Breaking Down Endocrine Therapy: Tailoring Breast Cancer Treatment for Young Women

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shephard, a Medical Oncologist here at Cleveland Clinic, directing the Taussig Early Cancer Therapeutics Program, and Co-Director of the Cleveland Clinic Sarcoma Program. Today, I'm happy to be joined by Dr. Erin Roesch, a Breast Medical Oncologist here at Cleveland Clinic. She's here today to discuss endocrine therapy for breast cancer in young patients, so welcome.

Erin Roesch, MD: Great. Thank you for having me. I'm really excited to be here and talk about this important topic.

Dale Shepard, MD, PhD: Excellent. So let's start off, give us an idea, what do you do here at Cleveland Clinic?

Erin Roesch, MD: So I am a breast medical oncologist, so I focus on the care for patients with a breast cancer diagnosis and develop their treatment plans. I also have a special interest in and a focus on young women with breast cancer.

Dale Shepard, MD, PhD: Okay, and so let's jump into there. So we're going to talk about breast cancer, young patients. What do we define as young?

Erin Roesch, MD: So there are different definitions and different organizations look at this in a different way, but for the purposes of our program that we've developed here at the Cleveland Clinic, we look at anyone with a breast cancer diagnosis up to and including age 45. Some groups look and include a little bit lower than that, age 40, but for the purposes of us here at the clinic, we look at age 45.

Dale Shepard, MD, PhD: Okay. And then when we think about therapies, when we think about cancer and therapies, people automatically think chemotherapy. We're going to talk about endocrine therapy, so give us a big picture. What is endocrine therapy?

Erin Roesch, MD: So endocrine therapy encompasses a very important component of treatment for many women diagnosed with breast cancer. So first even, we look at the most common type of breast cancer in women is driven by hormones, so hormone receptor positive breast cancer. Although younger women may tend to present with more aggressive biologies for example, hormone receptor positive disease is still the most common in this subgroup, so endocrine therapy represents a really important integral component of treatment for these patients.

So there are a couple of different options that I talk through with patients, and then the decision making of which is best depends on a variety of factors that we can talk about as well, but essentially, endocrine therapy refers to hormone blocking therapy. These are medications that essentially block the production and the effect of estrogen in young women, and again, a lot of different options that we have that we can talk about.

Dale Shepard, MD, PhD: Okay. And then I guess maybe just as we talk about some of those options, oftentimes, we think about traditional breast cancer being older women and they may get hormonal therapies, and we also have the younger women we're going to talk about. So give us an idea of what therapies are out there and what we think about in young patients instead of our more traditional older patients.

Erin Roesch, MD: So first, looking at physiology, and so how do young women differ from postmenopausal patients, so pre versus postmenopausal breast cancer. So importantly, young women are still making estrogen from their ovaries, whereas postmenopausal women do not have estrogen production from their ovaries. Postmenopausal women, the estrogen essentially comes from the conversion of other hormones to estrogen, which occurs in the peripheral tissues, the fat tissues of the body, but for young women, we also have the production of estrogen from the ovaries. And so treatment options for young women are what endocrine therapy looks like for young women, includes a very traditional, well-known drug called Tamoxifen. Tamoxifen acts by blocking the effect of estrogen at the estrogen receptor, so it acts as an antagonist in breast tissue at the estrogen receptor here. So young women can take tamoxifen as an effective endocrine therapy option.

Beyond that, another approach that we're using and that may often fit certain women better or certain young women may benefit more from includes an approach of essentially suppressing their ovarian function. So this includes use of a GnRH analog, so something such as leuprolide or goserelin, and this essentially blocks the production of estrogen from the ovary, so it creates a postmenopausal state really in young women. And then once we do that, those young women are then a candidate for a different set of medications called aromatase inhibitors or Ais, and these are also in the form of pills. And these pills are, again, historically the ones that we think of for postmenopausal women, but for young women who we've made them postmenopausal, these aromatase inhibitors are then options.

And you might say what is the difference between these two approaches? How do we decide if some women get tamoxifen versus the other I'll call it the more aggressive anti-estrogen approach of suppression of the ovarian function plus an AI? That decision-making process looks at patient risk level. How high risk was their breast cancer? Additionally, we look at bone density, patient preferences. There's a lot that goes into that decision making, but really, I think about that more aggressive approach for young women who maybe have some higher risk features of their cancer.

