Considerations for Endocrine Therapy for Patients With ER-Positive Early Breast Cancer

Systemic Treatments for ER-Positive Early Breast Cancer: Part 4

In this expert roundtable series, Cynthia Ma, MD, Washington University School of Medicine, St Louis, Missouri, leads a 4-part roundtable panel discussion on updates in selecting the optimal treatment for ER-positive early breast cancer with Neelima Vidula, MD, Massachusetts General Hospital, Boston, Massachusetts, and Seth Wander, MD, Massachusetts General Hospital.

In part 3 of this discussion, our experts talk about endocrine therapy, highlighting the debate on screening and duration for this treatment.

Transcript:

Dr Cynthia Ma:
Finally, we're just going to talk about endocrine therapy. I know that we have several trials now that support ovarian function suppression in premenopausal women. Dr Vidula, would you like to comment on that and how you select patients for ovarian function suppression?

Dr Neelima Vidula:
Thank you. For patients that are premenopausal, in terms of hormone therapy, we have multiple options. They can receive tamoxifen, or ovarian suppression with an agent such as leuprorelin [Lupron] or goserelin in combination with either tamoxifen or an aromatase inhibitor. Favoring the ovarian suppression approach is based on the SOFT-TEXT combined analysis, and this is predominantly for patients that have higher-risk disease. In this combination of studies, essentially, patients received either tamoxifen alone for 5 years in SOFT, or were randomized to tamoxifen and ovarian suppression or exemestane and ovarian suppression. In the TEXT study, they were randomized to tamoxifen and ovarian suppression or exemestane and ovarian suppression.

In summary, from both of these studies, when they did the combined analysis, there was an improvement in disease-free survival with the addition of ovarian suppression to either tamoxifen or exemestane compared to alone in these patients who are higher-risk disease typically had received chemotherapy. Based on this study the disease-free survival in patients who had received tamoxifen alone was 78.9% compared to 83% in patients who received tamoxifen and ovarian suppression and 85.9% with exemestane and ovarian suppression at 8 years. There also was data to suggest there may be an improvement in overall survival as well. We're awaiting further follow-up on that. Based on these data, it is important in particularly younger patients and patients who have higher-risk tumors to offer them ovarian suppression in combination with either tamoxifen or exemestane.

For patients who have lower-risk disease, for whom you are not going to be giving chemotherapy, tamoxifen is a reasonable option. However, it is also worth noting that it can be pretty difficult to tolerate ovarian suppression with tamoxifen and/or exemestane. Sometimes a graded approach can be helpful to patients: starting with the ovarian suppression and then maybe starting them on tamoxifen, watching and seeing how they're tolerating it. And then if they're doing okay, eventually switching out the tamoxifen to the exemestane or another aromatase inhibitor once their estradiol is adequately suppressed, can be a reasonable way to proceed.

Dr Cynthia Ma:
That's a very nice discussion on that topic. I'd like to talk about duration of endocrine therapy for patients with ER-positive, HER2-negative breast cancer. Dr Wander, would you like to comment on that topic?

Dr Seth Wander:
Both of these topics are a complex conversation and one that typically unfolds over a prolonged period of time in the adjuvant setting. We've had a number of different studies over the last 10-plus years looking at extending anti-estrogen therapy. We have the ATLAS and the ADAM studies, and the MA.17 study looking at 10 years of treatments, like tamoxifen to aromatase inhibitor (AI). We have additional data for tamoxifen to aromatase inhibitor.

And then we also have the, ABCSG-16 study from a few years ago, looking at a slightly smaller, shorter duration of AI therapy of 7 years. The standard used to be 5 years of treatment with an approximately 50% reduction in overall recurrence risk. The data would suggest, across large patient populations, looking at all of these studies together, extending that toward 10 years gets you some additional meaningful benefit in terms of recurrence risk reduction. Although the magnitude of that benefit is less than what you see in the first 5 years. It's really a 2% to 5% additional improvement looking across the different studies at recurrence risk.

