Breast Cancer Podcast

Adjuvant Endocrine Therapy

Lidia Schapira, MD; Norah Lynn Henry, MD, PhD

Disclosures

July 14, 2022

This transcript has been edited for clarity.

Lidia Schapira, MD: Hello. I'm Dr Lidia Schapira, and welcome to Medscape InDiscussion: Breast Cancer. Today we're talking about adjuvant endocrine therapy. And I can think of no better person to have this conversation with than my colleague Dr Lynn Henry. Dr Henry is associate professor of medicine at the University of Michigan, where she's the lead for the Breast Oncology Clinic at the Rogel Cancer Center. Lynn, welcome.

Norah Lynn Henry, MD, PhD: Thank you so much.

Schapira: Let's start by talking a little bit about those initial conversations we have with patients where we're recommending adjuvant endocrine therapy. What have you noted are some of the obstacles, perhaps to even patients accepting the recommendation to take the treatment? And how do you handle that in your practice?

Henry: Obviously, this is a discussion that we have a lot of times with our patients. Many of our patients have hormone receptor–positive breast cancer. Therefore, we are often having discussions about starting anti-hormone therapy or switching to a different anti-hormone therapy pretty much every day in clinic.

Any time I'm sitting down and talking with a patient, one of the things I always want to understand is what he or she is already aware of when it comes to these medications. They are so frequently used by patients with breast cancer that most patients know somebody who already took one of these medicines and may or may not have tolerated it very well. And even if they didn't, if they'd done any homework on the internet, you can find a tremendous amount of information out there about all the side effects and all the problems that these medicines cause, and you find very little about the good that they do. I think that's because we always see negative reviews on the internet much more often than we see positive reviews.

So I always like to sit down and explain why we're recommending the drug and the typical side effects that we often see, the ones that are most bothersome to patients. I reiterate that there's a lot that we can do to try to help manage these side effects if they occur. I try to stress that not every woman or man gets all the side effects, and I then really try to make sure I have an open discussion with the patient about his or her concerns. What have they heard before? Why do they think they will or will not tolerate the medicine very well? I try to start from there before we get into the nitty-gritty of exactly which medicine to recommend?

Schapira: It's a wonderful way to start the conversation. What I'm hearing you say is that you recognize that people come with their own beliefs, or some folklore, or even myths around some of these treatments that usually focus on the negative.

Let's imagine now that we've gotten past that in our conversation and you've made a recommendation for treatment. How do you actually check that somebody is taking the medication?

Henry: Often, we're only seeing patients about once every 3 months in clinic initially and sometimes even less frequently than that, depending on what other medical providers they are seeing. So I always make a point of asking the question specifically, "Are you taking your breast cancer pill?" Because if you use the medication name, a lot of patients know the name, but some of them don't but they know that they're taking something for breast cancer. Then, I also try to get a sense of how they're taking it, because occasionally people will decide to only take half a pill or they might decide to take it every other day, or they might intend to take it every day (which is what most people do) but then find it difficult to actually remember to take it every day, especially if they're not taking a lot of other medications. So I do specifically ask, "Are you taking the medicine?" Just to make sure that there isn't a miscommunication going on, that she maybe never picked it up from the pharmacy, or it never got ordered. It's also an icebreaker, to decide or to discover whether or not she's having difficulty with obtaining or taking the medicine.

Schapira: One of the things that I do in my practice, for instance, is I'll say something like "In the last month, how many times did you forget to take your pill?" And that's another way of sort of talking about problems, taking, remembering, or identifying issues with what we call adherence to the medication.

Let's talk a little bit about the side effects that many women encounter when taking aromatase inhibitors, a very effective class of drugs for postmenopausal women with hormonally sensitive breast cancer. How do you approach those conversations, and what do you find are the most common symptoms that your patients report? Not necessarily those that we read in studies, but what do patients bring to your consult room?

Henry: Aromatase inhibitors are a very important class of medicine because we have routinely been using them in postmenopausal women for the past 15 or so years. And now we're increasingly using them in women who are younger, and at higher risk for breast cancer recurrence. After we've made them postmenopausal, we definitely see some side effects with these medicines, although some women can take them and have zero side effects, which is always nice whenever people are coming to see me.

What they typically report are musculoskeletal symptoms, first and foremost. A lot of times, women will describe it as feeling like they're about 20 years older than they really are. It'll be a 60-year-old woman who comes to see me and says you know, when I first get up in the morning, I really feel like I'm 80. Often, once she moves around, though, she feels fine. It's this sort of morning stiffness that you get the kinks out after you get out of bed. Or if you've been sitting for a long time working around Zoom meetings, you end up getting pretty stiff, and then once you get going, it feels better. Unfortunately, for some women, it doesn't feel better — often joint stiffness, especially in the hands and feet. Sometimes if someone has chronic knee pain, they might have exacerbation of that pain or shoulder pain or something like that. The more unusual things that we see sometimes are carpal tunnel or trigger finger.

