SABCS 2019: Five More Years of Femara Seems to Reduce Breast Cancer Recurrence Risk for Some Women
At the 2019 San Antonio Breast Cancer Symposium, Dr. Mamounas presented the latest results from a study looking at whether an additional 5 years of Femara after five years of a combination of tamoxifen and an aromatase inhibitor or 5 years of only an aromatase inhibitor offers benefits to postmenopausal women diagnosed with early-stage, hormone-receptor-positive breast cancer.
Listen to the podcast to hear Dr. Mamounas discuss:
the results showing additional Femara reduced the risk of distant recurrence – the breast cancer coming back in a part of the body away from the breast
the amount of improvement in event-free survival
side effects associated with taking Femara for another 5 years
how he’s talking to his patients about these latest results
Dr. Terry Mamounas is medical director of the comprehensive breast program at Orlando Health UF Health Cancer Center.
— Last updated on June 29, 2022, 2:46 PM
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This podcast is made possible by the generous support of Lilly Oncology.
Jamie DePolo: Hello. I’m Jamie DePolo, senior editor at Breastcancer.org. We’re podcasting live from the 2019 San Antonio Breast Cancer Symposium. My guest is Dr. Terry Mamounas, medical director of the Comprehensive Breast Program at Orlando Health, UF Health Cancer Center. At this conference, he presented updated results from a study looking at whether adding an additional 5 years of Femara after a woman had taken 5 years of an aromatase inhibitor or a combination of an aromatase inhibitor and tamoxifen might offer extra benefits to postmenopausal women who have been diagnosed with early-stage hormone-receptor-positive breast cancer.
Dr. Mamounas, welcome to the podcast.
Terry Mamounas: Thank you for having me.
Jamie DePolo: So the results you presented 3 years ago, which was in 2016 at this very same conference, showed that taking 5 more years of Femara reduced the risk of distant recurrence, the cancer coming back in a part of the body that’s away from the breast, but didn’t improve overall survival. Can you now summarize your updated results that you presented?
Terry Mamounas: So yeah. I updated the results with 3 more years of follow-ups, so these are now 10-year results, which will be more mature. They’ll have a lot more events, as we call them, which include recurrence of breast cancer. It includes deaths from other causes, includes second primary cancers. So we had about 260 events more from the prior analysis. The original analysis at 7 years showed the benefit for disease-free survival, but that benefit was borderline significant because by the rules of the study we did not quite reach what we call statistical significance. But there was about a 15% reduction in the risk of disease-free survival event.
When we talk about disease-free survival, we include recurrences, as I said, deaths from other causes, second primary cancers, all possible breast cancer. All of these events together. But the prior analysis as well as this analysis also looked at distant recurrence, as you mentioned, risk of developing distant disease and breast cancer recurrence overall, which includes breast cancer, local recurrence, regional recurrence, or distant recurrence plus opposite breast cancer.
So the results now are 10 years for disease-free survival, which was the primary endpoint, showed a significant benefit. About a 4% absolute improvement. So 4% of the women did not have a recurrence or a disease-free survival event because of letrozole. The relative reduction was 16%. So very similar to the prior results, only got a little bit bigger in terms of absolute benefit with more follow-up, and the difference is not statistically significant.
In addition, we observed the same significant reduction in the risk of distant recurrence. It was about a 29% reduction and about a 26% reduction in recurrence overall. So the results are pretty solid showing the benefit as it did before.
But of course, at the end of the day the results show that only a small proportion of the women that we treat with additional 5 years will actually benefit from it. Only 4%, because the majority of the women it would not recur anyways and some will recur even with the 10 years. But in statistical terms this is significant and it’s possibly clinically significant, but of course the challenge is to identify who are the patients that need the extended adjuvant therapy.
Jamie DePolo: I’m sure for any of those women that it would improve and would offer benefits to, they want to know that and that’s very important, even if it’s only 1%.
Terry Mamounas: Of course in that update as well as the previous update, we did not show a survival benefit. Why is that? It’s actually a multifactorial issue. First of all, the differences are small. Second, women that do get a recurrence, the actual women that get a recurrence, they are treated at that point with additional therapies and usually survive for many years, therefore it’s very hard to show a difference in survival even with 10 years of follow-up. So we’ll continue to follow this study for at least 15 years or more to see whether the results change.
