Does 2.5 to 5 More Years of an Aromatase Inhibitor Offer Benefits? Maybe, For Some Women: 2016 San Antonio Breast Cancer Symposium
Terry Mamounas, M.D., M.P.H.
December 7, 2016

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In 2012, research results showed that taking the hormonal therapy tamoxifen for 10 years instead of 5 offered more benefits for women diagnosed with early-stage, hormone-receptor-positive breast cancer, including less recurrence and better overall survival. Since that time, researchers have wondered if extending the time a woman with early-stage, hormone-receptor-positive disease took an aromatase inhibitor would offer similar benefits.

In this podcast from the 2016 San Antonio Breast Cancer Symposium, Terry Mamounas, M.D., M.P.H., medical director of the University of Florida Health Cancer Center, discusses the results of his and other studies looking at whether 2.5 to 5 additional years of Femara (chemical name: letrozole) after 5 years of an aromatase inhibitor offered better survival or lowered the number of recurrences.

Listen to the podcast to hear Dr. Mamounas talk about:

  • the very specific group of women that may benefit from an additional 2.5 to 5 years of an aromatase inhibitor
  • which woman should not take an additional 2.5 to 5 years of an aromatase inhibitor
  • how women and their doctors can weigh the benefits and potential risks of extended aromatase inhibitor treatment
  • how he plans to talk to his patients about this issue

Running time: 9:09

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Jamie DePolo: This podcast is made possible by the generous support of Lilly Oncology. Hello, welcome to the Breastcancer.org podcast. I'm Jamie DePolo, the senior editor of Breastcancer.org. We're down here in San Antonio with the 2016 San Antonio Breast Cancer Symposium. My guest is Dr. Terry Mamounas. He's director of the comprehensive breast program at the University of Florida Health Cancer Center.

There were three studies presented today that looked at extending treatment with an aromatase inhibitor past 5 years for women who’ve been diagnosed with early-stage, hormone receptor-positive cancer. And the results seem to suggest that this might be a good thing, but only for a certain group of women. So, Dr. Mamounas, who are these women and what are the benefits?

Terry Mamounas: So, because of the study showing that extended adjuvant therapy with an aromatase inhibitor results in a small but potentially important benefit, but on the other side it may have some also significant side effects, we need to be very careful in terms of who we select to extend therapy. So there's two major things that we'll look: one is the benefit from treatment and the other one is the potential for significant side effects. Now, when we assess the benefits for treatment, obviously we like to select patients that are high risk — those are usually patients that have node positive disease, multiple positive nodes, potentially, or large tumors, high grade — those patients that are deemed from the beginning that would be at a high risk for recurrence. Now, what the studies have shown that even if you are at high risk from the beginning, if even after [an aromatase inhibitor] for 5 years, you still have significantly higher risk than the average person of recurrence. So the higher the risk of recurrence, obviously the more the benefit will be from extended therapy.

Now, another important part of the benefit may be also the age of the patient, because although all of these were postmenopausal women, women under 60 in our study, the B-42 trial, seem to have significantly better outcome than women over 60. And part of this may be the fact that part of our benefit is also the reduction in opposite breast cancer, and obviously the younger you are the longer life expectancy you have, the higher potential benefit for contralateral breast cancer. So we'll look at some of these characteristics, including also some potential genomic classifiers, which actually can predict recently the recurrence. So, all this can be assessed to come up with essentially sort of the composite risk of patients and then balance this with the potential for side effects. Now, what are those?

Those are of course the potential for osteoporosis and of course osteoporosis-related fractures, so if your bone mineral density is low you're probably not the best candidate. Obviously you can give a bisphosphonate and improve bone density, but sometimes this becomes still an issue. So being at risk for osteoporosis is an important endpoint. Being older is also a significant predictor of other malignancies, also other comorbidities, and if a patient has already comorbidities at the time of enrolling or considering the extension of therapy these need to be taken into account.

So again, osteoporosis-related factors, comorbidities, also how the patient tolerated the first 5 years of an aromatase inhibitor. If they are really struggling with it and they can't wait till they get off, they’re probably not a very good candidate unless they have a significant reason. So there's no magic formula at least as of now how to do that. Hopefully in the future we can refine this model, maybe even with a statistical model where we can just put all of these factors together and come up with a decision, or at least present to the patient what will be the benefit and what will be the risk of extending versus stopping.