Dale Shepard, MD, PhD: All right. And then I guess when you say aggressive, it's aggressive at treating the hormonal aspect of tumor growth, not necessarily more aggressive in terms of oftentimes, patients, if they think it's aggressive, they think it's going to be more symptomatic. Is that necessarily a correlation?

Erin Roesch, MD: It can be actually in this, and the reason I say that is because once we make a premenopausal woman menopausal, they can have more symptoms related to complete estrogen deprivation, whereas on Tamoxifen alone, although it's not without its possible side effects, generally, all of the menopausal symptoms, women don't necessarily experience all of those if they're only on tamoxifen. So it can. Potentially, that approach may in some young women carry with it more side effects.

Dale Shepard, MD, PhD: And we think about side effects. If someone chooses to go down one path in terms of management, how easy is it to switch over to the other path?

Erin Roesch, MD: I think that's super important and that's something I stress with my patients, particularly these young women. As I'm meeting with them and I'm talking about these options and presenting what the side effects can be is that it's not a moving train you can't get off of, I say, meaning that if we start something and it doesn't work for you, it doesn't fit your body, you're not feeling well on it, it is fairly straightforward to switch to something else, and that always exists as an option.

And I really try and highlight for young women that, in all patients really, is that it's not a one size fits all approach, and importantly, quality of life. We talk about endocrine therapy or anti estrogen therapy. Duration is at least five years, but many young women will continue up to even 10 years with endocrine therapy, and so it's important that during this time, that quality of life is not lost, that there's still a focus on that. So it can be fairly straightforward to switch between these, so I think it's an important concept too I like to make sure that patients know about.

Dale Shepard, MD, PhD: So clearly, if you're doing something like ovarian suppression, then you're more likely to get things like perimenopausal symptoms, things like that. I guess just for people who might be listening in and thinking, "Well, I have a patient that's on one track, are they likely to have benefit by switching?" What are the most common side effects we can alter by switching between one course or the other?

Erin Roesch, MD: When I think about side effects related to these different approaches, so tamoxifen, one of the more common things I can see is hot flashes, so that's something that can be seen with tamoxifen. Hot flashes can also be seen with the approach of suppressing the ovaries and the AI.

The aromatase inhibitors also have potentially joint aches or stiffness as a possible side effect, and that can be particularly bothersome to some young women who are very active, have families, are expected to and expecting themselves to be very active and engaged. So the joint aches is one thing that I might see improve with switching from an AI to tamoxifen, for example.

Vaginal dryness, that's also something that we tend to see more with the approach of suppressing the ovaries and converting someone to menopause, plus the AI, so that side effect can be improved or better on tamoxifen. The joint aches is one of the ones I really think about.

Also, importantly, when we think about bone density, that's one of the potential issues related to menopause, so complete estrogen deprivation plus the aromatase inhibitor therapy. So that's something also that I think particularly in these young patients, we need to be very proactive about monitoring and addressing if that does come up.

Dale Shepard, MD, PhD: You were talking about patient risks and things like that, so maybe can you just find a little bit more detail what some of those risks might be? And of course, hormonal receptor status is important, but is this ER and PR, or what are the factors as you have a checklist and you look in terms of who is the best candidate for which path?

Erin Roesch, MD: Yeah, so it's a great question and this is definitely an evolving space. Even over the last five to 10 years, I personally in my practice have utilized this approach of the ovarian suppression plus the AI more often in patients with some of the data that we have. And I think the most practice-changing data in this space was the combined soft and text analysis, which looked at these various anti-estrogen therapy approaches for premenopausal patients, essentially looking at tamoxifen versus ovarian suppression plus either tamoxifen or plus an aromatase inhibitor. And the data that came from that analysis showed that, again, some patients with higher risk features, so what is higher risk? So very young age, so in this trial, it was women who were 35 years of age or younger, and patients who received chemotherapy, who were deemed high enough risk to receive chemotherapy and remained premenopausal after chemo, those patients also derived benefit from the ovarian suppression plus the AI versus tamoxifen.

So very young patients and those, for whatever reason, whether it be clinical risk, lymph node involvement or some of the data that we get from genomic assays that can help guide us into understanding if a woman benefits from chemotherapy, and if they ultimately do, that can also be a situation where the ovarian suppression plus the AI approach would be more helpful in terms of reducing risk of recurrence.

