Managing the Side Effects of Endocrine Therapy for Breast Cancer

Drs. Hope Rugo and Kristin Rojas discuss advances in the management of menopausal symptoms, fertility preservation, and bone health for women on endocrine therapy for breast cancer. TRANSCRIPT Dr. Hope Rugo: Hello. I'm Dr. Hope Rugo, your guest host of the ASCO Daily News Podcast today. I'm a professor of medicine and director of breast oncology and clinical trials education at the University of California San Francisco's Comprehensive Cancer Center. And I'm also an associate editor of the ASCO Educational Book.   In patients with hormone receptor positive breast cancer, the most common subset of the most common cancer in women worldwide, adjuvant endocrine therapy significantly reduces the risk of recurrence and death. However, prolonged estrogen suppression associated with the use of endocrine therapy can cause life-altering menopausal symptoms, bone loss, and fertility concerns. These issues impact the use of endocrine therapy and potentially breast cancer outcome.    Today, we'll be discussing mitigation strategies to manage the side effects of endocrine therapy, which we hope will improve our patient's quality of life and adherence to treatment with Dr. Kristin Rojas, who addressed these issues in a recently published article in the 2023 ASCO Educational Book. Dr. Rojas is an assistant professor of surgery and a breast surgical oncologist and gynecologic surgeon at the University of Miami Sylvester Comprehensive Cancer Center.    Our full disclosures are available in the transcript of this episode, and disclosures of all guests on the podcast can be found in our transcripts at asco.org/DNpod.    Dr. Rojas, thank you for being on the podcast today.   Dr. Kristin Rojas: Thanks, Dr. Rugo, thank you so much for having me. Thank you to ASCO as well. It's truly an honor to be here with you today.  Dr. Hope Rugo: Your excellent article provides an updated overview of the existing approaches and a little forward thinking for improving the quality of life of breast cancer patients who are receiving estrogen deprivation therapy, a really broad term we use for all the hormone therapy we use in ovarian function suppression in the treatment of breast cancer. And then you had a very nice session education session at the ASCO Annual Meeting discussing these issues. Can you briefly discuss the educational session, your speakers and topics, and then we'll get more into the details of this important topic?   Dr. Kristin Rojas: At our educational session at ASCO this year, I chaired the session and presented on managing the sexual side effects and menopausal symptoms of estrogen suppression. And I had two wonderful colleagues with me: Dr. Matteo Lambertini, who shared guidelines regarding bone-targeted agents and managing bone health during endocrine suppression. And then we also had Dr. Terri Woodard, who is a reproductive endocrinologist from MD Anderson, who spoke on managing fertility concerns, which is a very important topic right now.   Dr. Hope Rugo: Yeah, that's great. And it was such a fabulous session. Our listeners can view it online at asco.org if you missed this session. But let's talk a little bit about what was in your article and what was discussed. First, I think the physical and psychological effects of cancer care we know are critical components of survivorship care. Can you tell me a little bit more about that and how we need to understand that as oncologists?  Dr. Kristin Rojas: So, as you know, as treatment continues to improve, our cancer outcomes are improving and the population of survivors continues to grow. So, I think that for many breast cancer patients, or having the diagnosis of breast cancer, becomes more of a chronic illness and less a life-threatening issue for some. I think that the conversation is now changing from “Will you live?” to “How will you live?” And I was thrilled to see that other big organizations, along with ASCO, are prioritizing managing these important symptoms in survivorship. Because I think that, as most patients will be on some form of estrogen suppression, managing the toxicity of these therapies, as you pointed out, probably does influence treatment adherence, which directly translates to an oncologic improvement. So, it's not just managing these soft symptoms, it actually will have a direct influence on probably overall survival along with disease-free survival.  Dr. Hope Rugo: Yeah, I think that's incredibly important and it's not just about doing the exam and finding out symptoms that might signify recurrence, it's really trying to address the effects of the treatment patients have gotten of chemo and their ongoing treatment with endocrine therapy that's so incredibly important. And now, of course, in medical oncology, we're adding on more agents which add to symptoms. That'll be the topic of next year's ASCO educational session. What do you do with the CDK4/6 inhibitors and managing those. But in more than 80% of women who are on the antiestrogen or various, I'm going to call hormone therapies, for early-stage breast cancer, vasomotor symptoms are a big issue. They're typically more severe in younger patients because of course they have estrogen and we take it away. So, how do we mitigate this problem in patients that can result in poor sleep and impact many aspects of one's psychosocial status? And these issues, not sleeping, of course, you make everything worse.  