These are definitely some symptoms that happen in women in the postmenopausal years anyway. But we do see them at a slightly higher incidence in women who are taking aromatase inhibitors. So any time someone comes in and says, "Oh yeah, I went and saw my primary care doctor because I have carpal tunnel syndrome," I'm like, "Wait, don't go for surgery. This might be due to the aromatase inhibitor." Sometimes we can stop it or do some more conservative therapy to try to get rid of it. So really, the musculoskeletal symptoms are the biggie, but they're not the only ones.

Schapira: Talk a little bit about the treatments that you offer, both pharmacologic and nonpharmacologic, for these musculoskeletal symptoms that are so common in women taking aromatase inhibitors.

Henry: There have actually been some studies done in this realm to try to understand why women get the symptoms in the first place and to figure out how to treat them. We think they're related to inflammation due to low estrogen levels. We can't increase the estrogen levels, though, to get rid of the symptoms because that's the whole mechanism of action of the drugs. One nonpharmacologic thing is that if you have a patient who is not doing a lot of activity, the most important thing is to try to encourage activity — cardio, resistance training. These have been shown to be helpful in women who are pretty sedentary to start with when they start these medications. Having people actually start doing activity has been shown to decrease pain and stiffness. So that's first and foremost. And even if you weren't doing that to try to help reduce these symptoms, it's good from a heart health and overall quality of life perspective as well.

There's also acupuncture, which has been shown to be beneficial. It's twice a week for 6 weeks and then weekly for another 6 weeks. Unfortunately, a lot of times it's not covered by insurance. But if you can get it, if there's a provider in the area, this can be quite effective, and actually, some data suggest that even if you only get those 12 weeks of acupuncture, there seem to be some benefits — long-lasting effects of the acupuncture out even to 12 months. So that is an intervention that may have a long-lasting effect, even from undergoing the intervention just for a short period of time.

Then, thinking about pharmacologic things, often people will have tried nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen (Tylenol). Really try to avoid any opiates for this, but there are some nontypical analgesics that have been tried as well. We did a study of duloxetine, which is an antidepressant medication that actually is FDA-approved for a number of pain conditions. Now I will say that treatment of aromatase inhibitor arthralgia is not one of the FDA indications, but we do have a phase 3 study, and it showed that in women who were able to tolerate the medicine, most of them got a benefit in terms of reduction in pain, and they felt a lot better and wanted to continue taking the medication. Some women did have side effects from it. You know pretty quickly, though, if you're going to have side effects, usually within a week or so. And also, you know pretty quickly if it's going to work; most people who got a benefit saw a benefit within 2 weeks. So you're not having to wait the 4-8 weeks that you sometimes have to wait for antidepressant benefit from these medications in order to know if it's going to help for pain.

Schapira: One of the common responses from clinicians when a patient describes having musculoskeletal symptoms or any other symptoms is to rotate the aromatase inhibitor. There are three commonly used FDA-approved drugs, and so the idea is perhaps you give a break and you rotate. Can you talk a little bit about why you think that there might be a benefit? Do you think it's physical or placebo, and whether or not you use it in your practice?

Henry: Switching from one to another is definitely something that I employ in my practice. We actually did a study looking at it specifically. Half the women were on one drug called exemestane; the other half were on letrozole. If they didn't tolerate the drug, for some reason, we switched them to the other one. And about half of them were able to keep taking it. The other half did develop side effects, but not always the same side effect that they stopped the first drug for.

So, why are we able to do this? It is a little puzzling; all of the drugs have the same side-effect profile. When you look in the manuscripts, all the drugs have the similar mechanism of action, but I don't think it's a placebo response. I mean, I think part of it is that women may end up just metabolizing drugs slightly differently, and maybe part of it is an off-target effect. It's not the estrogen deprivation per se, but something else is causing some of these side effects. And so I definitely employ that.

Usually what I do is I have someone stop the medicine for the first aromatase inhibitor medicine for about 2-3 weeks and really make sure that she's starting to have an improvement so that when we start on the next one, she's not starting from a point where she has a lot of pain and we're trying to help her tolerate it. She's starting from a better place and we're able to see, is she tolerating the second one better? So we definitely do that. And both our study and another study from a French group demonstrated that this is an effective treatment approach in a standardized clinical trial.

