Dr. Jame Abraham:
Welcome to The ASCO Post Roundtable Series on Ovarian Suppression in Breast Cancer. I'm Dr. Jame Abraham, Department Chair, Hematology Oncology at Cleveland Clinic. Joining me today are two of my colleagues, Dr. Roesch and Dr. Ali. Dr. Roesch, if you could introduce yourself.
Dr. Erin Roesch:
Hello, my name is Erin Roesch. I am a breast medical oncologist at Cleveland Clinic.
Dr. Azka Ali:
Hi, my name is Azka Ali, and I'm a breast medical oncologist at Cleveland Clinic.
Dr. Abraham:
Thank you, Azka. Thank you, Erin.
Today we'll be discussing ovarian function suppression and its role in the treatment of breast cancer with three patient cases. Our final installment will focus on management of metastatic ER-positive breast cancer. So let's dive into the case scenario.
So this is a young patient, she's 35 years old, of course, premenopausal. She palpated a right breast mass, and then of course, on imaging, it is fairly large, it's about 6 cm. Of course, she had suspicious lymph nodes. The biopsy showed invasive carcinoma of no special type, grade 2. She had right axial lymph node biopsy, which confirmed invasive carcinoma, and her biomarkers are ER strongly positive, more than 95%; PR 5%; HER2 IHC, 0. And because she's really young, she had a germline testing done, and that came back as negative.
Because of her young age and locally advanced disease, she had a breast MRI, which showed a nonmass enhancement in the right mass, and at least seven abnormal axillary lymph nodes. So during evaluation... So let me pause. Dr. Roesch, so this is a pretty unfortunate situation, right? She's really young, really locally advanced breast cancer. So what's going through your mind at this point?
Dr. Roesch:
Yeah, no, I completely agree. Very young woman, large tumor, ER positive, however, multiple lymph nodes involved. So the first thing going through my mind is, I think we need to obtain staging scans and take a look elsewhere and assess for any evidence of breast cancer spread.
Dr. Abraham:
Right. So it's interesting to see a PR-positive and a lot of time, we see triple-negative and HER2-positive in these young patients. And which patients you do staging, Dr. Ali? She meets the criteria. Of course, she meets the criteria, right?
Dr. Ali:
Yeah. So for my patients with larger tumors, that typically would be over 2 cm or more or T2 tumors. And the more I do this, I feel like any lymph node involvement is now starting to worry me. Of course, not all node-positive breast cancer is the same, but I think, once again, you look at the age, the biology, some of the other features like grade, PR status, HER2 status, of course, the triple-negative and the HER2 enriched are the ones I'm more worried about. But this patient, young patient with a large mass, with a lot of lymph node burden, I think I would definitely stage this person.
Dr. Abraham:
Right, right. Yeah. Locally advanced plus cancer. Yeah. Of course, stage III for sure, stage 2B and higher and stage II, as you said, depending upon some of the biology. So it looks like, and the story is even getting more complicated, in that she had back pain, she had an evaluation at the ER, and that she had a PET scan, which showed fairly extensive disease, which actually showed hypermetabolic right breast mass. She had nodal involvement in the right axilla. She had the hilum, mediastinum, and then multifocal bony metastasis and possibly, possibly early liver metastasis too. So Dr. Roesch, what do you think? Where will you go from here?
Dr. Roesch:
Yeah, so I think the first step, if feasible, I would assess for whether we could do a biopsy of a metastatic site. That might not always be, again, feasible or that we're able to do it, but I think that would be the first thing I would consider to, again, not only diagnose metastatic disease, but also to repeat the biomarkers, ER, PR, and HER2, to ensure that... This looks similar to the breast primary, which it most likely is, but I think that's important that we would do that, if possible. That would be the first step.
Dr. Abraham:
Right. Yeah, absolutely. Yeah, you're right. I always do that. Even though you're right, she has really extensive lesions, but I think it's good to do that and to make sure. So, Dr. Ali, how often do you see metastatic disease?