Dr. Kristin Rojas: Yeah, that's a really important point. And you're right, this is a really common symptom experienced by the majority of patients on endocrine suppression. And not only those patients, but patients with triple negative disease who are put into menopause from chemotherapy, etc., along with women with cancer of other disease sites. And so, as the director of our program at the Sylvester Comprehensive Cancer Center, the program is called MUSIC, which stands for Menopause Urogenital Sexual Health and Intimacy Clinic.    This is a very common symptom that patients often report. And one of the important things about this that I've realized is that hot flashes or vasomotor symptoms can actually have a pretty varied presentation. So, it's not just intense sweating. Sometimes these patients can present with palpitations, panic attacks, and they don't even realize that they're hot flashes. This is an effect of estrogen suppression and it's a central mechanism. So, it's probably related to hypothalamic dysregulation regarding how our body senses temperature changes, but it results in widespread flushing and sweating and those other aspects I told you about.   So, we've known for a long time that there are some behavioral modifications that can help with vasomotor symptoms or hot flashes. But now, we actually do have some pretty effective pharmacologic therapies for these patients as well, for whom behavioral modifications aren't completely helping the issue. Or, as you said, when patients are being woken up all night long with these hot flashes, it totally disrupts how their day goes and disrupts coping with their disease and all the other aspects of their treatment.   So, there's some effective treatments that we have. One of those being cognitive behavioral therapy has been shown to be helpful. The data on acupuncture is mixed, but I'm hopeful about this. And then the pharmacologic therapies we have. Traditionally or historically, clonidine, which is an alpha agonist, has been used along with gabapentin. But I think when choosing a medication to prescribe to a patient for hot flashes, you have to take into account the side effect profile. Clonidine does have some issues with blood pressure rebound, and gabapentin is really only effective in large doses, which can be very sedating for patients.    In the MUSIC Sexual Health After Cancer program, we typically stick to low dose SSRIs or SNRIs. I usually go with venlafaxine at a really low dose of 37.5 milligrams, and I can titrate up. I have patients take it at night in case they feel a little foggy when they first start it. But more recently, we've started using oxybutynin, which is an anticholinergic medication originally FDA approved for overactive bladder. I use the XL formulation, or you can do 2.5 or 5 milligrams BID. And this, in a study a few years ago, was shown to significantly reduce hot flashes and improve quality of life in a placebo-controlled trial.   So, important aspects of side effects of these medications with SSRIs or SNRIs working in the MUSIC Sexual Health After Cancer Program, sexual health concerns are often an issue, so those drugs can be libido zappers sometimes. But, the biggest side effect I've come across with oxybutynin for patients is dry mouth, and usually that resolves after a little while. So, we've had a lot of success in managing patients' hot flashes with these medications.  Dr. Hope Rugo: That's great and incredibly helpful. And I will say that as we're talking about these issues on this podcast, this is really important for all of our staff and our clinics because most of us don't have a fabulous clinic like the one you've started. But we are managing this with our staff, our APPs, and other areas that our patients are seeing. If everybody has this education, it will really help in the management of symptoms. And I just want to point out that venlafaxine was the first drug to be studied in this area really successful, but that we can use a whole host of different antidepressants. If people have side effects from one another, one may work really well, and generally low doses work well. The oxybutynin was such a very cool study. I think that's a great additional option.    