Schapira: I know your research interest is in collecting data from patients when they are taking these medications. Can you talk a little bit about innovative approaches to having more information, and more accurate and perhaps more frequent time points for patients who are taking these medications chronically?

Henry: There is an approach that's being used fairly commonly now in the metastatic setting called "active symptom monitoring." This has been studied by Dr Ethan Basch and others, where you really trying to get information from patients in between clinic visits. Because we see patients, and then we send them home and hope that they call us if they're having a problem. But not everyone's going to do that because they don't want to bother the doctor or they don't want to wait on line at the call center. So this automated approach is something that is being tested.

There's also some being done for management of chemotherapy side effects, for instance, where you're going to have patients obviously having a fair number of acute symptoms in the 3, 4, or 5 days right after they were seen in clinic. It hasn't really been tested in the adjuvant setting where we're treating patients with these chronic long-term medications, where we're not seeing patients very often but we're worried that they may develop symptoms in between visits and may not want to reach out and tell us.

We just got funding for a clinical trial where we're going to be able to prospectively look at this. It's going to be open through the SWOG Cooperative Group, and we're going to be able to see if someone fills out these sort of frequent questionnaires that would be electronic. If they have a certain level of symptom that they report on that questionnaire, the clinic is going to be notified — hopefully not interfering too much with clinical flow — and then they can reach out to the patient to try to help her manage her symptom in between visits. By increasing the physician-patient interaction, we're hoping that that is going to enable patients to better manage their symptoms when they're not as severe and be able to hopefully get that symptom managed. It's always easier to manage a symptom when it's not as bothersome and make an intervention sooner so that the patient can hopefully stay on that medication for longer while preserving her quality of life. Because really, what it boils down to is we don't want women to be going home, taking these medicines, and feeling miserable, and then either stopping the medicine because they feel miserable and they're not sure what to do but they feel better off the medicine, or suffering. Because we see that as well: They come into clinic 2 months later and say, I've been dealing with this for so long, and I can't live like this, and they are at the point where they're ready to give up.

Schapira: Listening to you, Lynn, it sounds to me like this would be a wonderful opportunity for integrating a coaching intervention by some team member that can have frequent contact with the patient and provide some reinforcement using some positive psychology approaches.

Henry: There are some studies under way that are trying to look at motivational interviewing and other techniques, especially from pharmacists. You know, I think that we really should be leveraging all members of our care team to help manage patients and take care of patients. And that is a group that is ideally suited. They know which medications people are taking. They can help look for drug-drug interactions, and they can also help promote adherence and persistence with therapy.

Schapira: That's so interesting to hear you say that I look forward to seeing how the study unfolds and what you find.

Another frequent recommendation from clinicians is for patients to take a break from treatment. So we're imagining treatment sequences that are 5, 7, 8 years long. Often we recommend a break. Tell me how you use that recommendation, or if you actually recommend that at all.

Henry: I will recommend short intervals of 2-4 weeks if we're switching from one treatment to another. The other thing I will recommend, which we haven't talked about, is switching to tamoxifen, which is the other medication and has a very different side effect profile. Sometimes women are able to tolerate that medicine much better.

I don't generally promote prolonged breaks. I think we just don't have the data, especially in the first 5 years of treatment, to say whether that may have a negative impact on disease outcomes. We do have data saying that if you are not taking your medication and if you're not adherent, so you're not taking all the doses, or if you're not persistent, meaning you stop early, that that can have a negative impact in terms of increasing your risk for breast cancer recurrence. So, I generally don't recommend prolonged breaks, but I'm a big fan of switching either among the aromatase inhibitors or to tamoxifen.

Schapira: Let's shift our attention to sexual health and some of the urogynecologic side effects of aromatase inhibitors. What are the most common ones that you see in your practice? And talk a little bit about what recommendations you have for the women who experience these side effects.

Henry: For the aromatase inhibitors, the main one that I see is vaginal dryness, which can be very, very difficult to treat. It is estrogen deprivation. We don't really want to add any estrogen back if we can avoid it. So usually what I will do is recommend different moisturizers, different lubricants, for women to use either on a daily basis or during intercourse as appropriate. And I'll have them see their gynecologist to make sure that there isn't something else going on that needs an intervention. However, just with the profound estrogen deprivation over time, some women can end up with a lot of difficulties with vaginal dryness and atrophy and end up with recurrent urinary tract infections and be fairly miserable. There again, one option is to switch to tamoxifen, which doesn't have the same mechanism of action, so it may be less likely to cause vaginal dryness and profound atrophy.

