Case 2

Dr. Matthew Goetz:

Well, I think we should move on to our next case.

This is actually a patient I took care of. She’s a 30-year-old, gravida 0, para 0 premenopausal woman who presented with a palpable mass. This was a clinical T3, grade 3, node-positive breast cancer. Obviously, this had aggressive features. She happened to be a woman who had a pathogenic variant in PALB2. When she underwent her workup, she did not have any obvious evidence for distant disease.

And a recommendation was made with this, obviously the clinically high-risk tumor, larger tumor, node-positive, to give neoadjuvant therapy. Now this particular patient, she brought up right from the start, her concern because she decided, she knew, she had done her homework, she desired fertility preservation. And, of course, we had referred her to reproductive endocrinology. But then the question comes up, “what about ovarian function suppression in this setting?

Ann, what would you tell this particular patient about the role of ovarian function suppression, obviously, in addition to the referral to reproductive endocrinology?

Dr. Ann Partridge:

I think just starting with stepping back and saying “what would we use it for in any given patient?” First, you want to think about “is it going to be part of her breast cancer treatment?” And this patient has hormone-sensitive breast cancer, and she has reasonably enough risk disease that you’re going to think about it as part of her treatment. That’s number one. And you think about that typically on the first day, right, you’re thinking about both chemo and you’re thinking about first endocrine, then plus or minus, do they need chemo? Sounds like this lady needs chemo. We could debate that, but I don’t think it’s that debatable based on how you described it. And so she’s probably going to get ovarian function suppression and remind me her age.

Dr. Matthew Goetz:

She’s 30.

Dr. Ann Partridge:

Yeah, she’s not going to get permanent suppression most likely from her chemo either. If they’re older, you can count on that. You’re going to end up wanting to give her an LHRH agonist along with any other systemic therapy. And then the question is, do you do it through the chemo or do you do it after the chemo? And as many of us know in TEXT, they did it through the chemo, and there’s some anecdotal discussion from the TEXT folks that it actually was more tolerable to get it through the chemo. We don’t know that it would make the outcomes better. That’s number one.

But number two, this lady is really interested in future fertility, and we do have a decent amount of data now and a large meta-analysis that suppression of the ovaries through the chemo, even though we’re going to want them temporarily asleep, may improve or does improve the risk of premature menopause early on and may improve babies born or fertility. Although that’s very, very controversial for lots of reasons from the reproductive endocrinology side.

Dr. Matthew Goetz:

Great. So, what I’m hearing from you is that clearly an LHRH agonist is going to play a role, and then since she’s getting chemotherapy, there is going to be the known benefit of reducing the chance of premature ovarian failure. But there is still this controversy about whether this increases the number of live births.

Katie, with regard to this patient, if you saw her in the clinic, when would you start the LHRH agonist? Just start it at the same day as the chemotherapy? Would you start it before, or how would you manage this?

Dr. Katie Ruddy:

Well, sometimes it’s a practical question, and we are starting the same day just because of urgency with getting chemotherapy going. But if there were time, and I think there likely is time in her, given that she’s going to hopefully have egg harvesting or at least discuss that, she potentially could start her GnRH agonist a week before. In the POEMS trial, I believe that’s how the GnRH agonist was administered. And if it works out for the patient from a scheduling standpoint, that’s usually what I aim for. And then if it doesn’t work out, I don’t think that there are clear data to suggest that we can’t start it the same day.

Dr. Matthew Goetz:

Thanks very much. And just a quick comment before we move on. There are a number of GnRH agonists available to us. Obviously used more commonly in Europe, triptorelin, which is approved there. In the United States, goserelin, of course, is approved as a treatment for breast cancer, but many of us do use and have experience utilizing leuprolide.

Ann, any comments from you about these different drugs that are available to us and how you utilize them in your practice?

Dr. Ann Partridge:

I think practically speaking, these decisions come down to formulary decisions and what people are trained on and used to using in their clinic or their hospital or cancer center. And then there’s also what formulations are there and what doses. And then, of course, there’s individual tolerance.

Dr. Matthew Goetz:

Great, thanks very much. Again, I think for the sake of time, we’ll just move on. And it’s actually the same case we’re going to talk a little bit about the further management of this patient.