In addition to hot flashes, we also see genitourinary syndrome of menopause, and that's part of what you deal with every day in your clinic, GSM. And this can be not just vaginal dryness, which is bad enough, but also increased infections, painful sex, recurrent bladder infections and also reduced libido, which is a really big issue, we just don't talk about very much. What's the most effective and safe treatment for GSM? And we use a lot of low dose vaginal estrogen and a variety of delivery mechanisms. What are the risk and benefits when patients really need something more?   Dr. Kristin Rojas: GSM, or genitourinary syndrome of menopause, is this newer umbrella term for what we used to call vaginal atrophy. And you're right, it encompasses not only dryness, but all the other changes that can happen to the vulvovaginal mucosa along with anatomic changes to the pelvic floor. This is critically important, I think, that we address these issues or these potential side effects at the time of endocrine therapy prescription because what we have found in our program is that while hot flashes might get better, these symptoms do not get better. And left untreated, they get worse.   And one of the surprising findings that we have presented earlier at another conference this year was that almost half of our patients, when they had their pelvic exam in the program, were also found to have vaginal stenosis. So narrowing and shortening of the vagina, making penetrative sex actually impossible. So it's really not just dryness, but a host of these other symptoms that go along with that. I like to break this down in a really simple way because I know that a lot of providers may be intimidated when patients might bring this up. But I think about it this way. Number 1, eliminate irritants. Number 2, moisturize. Number 3, lubricate. And 4, address the pelvic floor.   Oftentimes when patients present in the MUSIC program, they've been putting a lot of over the counter topical therapies on the vulva and the vagina using intravaginal washes. One of the biggest offenders of some of these symptoms is artificial fragrance, which we can actually develop an allergic reaction to, which manifests as burning and stinging. So these patients may also report burning and stinging in addition to dryness. These offenders can be in all kinds of products. So not only feminine washes, which I don't recommend in our program, but things like bath bombs, bubble bath, toilet paper. And so we kind of go through an inventory of everything that's touching the delicate tissues of the vulva and the vagina and try to back off those products.   The second thing is moisturization. It's important to talk to patients about the difference between moisturization, which I say is for maintenance, and lubricants, which are for PRN use sexual activity. But I tell patients, "lubricants for love." That's how I differentiate the use of these two different types of products because they have different properties. Usually after eliminating irritants, our first step is to start with a non-hormonal moisturizer because there's some really good high-tech non-hormonal moisturizers out there, specifically those containing hyaluronic acid, which pulls moisture from the environment and holds it on the skin. And by using this first—this is my personal opinion—but I think by improving the mucosa a little bit and kind of improving the dryness, maybe even the elasticity a little bit, I think that when patients do have persistent symptoms after using regularly these non-hormonal moisturizers at least three times a week, that adding in a low dose vaginal hormone at that time, instead of putting it on completely atrophic mucosa, you're putting it on kind of like a pretreated mucosa, which I think might decrease systemic absorption.   I'm so glad you brought up vaginal estrogen. I could give an entire talk just on that, so I’d be happy to do that next year for ASCO if anybody wants. But it is very controversial. Historically, there have not been studies showing an increased risk of recurrence with the use of local estrogen therapy, so estrogen in the vulva and the vagina. However, there was a recent study that came out this year that was a large analysis of breast cancer patients receiving different types of hormone therapy. And in a subset analysis of the group who got local vaginal estrogen, just in those patients on aromatase inhibitors, there was a slightly, but statistically significant–according to their analysis–increase in the risk of recurrence. I think there's some issues with this analysis because it was a large study and there's a lot of recall bias and measuring this in patients is really challenging. But I think it's still important to mention because a lot of patients are going to read about those things, these types of studies.   The way I approach it is to start with the lowest dose and I start with infrequent dosing. If patients have persistent symptoms, I start them with once a week or twice a week, which is different from the original pharmacokinetic studies of higher dose estrogens, which showed a bump in their serum estradiol when they used it every night for two weeks. So I actually do the opposite and taper them up. I'll do once a week to twice a week. And usually, patient symptoms are resolved at that point.   