Jamie DePolo: And I know one of the comments this morning was that it seemed to work better in women who had 5 years of tamoxifen or combination therapy with tamoxifen and an aromatase inhibitor and then extending the AI. Is there a reason for that?

Terry Mamounas: Well, I think that was known from before, because we had already done studies back in the '90s where we gave 5 years of tamoxifen and then if women were or became postmenopausal during that time, we then randomized them to 5 years of letrozole or exemestane or one of the other... or anastrozole versus 5 years of placebo. I mean, this time it's clear we showed that there is significant benefit from switching from tamoxifen to aromatase inhibitor, but what became more evident now was what do you do after you start with an aromatase inhibitor. Now, some of these patients, as you said, had already some tamoxifen, maybe some aromatase inhibitor, and then were randomized to extend it versus not. And it appeared that those that had some tamoxifen seemed to do better, maybe benefiting more from the aromatase inhibitor. There are some potential biological implications of these. Some studies have shown that the aromatase inhibitors may induce mutations in the estrogen receptor where tamoxifen does not, so maybe treat it for a while with tamoxifen, the tumor may be still sort of prime for endocrine sensitivity, and then they respond better to the aromatase inhibitor. Obviously this needs to be explored in additional studies, but clearly there are a lot of maybe potential biological implications of this observation if it holds true.

Jamie DePolo: I want to ask you about compliance. In the studies it sounded like there was about 60% compliance for the women who were taking an additional 2.5 to 5 years of an aromatase inhibitor. Other anecdotal evidence would suggest that's not what happens in the real world. A lot of people stopped taking aromatase inhibitors because of side effects, because they just don't want to take a pill every day. What would you say to doctors as far as convincing women of the benefits of taking an aromatase inhibitor for another 2.5 to 5 years?

Terry Mamounas: Right. I think that's an important question. I was actually sort of surprised how similar the compliance rates were in the three studies that were presented today, around 60%, it was like the magic number today. I don't know how that happened. But clearly this is within a trial where we coach the patients, where we send them questionnaires, are you taking your pills, we send a research nurse, you talk to the research nurse, so you have a lot of support to continue, and yet about 40% of the patients went off.

But interestingly, in our study and in other studies, too, side effects were not necessarily always the major reason when people get off the medications. Either it was patient preference or they got tired of it. So I think we have a good opportunity to continue to educate the patients about the potential benefits of the treatment, and if they don't have significant side effects or if they do have some, to potentially address those side effects so they can improve their compliance. But don't let them necessarily get off the treatment just because they don't appreciate what the treatment does for them.

So, I think we need to clearly educate and coach our patients for the potential benefits, what you hope to get out, and what, at that point of course, becomes a burden. Then obviously you can stop. But if it's not a burden, don't stop because you say, "Well, you know, I had 5 years, you know, I'm okay," even if you potentially have high risk. So you have to educate your patients, what is the baseline risk, what should they expect. And on the opposite side of things, if they have very low risk, then you can just say, “You know, maybe you're the one who should stop because maybe your benefit is not outweighing your risk from the treatment.” So education is clearly very important, and support to the patients.

Jamie DePolo: Is that how you are going to talk to your patients about it?

Terry Mamounas: Absolutely. I will, I mean — and that's sort of in my mind how I want to approach it Monday morning. You know, if I see another patient who comes around 5 years — and I already have, in the last few weeks knowing this data — have a very in-depth discussion with the patient, looking at all the factors and counsel them about what to do. And ultimately it's their decision, but — and certainly I will give them my recommendation what I think they should do and they can always take it or not — but sometimes they will usually agree, you know, with the recommendation. Particularly if they don't have significant side effects.

Jamie DePolo: So it sounds like this is sort of another twist on personalized medicine. This is going to be a very personalized situation for women making this decision whether to extend or not.

Terry Mamounas: Absolutely. And I think unfortunately, everything we do in medicine, and the more success we have, the more patients we will treat. If you continue to improve survival, from 20% death rate to 10% death rate to 5% death rate, every time you introduce a new modality you benefit less and less patients. So, the key is to try to identify who is at risk and who's at potentially even at higher benefit, and some of these genomic classifiers have been shown to potentially predict benefit from endocrine therapy. So it may not necessarily matter how much risk you have, but if you're not benefiting from the treatment, then you don't need it. So that's what we're going to be exploring in the next few years.

Jamie DePolo: Thank you very much.

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