Dale Shepard, MD, PhD: And certainly, genomics play an important part into chemotherapy. Has there been work to suggest that either ovarian suppression or which hormonal path might be more beneficial based on genomics?

Erin Roesch, MD: So it's a very good question, and I do, when I get my genomic information back, again, the purpose of it is really to help determine, at least in the world that we live in, we have a couple of different assays out there, but really the purpose of them is to help determine chemotherapy benefit or not. But the genomic information actually does give us some direction also because we've seen in the trials that took genomic information and they used it to make chemotherapy decisions. We also see that patients who might have lower risk tumors with genomic data that is in a low risk category, they might be very appropriate for tamoxifen by itself, whereas women that have maybe, I'm referring to Oncotype DX for example, scores within an intermediate range but not quite high risk so maybe not needing chemotherapy, but even in this intermediate range, that perhaps this more aggressive, I say. But the ovarian suppression plus AI approach is something that's superior to tamoxifen, but not necessarily chemotherapy.

In this vein, there's I think a really important clinical trial that we have opened here. This is a national trial that is essentially looking at and I think really focused at the biology of breast cancers in young women. Since we've talked about these genomic assays, the data that we have right now suggests, and this is based on the phase 3 RxPONDER trial, essentially showed that young women with hormone-positive breast cancer and presence of lymph node involvement, regardless of their oncotype score benefited from chemotherapy, whereas postmenopausal women, same on paper, did not benefit from chemotherapy. And so why are we seeing this difference in younger women versus postmenopausal women?

And so an important hypothesis that has stemmed from this data and prior studies also, is the biology of the cancer in young women truly different? And really, they do benefit from chemotherapy. Young women with ER-positive breast cancer, many of them that they might benefit from chemotherapy, or can we achieve the benefit with a more aggressive anti-estrogen approach? Is really the benefit we're seeing being driven by chemotherapy suppressing ovarian function? And now that we're using this ovarian suppression plus AI approach, will that yield similar outcomes with perhaps less toxicity? So a really important clinical trial is the OFSET, the phase III OFSET trial, which is essentially aimed to answer this important question, is randomizing women with hormone-positive HER2 negative breast cancer and some of these higher risk features, whether it be lymph node involvement or genomic assay data to endocrine therapy alone with ovarian suppression plus an AI or chemotherapy followed by OFS plus an AI. So a super important trial and we're really excited to have it open here at the clinic.

Dale Shepard, MD, PhD: And then of course it's going to be a little while before we have the data, but certainly important, right? This seems like a population, young women, lots of things going on, lots of reasons to avoid certain side effects and things. Tell me a little bit about what clinic looks like in terms of shared decision making. So I'm guessing most patients come in with an opinion about what they might want to do. What does that look like?

Erin Roesch, MD: And I love treating young women with breast cancer because our population of patients, they're knowledgeable and they're motivated and they're really interested in engaging in a shared decision making, and that's a big part of my clinic. And everyone is different, and again, it's not a one-size-fits-all approach and everyone is going to feel potentially differently on these various treatment regimens, but what it looks like for me is it's sitting down with the patient, talking about the data that does exist and why I might favor one approach versus the other in their specific case, going through a detailed list of the possible side effects of these agents with them, answering any questions they have from the beginning, and then asking them just purely, what is your opinion? What are your thoughts, what are your questions?

And it's not uncommon that women may have concerns about a specific side effect. Young women are at this time in their life, having families, raising children, developing their careers, so they don't want to be prohibited in any of that. So I think it's really important from, again, the beginning to talk about these things. And I think commonly, I'll have women who will say, "I'll try it." And just the knowing that we can switch to something else if I'm not feeling well I think is comforting for young women, is knowing that there are other options. So I usually will say that some endocrine therapy or any endocrine therapy is better than none, so whichever of these that might be ultimately will be okay. So it's my role to help get them through this, and again, to help make sure that quality of life is not compromised.

Dale Shepard, MD, PhD: You mentioned before just here about having families and raising families, and this is a young population. What's the impact on women you may be seeing that want to continue having children?