But I do want to point out, that's a great option for patients on tamoxifen because mechanistically, as you know, it probably doesn't matter if they have a little bump in their serum estrogen. But for the patients on aromatase inhibitors, we actually have a new kid on the block, a vaginal androgen called prasterone or DHEA. I dose this in the same way, titrate it up. But this can be really helpful for patients on aromatase inhibitors because the ALLIANCE trial showed that for those patients on AIs that their systemic estrogen levels do not increase. And so that's kind of how I manage that discussion. I do think it takes some multidisciplinary collaboration, so I always involve my medical oncology colleagues on this.    Lastly, lubricants. So, everyone seems to be really into using water-based lubricants, but I try to tell patients, unless you're depending on condoms for STD or contraception protection, silicone-based lubricants that are like preservative-free and don't have a lot of those gimmicks or additives, are great—they stay slippery for longer—and there's some really great brands out there. And then for patients who still have persistent pain with sex, we address the pelvic floor, which is either through the use of dilators, referring them to pelvic floor physical therapy, or other sexual devices that we use in the MUSIC program.  Dr. Hope Rugo: This is really helpful, and I think that for many of us in practice, we really want to get the specifics of what you use. I think this prasterone, the idea of DHEA is really very interesting and something that personally I haven't used, but we did use in the distant past before there was an FDA-approved version.   So I guess I have several questions just to ask about the details. So one is, when you prescribe this, do you find it's generally covered by insurance? And when you say low dose, do you mean just try it once a week? And then do you use the estrogen tablets, the brand names are often Yuvafem or Vagifem, we often use those twice a week. How often do you use them and do you use the estrogen ring also? What are the absolute specifics of what you're recommending to these women? And do you feel like sometimes in patients who are developing these symptoms that early use can help avoid the more severe symptoms and therefore reduce the exposure?   And lastly, just to say, that paper which was so interesting about the slightly increased risk of recurrence, I felt was so flawed in terms of what people were using and if they were taking their hormone therapy and risk of recurrence, the risk of the cancer itself, that I really felt like I couldn't make anything out of it in terms of the risk to patients. But I'm really interested in your specific recommendations.  Dr. Kristin Rojas: Thanks for asking about specifics. And I'm happy to give our treatment algorithms here, which we also discussed in our session and we listed in our EdBook manuscript. We do pelvic exams in the MUSIC program and I often find that there's very specific points in the vestibule or the opening of the vagina that are tender and have pain, specifically, what's known as the posterior fourchette, which is the kind of connection between the right and the left side towards the posterior aspect. So, I usually start with a 1% estradiol cream and have patients tap it to the outside and then bring in a dilator and have patients use not only a silicone lubricant, but put some of the estradiol cream on the dilator. And so that brings the product up to the top of the vagina for patients that have some of those anatomic changes that I discussed.   So this is 1 option, and we really don't have a lot of issues with insurance authorization for the cream, just every once in a while. We can also use a 4 microgram or a 10 microgram dose of estradiol, which is a tablet, which are newer options. This is in contrast to the old pharmacokinetic studies that use 25 micrograms. So this is much, much lower. I do run into some prior authorization issues with those because there tend to be newer versions of this. But as you mentioned, the estradiol ring, which I do think is a great option and when you calculate it out, releases a very low dose of estradiol every day. And it's good for patients who want a more low maintenance regimen. The only challenge I've had with that is it's a large rigid ring. And for patients who already have those anatomic changes, it can be really hard to place that in the vagina.   And so, just like you said, early prevention and treatment of these issues can prevent not only anatomic changes, but even potentially the need for exposure for larger doses of hormones. For all of those options, I tend to do it once or twice a week and then can move up. But we sometimes get kind of creative in how we use these options in terms of placing them on the dilator, placing them externally. For patients that have recurrent urinary tract infections, I also have them kind of tap some of the estradiol cream around the urethra as well to improve the urethral and potentially bladder microbiome and decrease risk of recurrent UTIs.  