In the previous analysis there were a little bit few more deaths for the letrozole compared to the placebo. In other words, it was the other way around. But in this analysis, the overall survival results became more even. In fact, there were more deaths with placebo than with letrozole but numerically few more, like a handful. But certainly there weren’t more with the letrozole. So the results are moving in the right direction, but it may take another several years before we can even show if we show a survival benefit.
Of note is that several studies that evaluated long-term duration of endocrine therapy have not shown a survival benefit, except one study that evaluated 10 years of tamoxifen versus 5 and showed both disease-free survival as well as overall survival benefit. That’s the ATLAS trial with tamoxifen in premenopausal women. But none of the aromatase inhibitor trials, even after tamoxifen or after aromatase inhibitors, have shown a survival benefit. That’s probably, again, because these women do pretty well and get treated at that time that they don’t die of the disease immediately after.
Jamie DePolo: And, too, I think it’s hard if you’re only following people for 10 or 15 years. I know that the women are postmenopausal so they’re a little bit older, but they could be in their 50s. So they could live until they’re 80 or something. And my understanding is, please correct me if this is wrong, that with hormone-receptor-positive cancer you can have recurrences 15, 20 years out. So I guess what I’m thinking is if you followed these women for maybe 25 years you might start to see that.
Terry Mamounas: And some studies have not even shown benefit from extended endocrine therapy until you reach year 15. So the early tamoxifen studies initially read totally negative at 5 years. So year 5 to year 10. And then for 15 to 20 years it started showing the benefit because it’s a very long-term disease, estrogen-receptor-positive breast cancer, absolutely.
Jamie DePolo: I kind of want to emphasize for people who might be listening that it doesn’t mean that these results are bad, it just means we need more time to see exactly what the benefits may be.
Terry Mamounas: Certainly also preventing a recurrence is a worthwhile event because first of all, the patients have to be treated to remain disease free and sometimes that treatment doesn’t work forever. It works for a while and then you have to change it, and eventually you may need chemotherapy when it becomes endocrine resistant. So it’s very noble endpoint to prevent recurrence, for sure, but survival is obviously an important endpoint. But the primary endpoint of the study was disease-free survival.
Jamie DePolo: I want to ask you about the first 5 years of hormonal therapy that the women took. It looked like, from your results, that women who took the combination — so tamoxifen and an aromatase inhibitor, however that was split up — did a little bit better than women who just took an aromatase inhibitor.
Terry Mamounas: Yes, that’s true. There wasn’t statistically significant but there was a trend towards more benefit for a woman that had prior tamoxifen. But interestingly, also, younger women tended to do better than older women. This is all for disease-free survival.
I have to emphasize again, the disease-free survival includes some events that are not related to breast cancer. If somebody dies from something else then it figures into the disease-free survival. So technically, older women are more likely to have another event outside of breast cancer recurrence or death and are counted as an event. So women that took prior tamoxifen usually tended to be the younger women because they were premenopausal when they started, so they took tamoxifen, and they became postmenopausal and they switched to an aromatase inhibitor. Versus a woman who took 5 years of an aromatase inhibitor who were well into menopause. So there’s a little bias in that assessment.
We’re going to look now in more details, given this result, to see whether other endpoints, such as recurrence of breast cancer and also contralateral breast cancers, those associate also with women that took prior tamoxifen. But there could also be a biologic reason for that because it may be the switch in the treatment and giving a few years of tamoxifen and then an aromatase inhibitor might be a better strategy than giving aromatase inhibitor followed by an aromatase inhibitor. So that’s it.
Jamie DePolo: You’re going to look into those things, too, as well.
Terry Mamounas: Yes.
Jamie DePolo: Okay. Now, I do also want to ask about side effects, because we know that that is a huge issue for women taking hormonal therapy. Did you see any new side effects or did side effects hinder anybody’s adherence in your study?
Terry Mamounas: So let’s start with the reverse, adherence. Adherence is well known for studies of extended endocrine therapy that it is not very good. In our study, interestingly, with a placebo-controlled trial — so half of the women get placebo, half had letrozole — and so about 60% of the women on letrozole and 63% of the women on placebo completed 5 years of therapy. So that means that about 40% of the women, irrespective of what they were taking, they give up.