She did receive goserelin along with her neoadjuvant chemotherapy. Unfortunately, she did have quite a bit of residual disease. So following chemotherapy, she elected for a lumpectomy and an axillary lymph node dissection. At the time of surgery, she had a 4-cm tumor, 80% cellularity with four involved lymph nodes including two with extracapsular extension. So, she did meet the criteria of a Residual Cancer Burden score of III.

This patient obviously continues to have a very high risk for distant recurrence. And as we think about now moving into the adjuvant setting, she obviously was referred for radiation therapy.

Katie, from your standpoint, what would you be thinking about for systemic therapy, and how would ovarian function suppression play into your decision-making?

Dr. Katie Ruddy:

This is a situation where I would definitely be interested in using ovarian function suppression. Ideally with an aromatase inhibitor, I usually use exemestane, just because that’s what was used in the SOFT trial and the TEXT trial. And I’d be giving ovarian function suppression with exemestane. And I’d also like to add abemaciclib based on the monarchE data to optimally reduce the risk of recurrence. She is at relatively high risk based on this multimode-positive disease even after her neoadjuvant chemotherapy.

Dr. Matthew Goetz:

Great. Ann, any additional comments with regard to systemic therapy for this patient?

Dr. Ann Partridge:

Well, this one I think really hard about should we be giving her olaparib just given she’s a PALB2-mutation carrier. And if she were a BRCA1 and BRCA2, then of course, that would be more consistent with current [data] and what was studied. And PALB2, I don’t think that they were included in OlympiA. But that said, our group has kind of agreed that based on the data we have and the neoadjuvant data we have, that we probably should include them and the metastatic data. And so, I’d be wringing my hands about that and I’d probably try and get it for her. And then if I could, I’d probably do it for a year and then do the abemaciclib for maybe a year or so. That’s making it up, but I’m just saying that’s what we’d think about at our tumor board.

Dr. Matthew Goetz:

I think this is a really good comment, a very good point. I mean, clearly this patient has a tumor that has deficiencies in homologous recombination, and we have really good evidence that these PALB2-mutation carriers do fulfill the role or the idea, if you will, of synthetic lethality in terms of utilizing PARP inhibitors. And really in a patient who’s so high risk, as we discussed, it certainly would not be unreasonable. With regard to this patient, I’m going to go on and just say that she did actually receive goserelin along with exemestane and additionally abemaciclib.

After completion of the abemaciclib, she did have some of the usual side effects. But it was noted that perhaps at about the beginning of the third year, she returned and was having quite a few side effects. So, she obviously remained on the exemestane and goserelin. Those side effects included moderate joint aching that improved with some exercise, but also a fair amount of vaginal dryness that resulted in dyspareunia. And to the point when I saw her, she said, “I’m ready to go off all these therapies and maybe I’ve had enough. You’ve given me the triplet therapy in this case, exemestane, goserelin, and abemaciclib. Do I really need any additional treatment?”

Katie, how would you manage a patient like this?

Dr. Katie Ruddy:

This is such a common problem and obviously from a vaginal dryness standpoint, I don’t know if she’s already tried nonhormonal approaches, but certainly I try to advise patients on nonhormonal approaches, even at the initiation of GnRH agonists. Just because vaginal dryness and dyspareunia are so, so common. Lubricants and moisturizers, assuming that those have already not been adequate, we do sometimes consider something like a vaginal DHEA in patients who are receiving aromatase inhibitors. From a joint ache standpoint, there’ve been some really good randomized trials to show that there are several options here. Acupuncture actually has been proven to be potentially beneficial for some patients for joint pain from aromatase inhibitors.

Duloxetine also has some randomized trial data supporting that. And then also just from an exercise standpoint, there was actually a randomized trial of exercise suggesting benefit for arthralgias in patients on aromatase inhibitors. I often discuss all of those with patients and then hopefully they can feel better with one of those approaches. Now the other thing to say is that of course, even despite multiple options for treatment, they don’t always work. And sometimes we need either to switch over to tamoxifen or both switch over to tamoxifen and stop ovarian function suppression, because as Ann said earlier, something is better than nothing. We don’t want to be pushing patients to continue treatments that really are not working for them from a quality-of-life standpoint when they might feel much better on tamoxifen monotherapy. And that is also a very reasonable option.