Dr. Hope Rugo: That's really interesting, and I think those specifics are incredibly helpful. We also will check, although I have to say there's no data to support it, the serum estradiol levels in patients who are using more than our minimal amount. We have plenty of studies that have shown that there really isn't systemic estrogen if people are using very low doses. But we will check sometimes, just sometimes people use these topical creams where they get premenopausal levels of estrogen, which of course we don't want. So, this is an incredibly helpful and useful discussion.    One of the other things that happens for these patients and our younger patients, which breast cancer is still increasing in small numbers in younger patients every year, and many of these patients have hormone receptor positive disease. And it just breaks your heart to see a 38-year-old who is planning to get pregnant next month with their new partner who develops a hormone receptor positive breast cancer. and we want to give people all the options they possibly can. We are strong proponents for harvesting eggs and either freezing eggs or embryos before you start treatment. And we figure we always have 2 weeks for breast cancer. We also use ovarian function suppression during chemo just for whatever help it might have.   But then after patients have finished their treatment and they're on hormone therapy, it's a really big issue for women about when they can have a child because we don't want to wait until they're 45. So, you had noted in your article that some women could take a break from endocrine therapy after 18 to 24 months to try and conceive. Can you tell me a little more about that?  Dr. Kristin Rojas: Sure. Well, this aspect of our discussion was very well presented by my colleague, Dr. Terri Woodard from MD Anderson, a reproductive endocrinologist, and she also put together the aspect of this for our manuscript. She talks about how fertility counseling and referral is probably underutilized, but definitely indicated for most of these patients who are of pregnancy age or premenopausal status. And observational data for a long time didn't show that pregnancy after treatment worsened oncologic outcomes. However, patients as well as many providers had reservations.   So, it's been very helpful that we now have a prospective, large, international trial known as the POSITIVE trial, the early results of which came out earlier this year, which showed that women, after 18 to 24 months, could interrupt endocrine therapy and did not have a worsened short-term oncologic outcome. And those are women with early-stage breast cancer. However, there is a concern that many patients do take longer to get pregnant in that age group or after treatment, potentially if they've received chemo. There is a concern about the duration of time that they're not on endocrine therapy afterwards, which might be further clarified in later analyses. So that's my takeaway from that study, which did show us that very helpful, reassuring information. But I think we're still waiting for the long-term data and it's definitely still a very important patient-centered discussion.   Dr. Hope Rugo: This is a really excellent point, and I think that one of the things of a trial like this, which is sort of a registry study, is that we're always going to speak with our feet to some degree. So, if patients have very, very high risk of recurrence and highly proliferative disease, we might not want them to stop at 18 months because their risks are so high early. So, it has to be a risk versus benefit discussion for individual patients, of course. But I think this data was incredibly reassuring.   It was interesting there were some patients who hadn't restarted their endocrine therapy. In the paper in the New England Journal, it told us that some of those patients were still trying to conceive. But one of the things that's going to be really important for these patients is to really make a big effort on the part of our clinical practices to get patients to restart their hormone therapy. It's very hard to do that, as you can imagine, in that setting.    Another area here is monitoring bone health. And I know that's not part of the MUSIC clinic per se because you're really focusing on GSM and other areas that we've just discussed, which are so incredibly important. And it's funny, bone health is silent, right? So, although some patients don't want to take aromatase inhibitors because they're worried about losing further bone density, they don't feel it. So that's, of course, a different kind of a toxicity. But we know that by suppressing ovarian function in young women, we cause a lot of bone loss, and in older women, already in menopause, that this continuous loss of bone increases the risk of fractures, which can be a huge impact on quality of life and even survival in some cases. So, we're really interested in trying to prevent bone demineralization and reducing the risk of fractures. I believe that Matteo Lambertini from Italy discussed this in your paper and that there's a lot of discussion about use of denosumab and zoledronate. I wonder if you could just comment a little bit on that in our last couple of minutes.  