Erin Roesch, MD: So another very near and dear issue to my heart too is the aspect of fertility and fertility preservation in young women. So importantly, this is a topic, onco fertility, that should be discussed at the time of diagnosis and should be revisited as someone goes through treatment and in the survivorship setting. I think it's important that that conversation is had. If a young woman is either interested in what fertility preservation looks like or even doesn't know, I think it's important to make those referrals as appropriate to a reproductive endocrinology provider who can talk with them about their options. Because it's a very, very challenging, overwhelming time at the beginning, and a lot of patients and some providers think we don't have time to address this, or How important is it? It's very important, and so I think addressing it early on, making appropriate referrals. If patients are interested in fertility preservation, there's studies that have not shown any detrimental impact on breast cancer outcome related to the pursuit of fertility preservation options.

And we also have some additional or adjunctive therapies or modalities that be used such as utilization of a GnRH analog during chemotherapy that can help for ovarian protection purposes. That was a really important trial that was conducted by Dr. Moore here at the clinic. So I think, again, early conversations about it, and then even in the post-treatment setting, the survivorship setting, we now have data that also suggests that women with estrogen-positive breast cancer can safely interrupt endocrine therapy after a period of time to attempt conceiving. So these are, again, important conversations that we are now able to have with our patients, backed up by trials and data.

Dale Shepard, MD, PhD: And if you know up front that a patient is interested in having children, is it better to avoid ovarian suppression or do you find that it doesn't really matter?

Erin Roesch, MD: To some extent, it doesn't really matter because I think still, importantly, we have the data that we can interrupt endocrine therapy in the adjuvant setting for these patients, or at least that conversation can be had. Of course, it's an individualized decision of whether it's appropriate for a patient. But I also think too, why that early referral to a specialist in fertility preservation rather is important, because then they can look at the treatment plan that is outlined, and then we can counsel patients as a group or as a team appropriately on what does your ovarian reserve look like? What are the chances after treatment XYZ that you'll be able to have a pregnancy? And then patients can make decisions based on that information.

Dale Shepard, MD, PhD: One thing it seems there always is a little bit of confusion is about risks of hormonal therapies, risk for other cancers, ovarian cancers or uterine cancers. How do you counsel women about the choices and risks?

Erin Roesch, MD: So first, I'll comment on Tamoxifen as the agent that we use for treatment for some women, or endocrine therapy treatment does have a very rare risk of uterine cancer. Mostly, that risk was seen in older women, but still, any of my patients on Tamoxifen, I have them see a gynecologist annually and make sure they know that they are on this medication, and if they were to have any irregular heavy menses, they would let me know and we would address it. From the standpoint of taking hormones or other hormone replacement while being on endocrine therapy or while in the setting of a history of breast cancer, we get this question a lot. And so across the board, I recommend avoiding any systemic hormone replacement therapy for patients.

Not uncommonly, for the symptom of vaginal dryness, we get the question from gynecologists about what is the safety of using a low dose vaginal estrogen to help manage painful intercourse or vaginal dryness? And I always prefer non-hormonal methods if possible, but in refractory cases, and again, to assist with keeping patients on endocrine therapy, low dose vaginal estrogen preparations, there is data that has demonstrated relative safety. So I think that's an option for certain select patients with an appropriate conversation, and so we know the data that does exist and can go from there.

Dale Shepard, MD, PhD: There are definitely some nuanced decision-making that happens here. Who's an ideal patient that might have questions, might have concerns that would benefit from seeing a specialist like yourself?

Erin Roesch, MD: We welcome any patients that want to have these conversations really, and again, we're very fortunate here at the clinic to have the development of this program for young women with breast cancer, and the purpose of it is to highlight the unique aspects of care for these patients. So I welcome anyone to come to see us for these discussions, and whether that be for symptom management, the clinical trials such as the OFSET trial I alluded to, or just to get an opinion and see if they're on the right course, I'm always happy to be involved in those conversations and work with the patient and other providers. But it truly is a multidisciplinary effort because it involves us as medical oncologists, gynecologists, fertility specialists, psychologists, social workers, geneticists. You name it, it's just such a comprehensive list, so again, lucky to work with a team here where we have all those assets.

Dale Shepard, MD, PhD: It's a really important area that you're working in, and I appreciate you being here for your insights.

Erin Roesch, MD: Great. Thank you for having me.

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