The 7-year data is somewhat reassuring for the aromatase inhibitor because in that study, they looked at 2 years versus 5 years of additional treatment beyond the first 5 years of aromatase inhibitor. That suggested there really wasn't a meaningful difference between them. I think the impact on survival is less clear. The benefit for recurrence risk is really on the order of 2% to 5%.

The benefit on survival has not necessarily been borne out in some of these longer studies, particularly with the 7 to 10 years of aromatase inhibitor. The conversation will boil down to a number of different factors, on the ground, in the clinic.

The first question is, how high was the initial risk for the patient's breast cancer? Is it a T1a or a T1bN0 low-grade tumor with overall very low recurrence risk? Or is it a T2 or T3N2 tumor, the type of patient we're thinking about ovarian suppression as we just heard about, the type of patient who got combination chemotherapy, the type of patient who's getting CDK inhibitor therapy. You would imagine that person who starts off at a higher recurrence risk has more relative risk to gain with that additional 2% to 5% than the patient who starts off with a T1a T1bN0 tumor. Not to say those patients can’t extend the duration. It's just a different conversation in terms of potential relative benefit.

You have the tumor-specific factor, then you also have patient- and drug-specific factor. How well did they do? Were they on the drug for 5 years, tolerating it extremely well, with minimal toxicity, or were they really struggling with side effects? Arthralgia for the aromatase inhibitors, hot flashes for either of these agents. What does their bone density look like? Are they struggling with osteopenia, osteoporosis? When I have this conversation in-clinic, I'm thinking about how high the risk was to begin with. I'm thinking about what their bone density looks like and how well they did, over the first 5 years of treatment, and we're trying to come to a determination based on those factors. The 7 years of aromatase inhibitor helps you split the difference. You seem to get that extra few percent benefit, but maybe less detriment to bone mineral density and risk of worsening osteopenia osteoporosis.

Dr Cynthia Ma:
That's very good. One question I have is, how do you make a decision as to which patients benefit the most from 10 years versus 5 years of extended adjuvant endocrine therapy? Dr Vidula, do you use Breast Cancer Index?

Dr Seth Wander:
That was my next question for both of you.

Dr Neelima Vidula:
I had a feeling you were going to ask us about that. In general, when I'm counseling patients about extending the duration of endocrine therapy, the patients that I usually try to really make a compelling argument to them about continuing are those that are higher-risk patients. Patients who are premenopausal at diagnosis and had a high burden of disease, lymph node-positive tumors. We think they will likely benefit more from an standard duration approach. I am very frank with patients and tell them, unfortunately, we don't have a whole lot of data to support that this will improve survival, in terms of overall survival right now, but it can reduce the risk of recurrence by somewhere between 2% and 5%.

Generally, I'm thinking about this in lymph node-positive tumors. With regard to the Breast Cancer Index, I don't actually send that routinely. There have been a handful of times when a patient has been motivated and wanted to know that information. And sometimes some patients want that information to be able to say, “It's okay for me to come off endocrine therapy.” But I do not routinely send this because at the end of the day, it really is a discussion of risks and benefits.

Again, if you have a patient who is struggling for 5 years, then it's really going to be hard to get them through another 5 years. Quality of life is also important. And if they're developing other side effects, osteoporosis from an aromatase inhibitor or there's concern for endometrial changes with tamoxifen, then I think you have to be cognizant of those other factors as well, but I wouldn't send it routinely. I think that there have been a handful of times in my practice where someone has been motivated or wanted to use the test to help give them confidence that it was okay to come off the endocrine therapy. I think in that type of situation, you could consider it.

Dr Seth Wander:
I concur. As a group, we have not used Breast Cancer Index a lot, although it’s a well-validated test. My understanding of that data is that clinical risk factors we're alluding to, tumor size, lymph node status, etcetera, correlates with the Breast Cancer Index result about 80% of the time. That’s 8 out of 10 times your clinical acumen and your clinical gestalt will reflect the correct patients to extend treatment.