Dr. Ali:
Yeah, it's not real common, but I feel like more and more young patients we're seeing a higher incidence of de novo metastatic patients. With some of the more aggressive tumor biologies, we think there may be a correlation with race and Black women and even Hispanic women, especially in particular with triple negative breast cancer. But I would say the more common picture in a young woman is going to be an early cancer, just the general demographic of breast cancer. But certainly, we do catch these patients that are unfortunately young, pre-perimenopausal and de novo metastatic.
Dr. Abraham:
Right. And again, of course, breast cancer, it's global, and it's all over the world. And I'm born and raised in India, and again, the staging is still in different parts of the world. India, in general, tend to have more of de novo metastatic, or let's just say about 10% to 15%. And then of course, stage III, locally advanced, again, about 10% to 15% or so. So you're right, yeah. Again, young patients, it's a totally different story. Okay, so now, as Dr. Roesch said, let's just say we do the biopsy, confirm the diagnosis, and then she has pretty fairly disseminated disease, and let's just say that's ER positive, HER2 negative. Where do you go from there, Dr. Roesch? How do you treat from here?
Dr. Roesch:
Yeah, so I think that after biopsy, I would discuss and begin first-line endocrine therapy. This is a premenopausal patient, so that would include a GnRH analog as well as an aromatase inhibitor. And then I would combine that with a CDK4/6 inhibitor. And this would be the standard first-line approach for this patient. There was data presented, the RIGHT Choice trial recently at San Antonio, which did show that this approach of endocrine therapy plus a CDK4/6 inhibitor produced outcomes that were just as good or better, rather, than chemotherapy for these patients with high tumor burden, a lot of visceral involvement, visceral crisis, if you will, and less toxicity. So I would feel comfortable with that approach for this patient.
Dr. Abraham:
So that's a good point. Before 2015 or let's say 2014, if you see a patient like this, we are jumping into chemotherapy. So that is a huge difference in the last, roughly, 10 years or so. Right?
Dr. Roesch:
Right. And I think that trial confirmed what many of us were already doing, I think in practice. And so, very reassuring for, again, this approach for our young patients.
Dr. Abraham:
Right. So Dr. Ali, so let's say ovarian function suppression and then AI. So you select a CDK4/6. You have any preference for the CDK4/6 or any comments or any thoughts on that?
Dr. Ali:
Yeah, I think we have pretty good data from MONALEESA-7 which looked at pre- and perimenopausal patients, and 60% of those were truly de novo metastatic that had not received any endocrine therapy in the adjuvant or neoadjuvant setting with both a short-term progression-free survival benefit and an overall survival benefit. So that would be probably my CDK4/6 of choice in this patient. There's also some good data with abemaciclib, which is another CDK4/6 inhibitor. So I think right now, especially in light of some of that lack of survival data from PALOMA-2 featuring palbociclib, I would say for my pre-, perimenopausal, even postmenopausal patient, incorporating the palbociclib data, I think my preference would be ribociclib or abemaciclib in this young patient. I agree with Dr. Roesch of partnering that with ovarian function suppression and aromatase inhibitor once ovaries are adequately suppressed.
Dr. Abraham:
So let's just say you pick letrozole and you pick ribociclib, how do you do the ovarian function suppression? Dr. Roesch, how do you do that?
Dr. Roesch:
Yeah, so in this case, and again, being that she is very young, I would recommend a monthly GnRH analog in this case with monitoring of estradiol, of hormone levels. One of the things that could be discussed with these patients who are going to be recommended ovarian suppression longer term is the option of a bilateral salpingo-oophorectomy, or BSO, but at least initially, I would start out with monthly GnRH analog.
Dr. Abraham:
Do you have a choice? Or with goserelin vs leuprolide?
Dr. Roesch:
It's a great question. Oftentimes nowadays I'm finding it dictated by insurance. So I wouldn't say a particular preference. It often will depend on what is approved for the patient.
Dr. Abraham:
So Dr. Ali, so one of the thing Dr. Roesch was saying, a patient she will do monthly. So are you worried about ovarian escape in these patients?
