a lot of that is kind of made up in terms of the convenience, although we’re trying to do it more systematically at our place. In TEXT, they actually started it at the same time as the chemo if people got chemo. So that’s kind of important to know. And there was — and same thing when people got their ovarian suppression for preservation, there’s not a safety single. And obviously, in TEXT, the ovarian suppression, or SOFT, it won.

And so, I think you shouldn’t worry about doing it through the chemo if you know it’s someone who want to have suppressed. And anecdotally, and there’s a little bit of data from SOFT, the people who got ovarian suppression through their chemo may have tolerated it a little bit better. As you can imagine, it might be a little easier to tolerate it if it’s, like, distracted by all the chemo as opposed to kind of going up and down, emerging from your chemo, and then getting slammed again with ovarian suppression.

If I don’t start it with the chemo, which I did with our young patient, I will typically start it and then after about 4 to 6 weeks, I’ll have them start the aromatase inhibitor.

If they’re really young, I may check and make sure their suppressed. When they’re older, I tend to assume they’re going to be suppressed. And I do check everybody a couple of months out to make sure they’re suppressed, especially on an AI.

DR LOVE: So again chatroom, Kathy — premenopausal woman, this is from Jennifer, T3N1, ER-positive but HER2-positive, Gets neoadjuvant TCHP and has a path CR. What are you going to be thinking about in terms of adjuvant hormonal therapy, Kathy?

DR MILLER: So this woman still has substantial risk of recurrence. I’m sure everybody, myself included, feels a whole lot better about this woman’s future now that you know she’s had a pathologic complete response than when she was first diagnosed. But the most recent data suggests that even in those patients who have a pathologic complete response, that the extent of initial disease still impacts their risk of recurrence.

So, to say that a different way, her recurrence is still higher than somebody who had only a T2 node-negative tumor, who had a pathologic complete response.

So if she is willing, would still be thinking about initial ovarian function suppression and an aromatase inhibitor for her.

DR LOVE: Ann, I see you shaking your head.

DR PARTRIDGE: Yeah, I think she’d be someone I’d be more comfortable if she didn’t tolerate it. And it kind of depends on the extent of disease up-front. I totally agree with Kathy though, there you feel a little better peeling it all off and having a lower threshold for going to tam alone.

DR LOVE: So this is another issue that I hadn’t really thought about, but Ann brought it up to me — I thought it really made a lot of sense in very young patients — which is, we talked about the issue of using LHRH during chemotherapy for fertility preservation, but we also asked about the issue of avoiding premature menopause, which, also, in many of these scenarios that we ask people about, they use ovarian suppression not just for people interested in future childbearing but for very young patients who don’t want to go through premature menopause. Again, Ann, is that a strategy you think about?

DR PARTRIDGE: Yeah, I probably don’t think about it enough because there’s so much going on with patients. But that’s one of the — was one of the main outcomes of that POEMS trial. It was not just potential preservation of fertility where there was a modest improvement, a doubling of babies but a small number, and they were only in women under 40, but there was also a pretty significant preservation of menses and as a surrogate for ovarian function. And especially in someone with an ER-negative cancer where you’re not using endocrine manipulation to treat the cancer, why not allow that patient to have ovarian function and be able to benefit from the other good that can have for her other organs an long-term health.

DR LOVE: So yeah, thriving. Thriving. Great thought.

Case: A woman in her early 30s with ER/PR-positive, HER2-negative inflammatory breast cancer — Dr Miller

DR LOVE: All right. One more case Kathy, 32-year-old woman presents with inflammatory breast cancer. What happened with her?

DR PARTRIDGE: So this is a 32-year-old woman who, when I first met her, was 354 pounds, with gross inflammatory disease. She’s quite hirsute. She tells me she’s had irregular menses throughout her life. Very unpredictable, but rarely does she have more than 2 or 3 cycles per year.

She’s never been pregnant. She’s never attempted conception. She identifies as a lesbian and tells me she has really no interest at all in preserving her fertility.

She did not have overt metastatic disease. Her tumor was ER- and PR-positive, HER2-negative. So we did not begin ovarian function suppression or arrange oocyte harvest for her. She began chemotherapy using her actual weight to calculate the doses. Tolerated that exceedingly well. And at the time of surgery, honestly, to my surprise with an ER-positive tumor, she did have a pathologic complete response.

She proceeded with radiation and actually enrolled on a SWOG trial specifically for patients with inflammatory disease that randomizes them to olaparib-only during the time of radiation as a radiation sensitizer or not, and then began ovarian function suppression. The real challenge for her, given her history, is figuring out was she postmenopausal. She had had 1 light menses early in her chemotherapy. She had had none since. But really difficult to know, given her history, if that means she’s postmenopausal. She shouldn’t can’t meet a formal, technical definition of postmenopause.

So, she and I had long conversations about an LHRH agonist to ensure ongoing ovarian suppression. We talked about checking hormone levels, the challenge being they would tell us what her ovaries were doing on the day we drew the blood. It wouldn’t allow us to predict what her ovaries are going to be doing the next day or the next week or the next month. So if we just put her on an AI, I felt that was going to require ongoing monitoring of her hormone levels and a risk that she would only be intermittently suppressed. And that we may not know that she was not fully suppressed if we weren’t continuing to check those levels.

We did talk about a GnRH agonist. This is a woman of quite modest social means. Transportation is a challenge. So the monthly clinic visits for medical suppression was going to be difficult for her. So for all of those reasons and the fact that she preferred a permanent solution that was done and then we did not need to be concerned about suppression and whether she was on hormone therapy and fertility was not a concern, she elected for oophorectomy.