The way we've often approached it as a group is if the patient's doing well, even for the lower-risk tumors, and the bone mineral density looks good and you have an informed conversation with them about that 2% to 5% benefit in the survival data, they may want to stay on it. The patients you're really being forced to come down to the 5-year mark are the ones who are struggling with all the side effects and the bone density that we were just alluding to.

I wanted to pose a question to both of you. I'm curious, with the emerging data related to Natera and minimum residual disease, how do you see this unfolding in the context of this conversation? Because one of the struggles in my mind with these tests that are coming up, to Dr Vidula’s point, patients are saying, “What about this test? I want this test. How are we going to use it?” Again, it's a test that has really strong prognostic value. But we don't have great actionability data. We don't have great guidance to say, if it's positive or if it's negative, do x or do y.

Dr Cynthia Ma:
Doctor Vidula, would you like to comment on that?

Dr Neelima Vidula:
Yes. This is an area where we need to have more data from clinical trials. At this particular time, we just don't know what to do with a positive MRD test and whether that truly reflects that there's residual disease, or does this patient have frank metastatic disease that's occult, and we just haven't found it. I think before sending this kind of test, it's really important, first of all, to have a conversation with the patient and, make sure they understand what the implications of the test could be. Are they going to be okay to sleep at night knowing that they had a positive assay, or is that going to cause a lot of anxiety?

In general, when we see a positive assay, we are thinking about staging these patients. Again, not every patient with early-stage MRD-positive disease will have necessarily had staging scans, but I think if you have a positive assay, you should consider that, to make sure that patient doesn't have a metastatic disease you haven't just seen yet. That’s one thing we need to be aware of.

A second point is that we just don't know how to manage a positive result. If you have a positive result, then what are we supposed to do with that? Should we treat you with a CDK4/6 inhibitor? If you've been on an AI for 5 years and then you still have a positive result, is there a benefit to continuing the AI, or should we be taking you off of it because it's still positive?

We just don't know at this point. I would say the best case scenario, in my opinion, is if you have a clinical trial available at your institution that is enrolling patients MRD-positive assays, then you could certainly offer that type of trial to a patient. And in our case, we have a trial that is looking at an adjuvant CDK4/6 inhibitor in that setting.

Dr Cynthia Ma:
Yes, I agree with both of you. In my institution here and also my own practice, we don't routinely test Signatera. Patients have heard about this test, and we discussed the sensitivity and specificity of it. The test is very specific, but the sensitivity still needs time to provide more data on that. Especially, we don't know the clinical utility whether changing our management would make a difference based on the test result. If you have negative results, you have to keep checking because it could show up positive later on. So, yes, I agree with you. We need more prospective data to support the routine use of it.

Dr Neelima Vidula:
My general feeling about testing is that you should talk to your patient and ask them, “What are we doing this test for?” We should only be sending tests if they're going to change our management. In this case, especially when patients may have to live with that potential fear of recurrence if they have a positive assay. It's really important to counsel patients about this.

Dr Seth Wander:
I agree. And, Dr Ma, out of curiosity, in your group are you using, Breast Cancer Index to decide for the 10 years?

Dr Cynthia Ma:
Sure. Thank you for asking. We use a lot of the CTS5, which is looking at the clinical factors: tumor size and tumor grade, the patient's age at initial diagnosis, etc. And then if the patient is at the intermediate risk, I would do Breast Cancer Index, at least discuss it with the patient. Sometimes patients have a preference and also the physician might already have a preference, whether patient should be on extended endocrine therapy.

For example, if a patient had a higher-risk, node-positive disease. I don't think Breast Cancer Index might help too much in this patient. We don't do that. And also in select patients who have clinically low-risk disease, but who are really worried about recurrence risk in the future, we tend to do the Breast Cancer Index in these situations when clinical decisions are really not very helpful yet.

That concludes our discussion. I would like to thank our panelists for their very informative discussion and also thank the Oncology Learning Network for organizing this discussion. Thank you for taking the time to listen, and please also check out www.oncnet.com for the latest updates and research and patient care. Thank you.

Dr Seth Wander:
Thank you.

Dr Neelima Vidula:
Thank you.