The main reason for treatment discontinuation actually was patient preference. Patients either had some effects... It wasn’t side effects though. At least recorded side effects. Side effects was one of the reasons, but that was down the list of reasons why they stopped. I think women just get tired after so many years. You took, already, 5 years, yeah, now you’re supposed to take another 5 years. So maybe at year 6 or 7 or whatever, you may say “enough of that” even if you don’t have a lot of side effects. Or sometimes maybe we perceive side effects which are not related to the medication, because the placebo was about the same rate, 60% only completed. So that’s a well known fact, and that may affect, actually, the outcome of the study. So we’re going to go back now and look again to see.
One question was asked in the presentation, what about the women that completed the 5 years, did they do better than those that did not? Now, there are some biases in this type of analysis, maybe different women complete versus those that don’t complete, but nevertheless, we’re going to look at that.
Now, the side effects, interestingly enough, there were two severe side effects that we followed, and those were osteoporotic fractures. In other words, fracture your bones based on osteoporosis, which is hips, spine, and close fracture on the wrist, which we monitor very carefully, and there was no significant differences in osteoporotic fractures. Now, we know that aromatase inhibitors cause loss of bone density and may lead to osteoporosis, but certainly in our study we didn’t see osteoporotic fractures to be increased. It was 6.1 versus 6.7, nonsignificant difference.
The other thing that we were following from the previous analysis was arterial thrombotic events. That includes strokes, transient ischemic attacks, myocardial infarctions, angina, all this heart and vessels, everywhere. So what we have noticed there was that the rate of these arterial thrombotic events were initially lower with letrozole than with placebo. But at 2.5 years, the curve switched and letrozole had more.
So when we present the 7-year data, we said we deliver the cautionary note, what if we see that continue to increase? So maybe that would explain some of the differences in survival for example. But in this analysis we found that essentially the rates have remained very stable and very close to each other. So there wasn’t, again, a statistically significant difference in favor of any of the arms for arterial thrombotic events. It was a little bit more for letrozole but not statistically significant. Four point one versus 4.7 or some very small difference. So that’s reassuring. Ten years later — of course treatment had stopped, so maybe stopping the treatment that you’re not going to get anymore, so certainly that’s not a reason to be concerned.
But those are the long-term and potentially serious side effects. But on a more daily basis there are constitutional side effects that we see with this agent. And some people, for example, may get menopausal symptoms, hot flashes, vaginal dryness, emotional changes, depression, fatigue, musculoskeletal symptoms such as arthralgias, myalgias. And those are real, and this doesn’t happen on everybody, but sometimes women have very severe ones.
I have women who tell me when they stop the aromatase inhibitor for 5 years they say I feel young again. Because what happens is you start getting this little joint stiffness and all that, little by little, so it becomes part of your life. Then when you stop all of a sudden, all of a sudden you can move again. So those are real side effects, and some women may stop for those. In our study, some did stop because of side effects and were more on letrozole than with placebo. But overall, the significant side effects were very small and not significantly different. So that’s reassuring.
Jamie DePolo: I do want to ask you when you mention the osteoporosis, were the women screened at all upfront to see if they had issues and were they treated?
Terry Mamounas: One of the stratification factors for the study was bone mineral density. So in other words, everybody had the bone density test and we categorized them according to have a low density, less -2, as we call it, or a T-score more than -2. Twenty-five percent of the patients had less than -2. The majority of those patients, 60% of those patients, were getting bisphosphonates at the time they entered the study, and 99% of those patients said they would continue. So we were covering them. They were being covered by the physician because of the low bone density.
But how many of them continue or stop later on, we don’t quite know. That’s an analysis we need to do, because we also found in this particular presentation that bone density score was a significant predictor of benefit from extended letrozole for reasons that we don’t quite understand why. It came out as a significant interaction in the multivariant analysis of benefit. So we’re going to look into this further.
