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Treatment for Early-Stage ER+ Breast Cancer

Insights From:Ruth O’Regan, MD, University of Wisconsin;Hope S. Rugo, MD, UCSF
Published: Monday, Oct 24, 2016


Transcript:

Hope S. Rugo, MD:
My approach to adjuvant endocrine therapy is a big question. It very much depends on a number of different clinical factors and biologic factors, as well. So, it’s related to the age of the patient, the stage of their cancer, their residual risk of recurrence, particularly distant recurrence, and whether or not they have a risk of a contralateral breast cancer. Local recurrence plays a role, as well, although it’s a secondary consideration after the risk of distant recurrence. And then, the biology of the tumor is also important. I recently had someone send me a question about hormone therapy for a patient whose cancer was ER 2% and PR 0. In that situation, hormone therapy is unlikely to provide much of a benefit. On the other hand, a patient who has a slow-growing tumor that has strong expression of ER and PR will benefit significantly.

It’s been interesting that we’ve been learning more about the risk factors that actually play a role in both early and late risk of recurrence for hormone receptor–positive disease. And, this has played a significant role in influencing my choices for adjuvant endocrine therapy. For postmenopausal women, I tend to use an aromatase inhibitor (AI) to start with, but I am quick to hold or change, as needed, to try and ensure compliance. For premenopausal women, I recommend treatment very much based on their risk and then, of course, over time, on tolerance, with the idea that some hormone therapy is always better than none. So, therapies like ovarian suppression for very young women, for women who have very high-risk disease, and tamoxifen or an aromatase inhibitor depending on their age, their tumor risk, and how well they tolerate treatment with careful monitoring of estradiol to ensure that the ovaries are adequately suppressed. The second part of this, which is determining duration of therapy, again, is very much determined by the patient’s initial risk and their tolerance of treatment.

Ruth O’Regan, MD: I think the role of neoadjuvant endocrine therapy for patients with estrogen receptor–positive disease is actually evolving quite a bit over the last several years. And, one of the problems we have in patients with ER–positive breast cancer who need preoperative treatment to downstage their tumor is that, very often, the cancers just don’t respond to chemotherapy very well. It’s a very rational thought to try and use neoadjuvant endocrine therapy as an alternative for these patients. The problem is that neoadjuvant endocrine therapy takes a long time to work, which is one of the reasons I think a lot of people shy away from giving it in this scenario.

I think the patients that we traditionally have treated in this manner are patients who are older, maybe aren’t candidates for chemotherapy, and who have larger cancers that are ER–positive. Maybe we’re contemplating doing surgery at some point or maybe not. They’re the type of patients that typically we’ve treated. But, I do think this is evolving. And the ALTERNATE Trial is a very interesting trial where patients of, really, pretty much any age, who have estrogen receptor–positive breast cancers, and who are felt to be candidates for preoperative treatment, are given either anastrozole or fulvestrant for 4 weeks, after which they get a biopsy. What they do is they compare the Ki67 from the diagnostic biopsy with the post 4-week biopsy to see if it’s dropped or not. If it has dropped, then the thought is that these are cancers that are sensitive to endocrine therapy, and the patients can either go to surgery or continue on the endocrine therapy. If it doesn’t go down, the thought is that these patients are more likely to benefit from chemotherapy. So, I think that’s a very good approach, and I would definitely refer patients for a trial like that.

We actually, also, a few years ago, looked at the 21-gene recurrence score as a means of choosing therapy for patients with ER–positive breast cancer preoperatively. So, we tried to do a TAILORx-type trial in the preoperative setting, but the numbers were kind of small. We didn’t see any pathologic complete responses in patients with recurrence scores between 10 and 25, which I guess is in keeping with what we know about the 21-gene recurrence score. And, in the patients with higher risk cancers with recurrence scores over 25, the pathologic complete response rate to chemotherapy was only 20%. So, even in a group where you think they might benefit from chemotherapy, they really don’t.

I think this is an evolving area, but [I], traditionally, it does tend to be older patients who aren’t candidates for chemotherapy. But, because of the fact that these estrogen receptor–positive cancers just don’t really respond very well to chemotherapy, I think we are going to see increasing use of preoperative endocrine therapy.

Hope S. Rugo, MD: It leads nicely into the question of how long we should treat patients with endocrine therapy? Who should receive treatment after 5 years? And, of course, we do have recent data that helps us think about this question a little bit more. We have data about the use of extending hormone therapy, either with tamoxifen or aromatase inhibitors, and we have data on the natural history of patients who have hormone receptor–positive disease. If you think about all of this information together, I think what it suggests is that hormone receptor–positive disease—a fact we’ve known for a long time, but we’re really understanding much better now—is a chronic disease.