So, she’s had that. She is continuing on an AI, which she’s tolerating quite well.

DR LOVE: So, interesting she had a path CR, ER-positive/HER2 — you didn’t happen to do a preop Oncotype on her, or pre- on her to see if —

DR MILLER: With inflammatory disease? No, didn’t cross my mind.

DR LOVE: I guess not on inflammatory. That’s right. I forgot it was inflammatory. But just interesting she had a path CR.

What’s the deal with this trial with olaparib and radiation therapy? That’s an interesting concept.

DR MILLER: So, actually many people are not aware that PARP inhibitors were first proposed as a therapeutic a couple of years before the first BRCA gene was reported. And it was based on understanding of DNA repair pathways and a thought from Sir Hillary Calvert that PARP inhibition could be helpful in therapies that are effective by causing damage that would require homologous combination to repair. And one of those is radiation. So his original thought was that this could be potentially effective as a radiation sensitizer.

There’s been some small studies looking at safety. And they certainly can be given safely, at least for a short period of time, with radiation. Because the treatment duration is only 6 to 7 weeks, the myelosuppression that we’ve all come to recognize from longer-term PARP inhibitor therapy, at least thus far in our experience, has not been a problem. And this is the first randomized trial that will randomize these women with inflammatory disease, who have a 20- to 25% risk of local recurrence even with radiation, to add a PARP inhibitor or not to see if it reduces local recurrence. It has overall survival and distant recurrence as a secondary endpoint, but it’s really powered for the local disease control.

DR LOVE: So final issue I’d like to —

DR MILLER: The trial’s still going on, by the way.

DR LOVE: Yeah, it sounds like a great trial to consider.

So Ann, I’d like to just finish with some of your clinical pearls that you tell your fellows about dealing with the side effects and complications of ovarian suppression or ablation. We asked people what they do. I thought it was interesting, what kind of cognitive behavioral therapy are you doing?

DR PARTRIDGE: So, I mean I don’t do it myself for patients because it’s really generally given by a psychologist or a trained mental health provider, but CBT has very nice data for things like menopausal symptoms. And there is a, kind of canned course of 6 weeks I think, that’s been studied and shown to be effective for reducing menopausal symptoms. It also can reduce insomnia. And there have been nice, randomized trials to show that, along with anxiety. It’s the best treatment for anxiety. And of course, all these things kind of go together for many of our patients. So it’s not a bad thing.

So that’s one of my favorites if we can get access to that. Exercise, it’s plus or minus for people. I would also say — and any of the integrative therapies, or you can use, of course, the more mainline gabapentin and SSRIs. And oxybutynin is one of the latest kids on the block for the hot flashes. But often, patients don’t want to add another medication. And so, I think going with the behavioral stuff and kind of dressing in layers and cool packs is an approach many people want to take. But I tell people to have a low threshold of calling me.

And then I always step back, especially given this conversation today and some of the indications for the additional endocrine therapy can be, while risk-reducing, the benefits can be modest — I always step back and say, does she really need this? How much does she really need it? And if the answer is yes, then you continue to give them things to help them tolerate it.

DR LOVE: Yeah. Well, that’s a great thing about having a therapy that you can stop in the middle.

Kathy, you put down there breathing exercise. And maybe you can elaborate a little bit more about exercise in general, because I know you’ve studied it.

DR MILLER: So there have been some studies suggesting that aerobic exercise reduces the frequency and severity of hot flashes. There’s been at least 1 randomized study with some breathing exercises that also reduced hot flash frequency and severity. Acupuncture, in a study of sham acupuncture, significantly reduced hot flashes.

So there are a lot of options. This becomes really a question of what specialized practitioners, who are familiar with these techniques and they’re used to manage menopausal symptoms, are available in your community, available to your patients, that are going to be accessible to them.

DR LOVE: Okay, one final comment or question. Again, back to the chatroom Ann, Karen Green — she’s like my co-moderator here today — wants to know about acupuncture and menopausal symptoms. And Daniel wants to know how do you manage patients with vaginal dryness? We actually had a slide in there if you want to check it out. But acupuncture and vaginal dryness, Ann.

DR PARTRIDGE: So yeah, it does seem to work for some patients. It can reduce the symptoms and it can help some of their musculoskeletal complaints, too, if they’re on an aromatase inhibitor.

In terms of vaginal dryness, we try non-hormonal as first-line, particularly in people on an aromatase inhibitor with ovarian function suppression. We’re a little more liberal in our group when it’s tamoxifen because any systemic absorption presumably would be blocked to some degree. But if it’s a particularly burdensome thing for somebody’s quality of life, the data are pretty squirrelly, in that there’s 1 study recently out of, I think Denmark, that suggested that there was an increased risk from vaginal estrogens. But it was modest and you have to consider how bad the symptoms are for our patient.

DR LOVE: So Kathy and Ann —

DR MILLER: I’ve actually switched a couple of patients to tamoxifen because of their vaginal symptoms in that we were not able to really get their vaginal symptoms under control. So I’ve actually switched a few patients from an AI to tamoxifen because of that problem.

DR LOVE: Yeah, that’s a great point.

So Kathy and Ann, thank you so much for working with us tonight. Audience, thank you for attending. Come on back next Wednesday night, we’ll hear how people approach first-line therapy of metastatic renal cell. Are they ipi/nivo fans or TKI/IO fans? Thanks so much for attending.

Be safe. Stay well. And have a great night.

Thanks, Kathy. Thanks, Ann.

DR PARTRIDGE: Thanks, Neil.