Dr. Ali:
Yeah, it's interesting you mention that. When we look at the efficacy data between the monthly formulation featuring leuprolide or 3 monthly formulation, every-3-month formulation of leuprolide from the U.S. data and some of the international data featuring some of the other GnRH analogs, the efficacy looks similar, which I think is reassuring on some level. But there is a notable incidence of ovarian escape and I think from SOFT-EST, what we find is that there's about a 17% or so patients that do get that ovarian escape, and possibly those are the patients that are extremely young, like 35 or younger, like this patient. There's also correlation with a high BMI, which could be correlated with ovarian escape. So I agree with Dr. Roesch. In a young patient typically that are not close to natural menopause, 45 or under, I typically favor the monthly formulation. For that reason, once again, is 3 months wrong? I'm not sure it is, but I think that's what I've done so far and I think that's what I've seen done.
Dr. Abraham:
Right, right. Yeah, you're right. I do the same thing too. In general, I'll say something like, under the age of 40, let's go for monthly injection, 40 to 45, I may still do monthly or, I'm going to talk about every 3 months, older than 45. I'm really comfortable with every 3 months, but as we were talking before, I'm getting more and more comfortable with every-3-month injection now with what happened in the past 2, 3 years. And I think at least some of the data is showing comparable variant suppression. So Dr. Roesch, do you check estradiol level?
Dr. Roesch:
I do, and I think that, again, I emphasize the importance of doing so, particularly in these very young patients or patients who you have on the every-3-month formulation. I think an interesting question is, how often do we check? I think an every-3-months interval is reasonable. And of course, if you see that estradiol is suppressed over a period of time, a couple of years, for example, you could certainly consider lengthening that interval. But I think it is an important consideration in these patients. I also think it's important to think about, what are the clinical implications of detecting ovarian escape and such. Just a thought-provoking question in my mind. But to answer your question, yes, I do monitor estradiol.
Dr. Abraham:
So, Dr. Ali, the same? Do you agree with that?
Dr. Ali:
Yeah, I typically do every 3 months, but I will say that in some of the big trials, especially the metastatic trials, I don't see that this was done. So I've questioned the practice, but I will also admit that I do also do it.
Dr. Abraham:
Right, right. Yeah. So it's interesting. You're right, there's lack of a consistency in recommendation, and then there's a variation in the tests and so, sensitive vs ultra-sensitive tests. And so I think those are all variable factors. Good, very good. So that's why in general, and as Dr. Roesch initially mentioned, young patients, those who we are thinking about, of course, long-term ovarian suppression like this patient, I discussed the pros and cons about bilateral salpingo-oophorectomy once they're comfortable with the ovarian function suppression.
Thank you, Dr. Roesch and Dr. Ali for the excellent discussion. Again, this is an unfortunate young woman with de novo metastatic disease. So here, of course, when the tumor is ER-positive, HER2-negative, the mainstay of treatment, even in extensive metastatic setting is an anti-estrogen therapy plus CDK4/6 agent. Here, of course, the patient has bony metastasis, patient will have zoledronic acid on top of anti-estrogen treatment. In a premenopausal patient, ER-positive, ovarian function suppression is a major treatment modality. So you can do ovarian function suppression by different ways, either by leuprolide or goserelin, or after starting the patient on the treatment. And when we are applying to do the ovarian function suppression for a longer period, definitely we can talk about bilateral salpingo-oophorectomy.
So some of the other takeaways are, it's important in younger patients, about 14% of the patients can have breakthrough bleeding, so it's really important to keep that in mind. There's no consistency in recommendation of how often we should be checking and what type of testing. But 3 months or 3 to 6 months, that's very reasonable depending upon the patient's age. But it's important to keep that in mind, they can have breakthrough bleeding. And then again, of course, this situation had bilateral salpingo-oophorectomy, at least we can make sure that 100% ovarian function is suppressed.
This bring us to the end of this case. Please see the other segments for further discussion about the latest data in breast cancer, or visit ascopost.com. Thank you Dr. Roesch, and thank you Dr. Ali for this exciting conversation.