Again, the fact is we do have something to do for these patients that have osteoporosis, we give them bisphosphonates and usually we can keep it in check or reverse it. But baseline bone density was a significant predictor. Maybe because most of these women, because they have low density, maybe they were older, maybe they had taken more of the aromatase inhibitor than tamoxifen and the density was lower. So there is a lot of interaction between different factors that cause this phenomenon. But we observed it, so we have to look into it a little bit further.
Jamie DePolo: That actually kind of makes my next question maybe not as important as it was, because there has been some suggestion that bisphosphonates can reduce the risk of recurrence. I wondered if that could possibly affect the results at all, if you’re going to look at that.
Terry Mamounas: It’s possible, but first of all, even if people had low bone density and they were given bisphosphonates, they were equally randomized to placebo and letrozole. In other words, the randomization takes care of that so they had equal chance to get letrozole or placebo. Why, for example, those with lower density had a lot more benefit? It may be bisphosphonates but the fact is that they were equally taking bisphosphonates.
In other words, if you had the low density, you have a 60% chance of getting bisphosphonates before you started. But those patients equally get letrozole or placebo. So it’s not like they were preferentially getting bisphosphonates in one arm versus another.
Jamie DePolo: You didn’t have a big clump of low-density people in one arm.
Terry Mamounas: Right. It was all equally distributed. But it’s possible there is an effect of bisphosphonates, for sure. Studies have shown an effect, particular in postmenopausal women, but the effect hasn’t risen to the evidence that we can recommend bisphosphonates without having osteoporosis. In other words, you don’t give bisphosphonates to reduce risk of recurrence because it didn’t work that well. But if you have osteoporosis, it’s very easy to say yes, you take bisphosphonates, you may get some benefit as well.
Jamie DePolo: So overall, how are you going to talk to the patients that you treat about these study results?
Terry Mamounas: These results reinforce a little bit of the belief that certainly the treatment works. However, we know still the benefit is modest, only about 15% relative reduction and 4% absolute improvement. So we still need to talk to our patients about risk factors for late recurrence and also factors potentially that benefit from extended endocrine therapy.
So the factors that you consider, for example, is the age of the patient, the nodal status of the patient. If somebody was node positive, had a big tumor before, they have more risk of recurrence. So clinical pathology factors figure into the remaining risk of recurrence, and the rate is higher if you were node positive upfront, even if you go 20 years later. You notice essentially that the rate continues to be higher.
We also have to talk to them about their tolerability of the drug for the first 5 years, because if they don’t tolerate it well they can’t wait until they get off, and that’s not a good quality of life. But if they tolerate it well and say, “I’m doing fine, I don’t have any problems, should I continue,” then we’ll look at other factors. With clinical pathology factors we can only get so far.
Nowadays, we’re looking more into the biology of the tumor to predict who may benefit from extended endocrine therapy, and there’s tests that do that. Genomic profiling tests, one for example is the Breast Cancer Index that is being used in year 5 to determine how much benefit you get from additional therapy and also what is your risk of recurrence. There are several other tests that also predict risk of recurrence. We’re evaluating now several of these tests in material from this trial to see whether they will predict risk of recurrence and whether they will predict benefit from endocrine therapy. Because so far there haven’t been many studies that looked at the aromatase inhibitor over 5 years followed by an aromatase inhibitor. That’s sort of the missing puzzle.
There are studies with, for example the Breast Cancer Index, that it shows if you take tamoxifen for 5 years versus 10, you can predict benefit from endocrine therapy for extended endocrine therapy. If you give tamoxifen followed by an aromatase inhibitor, you can predict. But there is no data with the aromatase inhibitor followed by an aromatase inhibitor. So hopefully we will get some data to help us with the decision for a patient, too.
The other thing, of course, is comorbid conditions. If the patient has a lot of cardiac events or severe osteoporosis that does not reverse with bisphosphonates, then that may not be the best option.
Jamie DePolo: I’m thinking, too, maybe women that already have arthritis and already have a lot of joint pain, it may not be the best.
Terry Mamounas: There are some things you can do to alleviate some of this, including things like acupuncture or anti-steroidal anti-inflammatories, exercise, and they do help. But in general not everybody gets it, but the patients that get it sometimes they get it severely. Fortunately few but yet it is a problem.
Jamie DePolo: Thank you very much. I appreciate it.
Terry Mamounas: My pleasure. Thanks for having me.