Sometimes I will also consider using vaginal estrogen products. There are mixed data out there about their safety and in terms of breast cancer recurrence risk. It does seem like you will have more systemic absorption initially when a woman first starts to use them. Therefore, there is a little bit of worry, but over time you may not be absorbing as much and so there may not be as much of an issue in the long run. Again, it's a discussion I have with a patient. It's a discussion I have with her gynecologist, and we really have to weigh the risks and benefits. But I do have a very small number of patients in my clinic who are using vaginal estrogen products that don't use either topical estrogen, like a patch or oral estrogen. Occasionally, we'll think about either the inserts or the rings.

Schapira: The question has come up in my practice about the use of testosterone. Do you get asked that as well?

Henry: I have only been asked that once or twice, and so I generally don't recommend it. The same is true with dehydroepiandrosterone (DHEA). I generally have not been recommending those products, in part because we're able to deal with the symptoms using either the vaginal estrogen or switching to tamoxifen. But I know it is a question that has been addressed in a number of clinical trials over time.

Schapira: Are there other important side effects that interfere with a tolerance to the medication that come up frequently in your practice?

Henry: I will say the other one that comes up less frequently with aromatase inhibitors, but more frequently with tamoxifen, are the hot flashes. With hot flashes, a lot of times people think, Oh, well, it's just hot flashes. But if it's interfering with your sleep and you can't sleep because you're waking up a few times every night, I consider that to be a problem. So I do talk with patients about all the different options that we have for hot flashes now. Most of them are pharmacologic. We will use low-dose antidepressants. We will use low-dose gabapentinoids. Now we can even use low dose antimuscarinics, like oxybutynin. For all of these, we have data to say that they are helpful for hot flashes. If a woman is also having anxiety or depression, then I will use the antidepressants because then you might get two benefits from one pill. I will say, though, in general, I hate having to give a medicine to treat the side effects of a medicine because you know, a lot of times people are reluctant enough to want to take one pill, and they certainly don't want to take more than one.

Schapira: Well, thank you. That has been such an informative conversation. I hear the message from you loudly and clearly that we need to be responsive to our patients' concerns about taking the medication and encourage them to tell us if they're having difficulties. Because for most of these difficulties, we have both pharmacologic and also many nonpharmacologic interventions that have been shown to be effective.

As we wrap up, is there something else that you would like to share with our listeners?

Henry: You know, we learn so much from our patients, but we can't know what's going on with them unless we ask. So we really need to listen about their experience, what barriers they are facing when it comes to taking these medications. I think there's something psychological about being told that you have to take a medicine for 5-10 years, that somehow that's worse than being told you're just going to take it forever and really validating concerns that people have. Making concrete suggestions for how to feel better will hopefully enable people to continue taking these medications and still have a good quality of life and be able to do all the things that they want to do.

Schapira: Thank you so much, Lynn.

Henry: Thank you very much.

Resources

Adjuvant Endocrine Therapy for Women With Hormone Receptor–Positive Breast Cancer: ASCO Clinical Practice Guideline Focused Update

Evidence-Based Approaches for the Management of Side-Effects of Adjuvant Endocrine Therapy in Patients With Breast Cancer

Acupuncture for Arthralgia-Induced by Aromatase Inhibitors in Patients With Breast Cancer: A Systematic Review and Meta-analysis

Long-Term Results From a Randomized Blinded Sham- and Waitlist-Controlled Trial of Acupuncture for Joint Symptoms Related to Aromatase Inhibitors in Early Stage Breast Cancer (S1200)

Adverse Events and Perception of Benefit From Duloxetine for Treating Aromatase Inhibitor-Associated Arthralgias

Predictors of Aromatase Inhibitor Discontinuation as a Result of Treatment-Emergent Symptoms in Early-Stage Breast Cancer

Active Symptom Monitoring and Endocrine Therapy Persistence in Young Women With Breast Cancer

Patient-Reported Outcomes and Early Discontinuation in Aromatase Inhibitor-Treated Postmenopausal Women With Early Stage Breast Cancer

Effect of a Switch of Aromatase Inhibitors on Musculoskeletal Symptoms in Postmenopausal Women With Hormone-Receptor-Positive Breast Cancer: The ATOLL (Articular Tolerance of Letrozole) study

Benefits of Digital Symptom Monitoring With Patient-Reported Outcomes During Adjuvant Cancer Treatment

Cohort Study of Adherence to Adjuvant Endocrine Therapy, Breast Cancer Recurrence and Mortality

Atrophic Vaginitis in Breast Cancer Survivors: A Difficult Survivorship Issue

Caution: Vaginal Estradiol Appears to Be Contraindicated in Postmenopausal Women on Adjuvant Aromatase Inhibitors

Management of Genitourinary Syndrome of Menopause in Breast Cancer Survivors: An Update

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