Dr. Kristin Rojas: Well, as you said, my colleague Dr. Lambertini put this aspect of our paper together, but he did put together a very nice summary of bisphosphonates and denosumab and separated their use by premenopausal and postmenopausal patients because the data surrounding those patient populations is slightly different or nuanced. But as you mentioned, it is important to monitor these patients' bone density. We have our standard recommendations such as a calcium-enriched diet, resistance and weight-bearing exercise, and vitamin D for patients, for those patients with a vitamin D deficiency or at risk of bone density loss. And so these pharmacologic agents can also help decrease bone mineral density loss and potentially decrease or likely decrease bone recurrences, which, as we know, influences survival. I think he provides a very nice summary of that, as you mentioned.  Dr. Hope Rugo: I think that's so incredibly important. And thank you for really emphasizing the weight-bearing exercise and checking vitamin D and making sure patients are taking vitamin D and at least some calcium. And then, of course, our institution, we work closely with our endocrinologists specializing in bone as well, when issues come up about risk of osteonecrosis of the jaw, and we require dental clearance for everybody starting medication just to make sure that we've reduced risk to the patient. And then when we're trying to think about stopping denosumab and should we bridge with zoledronate to reduce the risk of fracture, we also talk to our bone doc. So it's really important.   And in our last just 1 minute, I know you were thinking of saying something about measuring estrogen in the blood in patients who are using vaginal estrogens. Do you do that?   Dr. Kristin Rojas: Yeah, great question. I'm glad you brought that up. We actually don't routinely do this in the MUSIC program, but it is an important aspect to think about today, because I don't know about where you are, but here in South Florida we have a lot of patients who are receiving therapies outside of the FDA-approved space and these are typically marketed as bioidentical hormones, which is a marketing term. Oftentimes, they'll get either transdermal formulations or pelleted hormone therapy that can result in really high superphysiologic testosterone or estrogen levels. And so we typically, for those patients, do try to get them off those non FDA-approved therapies because the safety of those is unknown.   Dr. Hope Rugo: That's really interesting and so helpful. Yes, I know this whole idea of bioidentical hormones drives me crazy, but I think that's great that you brought that up, actually. We do measure it. Who knows? I think if you're really worried, measuring “Yeah, everybody's hot flashes went away,” it's probably worthwhile checking.   This was such a fabulous conversation. I learned so much. We really appreciate your contribution to the educational manuscript, to the educational program, and your fabulous insights with us today. Thank you so much for participating on the ASCO Daily News Podcast. I think everyone will find this very helpful.   Dr. Kristin Rojas: Thank you so much for having me.   Dr. Hope Rugo: And thank you to you, our listeners, for joining us today. You'll find a link to Dr. Rojas and her colleagues' article in the transcript of this episode and in the 2023 ASCO Educational Book, which features practice-changing oncology research and a wide range of compelling studies on quality and equitable cancer care.    Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thanks again.    Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    Follow today’s speakers:   Dr. Hope Rugo  @hoperugo  Dr. Kristin Rojas  @kristinrojasmd    Follow ASCO on social media:    @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:   Dr. Hope Rugo:  Honoraria: Puma Biotechnology, Mylan, Samsung Bioepis, Chugai Pharma, Blueprint MedicinesConsulting or Advisory Role: Napo PharmaceuticalsResearch Funding (Inst.): OBI Pharma, Pfizer, Novartis, Lilly, Genentech, Merck, Odonate Therapeutics, Daiichi Sankyo, Sermonix Pharmaceuticals, AstraZeneca, Gilead Sciences, Ayala Pharmaceuticals, Astellas Pharma, Seattle Genetics, Macrogenics, Boehringer Ingelheim, Polyphor  Dr. Kristin Rojas:   Honoraria: Pacira Pharmaceuticals  Consulting or Advisory Role: Roche Diagnostics, Merck  Research Funding (Inst): Bristol Myers Squibb Foundation