Dr. Matthew Goetz:

And just a follow-up to that, if you look at, for example, the Oxford Overview as it relates to the postmenopausal setting, and by the way also data now that are recently published in the premenopausal setting, the real benefit of what I call “deep estrogen suppression” occurs early on. And I think this is something again we need to really think about in terms of if we have a patient that’s out 2 and a half years and is having quite a bit of difficulty. Just feeling comfortable about making that switch to perhaps a slightly less aggressive approach in light of the other alternative option, which of course is to do nothing at all.

Ann, I wanted to ask you about this particular patient. Assuming that the patient for whatever reason has exhausted the nonhormonal approaches to manage some of her vaginal symptoms and dyspareunia. What are your thoughts about utilizing estrogen-based therapies in these patients?

Dr. Ann Partridge:

Well, Matt, I think it’s a tricky area. I think we’re more comfortable letting people or supporting people to use estrogen-based therapies topically. If they’re on tamoxifen, given they’re on the blocker, and then typically they’re a little lower risk as we just discussed. I think when people are on aromatase inhibitors, it’s trickier because there is some systemic absorption. There are some data that suggest that there may be some increased risk of recurrence, and then there are data that suggest probably not. And it’s really, I think, quite controversial. As Katie said, we try all nonhormonal approaches first, and if people are really intolerant, then it’s a very personal decision. How uncomfortable are you and how high a risk? And even then, at some point, that person needs to live their lives. And so typically, it’s try it for a while, use the least amount possible, try and switch over to regular moisturizer and lubricants that are nonhormonal as tolerated.

Dr. Matthew Goetz:

Yeah, I think this is such a good point because sometimes I think as clinicians, we sort of think in terms of the black and white, it’s either yes or no, but there’s oftentimes shades of gray, and we want to get our patients through therapy. And I think your approach there, Ann, there’s a lot of wisdom there.

I’m going to just take one step farther on this case, Ann, this is for you. Let’s just say the patient actually did well. She received a total of 5 years of therapy. She was actually able to take the goserelin and exemestane and finish out 5 years. Obviously, she remains at higher risk. And I think the role of extended adjuvant hormonal therapy in these younger women is an area where we have perhaps not as much data. What would you counsel her with regard to the role of extended adjuvant hormonal therapy here, and what would be your approach?

Dr. Ann Partridge:I’m so glad you asked this. Katie and I have been working actively on this question now for many years. And I think to date, the answer is we don’t have much data for premenopausal women in the second 5 years. The only kind of robust randomized data we have are from the aTTom and the ATLAS trials, which studied tamoxifen 5 versus 10 years for all-comers and included both premenopausal and postmenopausal patients. The vast majority, of course, were postmenopausal in those studies, but there did appear to be benefit in both pre- and postmenopausal patients for a second 5 years of tamoxifen after a first 5 years of tamoxifen compared to not taking more tamoxifen. Now of course, that's not what we do anymore. And for our higher-risk people, we’re giving them ovarian suppression with either an aromatase inhibitor usually or tamoxifen in the premenopausal setting.

But for those young women who either didn’t get chemo or didn’t go into menopause, they still often remain premenopausal. So, there’s a very open question of what to do in that second 5 years. And if you took them off their ovarian suppression, their ovaries would likely come back. And especially in the highest risk women, we say, “Ooh, is that a good idea or not?” Now, because we only have data in the second 5 years for tamoxifen in premenopausal women, that’s typically what I do.

But I’m interested in hearing what you guys do. And we looked at our young women’s cohort, and the majority of women who were on extended endocrine therapy, it was tamoxifen that they were on. But that being said, we’re not sure whether that’s better or worse or the same as someone staying on ovarian function suppression and staying on either an AI or tamoxifen. This is an area I think we need to study.

Dr. Matthew Goetz:

Yeah, I think this is really critical. And obviously what’s happening in front of our eyes is we’re changing our practice. We’re using more ovarian function suppression. We’re using more aromatase inhibitors, and we’re beginning to feel much more comfortable about that. There was a little bit of concern when data first came out, but we were really getting longer-term follow-up, obviously from SOFT and TEXT. But this remains an unanswered question.