Recurrences can occur out past 20 years, even for relatively low-risk disease. About half of the recurrence risk occurs after 5 years, so for patients who have a high-risk disease when they start, their risk after 5 years is still much higher than the women who had tiny cancers. So, a stage I cancer that is low-risk, by all other features, I will likely treat for 5 years. For a woman who has a higher-stage cancer, I tend to extend therapy as long as they can tolerate it, for longer than 5 years, usually out to 10 years. Again, really, we have to individualize therapy based on the patient themselves. And, I tend to not talk about that duration when they start with treatment because I found that that can lead to a sense of less hopefulness about outcome. We discuss it over time, as new data is obtained, but also as we see how the patient is tolerating treatment themselves. If a patient starts with tamoxifen because they’re perimenopausal, I will switch to an aromatase inhibitor after 2 or 3 years when they are menopausal, and then continue that treatment usually for 5 years.

Transcriped Edited for Clarity
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Transcript:

Hope S. Rugo, MD:
My approach to adjuvant endocrine therapy is a big question. It very much depends on a number of different clinical factors and biologic factors, as well. So, it’s related to the age of the patient, the stage of their cancer, their residual risk of recurrence, particularly distant recurrence, and whether or not they have a risk of a contralateral breast cancer. Local recurrence plays a role, as well, although it’s a secondary consideration after the risk of distant recurrence. And then, the biology of the tumor is also important. I recently had someone send me a question about hormone therapy for a patient whose cancer was ER 2% and PR 0. In that situation, hormone therapy is unlikely to provide much of a benefit. On the other hand, a patient who has a slow-growing tumor that has strong expression of ER and PR will benefit significantly.

It’s been interesting that we’ve been learning more about the risk factors that actually play a role in both early and late risk of recurrence for hormone receptor–positive disease. And, this has played a significant role in influencing my choices for adjuvant endocrine therapy. For postmenopausal women, I tend to use an aromatase inhibitor (AI) to start with, but I am quick to hold or change, as needed, to try and ensure compliance. For premenopausal women, I recommend treatment very much based on their risk and then, of course, over time, on tolerance, with the idea that some hormone therapy is always better than none. So, therapies like ovarian suppression for very young women, for women who have very high-risk disease, and tamoxifen or an aromatase inhibitor depending on their age, their tumor risk, and how well they tolerate treatment with careful monitoring of estradiol to ensure that the ovaries are adequately suppressed. The second part of this, which is determining duration of therapy, again, is very much determined by the patient’s initial risk and their tolerance of treatment.

Ruth O’Regan, MD: I think the role of neoadjuvant endocrine therapy for patients with estrogen receptor–positive disease is actually evolving quite a bit over the last several years. And, one of the problems we have in patients with ER–positive breast cancer who need preoperative treatment to downstage their tumor is that, very often, the cancers just don’t respond to chemotherapy very well. It’s a very rational thought to try and use neoadjuvant endocrine therapy as an alternative for these patients. The problem is that neoadjuvant endocrine therapy takes a long time to work, which is one of the reasons I think a lot of people shy away from giving it in this scenario.

I think the patients that we traditionally have treated in this manner are patients who are older, maybe aren’t candidates for chemotherapy, and who have larger cancers that are ER–positive. Maybe we’re contemplating doing surgery at some point or maybe not. They’re the type of patients that typically we’ve treated. But, I do think this is evolving. And the ALTERNATE Trial is a very interesting trial where patients of, really, pretty much any age, who have estrogen receptor–positive breast cancers, and who are felt to be candidates for preoperative treatment, are given either anastrozole or fulvestrant for 4 weeks, after which they get a biopsy. What they do is they compare the Ki67 from the diagnostic biopsy with the post 4-week biopsy to see if it’s dropped or not. If it has dropped, then the thought is that these are cancers that are sensitive to endocrine therapy, and the patients can either go to surgery or continue on the endocrine therapy. If it doesn’t go down, the thought is that these patients are more likely to benefit from chemotherapy. So, I think that’s a very good approach, and I would definitely refer patients for a trial like that.

We actually, also, a few years ago, looked at the 21-gene recurrence score as a means of choosing therapy for patients with ER–positive breast cancer preoperatively. So, we tried to do a TAILORx-type trial in the preoperative setting, but the numbers were kind of small. We didn’t see any pathologic complete responses in patients with recurrence scores between 10 and 25, which I guess is in keeping with what we know about the 21-gene recurrence score. And, in the patients with higher risk cancers with recurrence scores over 25, the pathologic complete response rate to chemotherapy was only 20%. So, even in a group where you think they might benefit from chemotherapy, they really don’t.

I think this is an evolving area, but [I], traditionally, it does tend to be older patients who aren’t candidates for chemotherapy. But, because of the fact that these estrogen receptor–positive cancers just don’t really respond very well to chemotherapy, I think we are going to see increasing use of preoperative endocrine therapy.

Hope S. Rugo, MD: It leads nicely into the question of how long we should treat patients with endocrine therapy? Who should receive treatment after 5 years? And, of course, we do have recent data that helps us think about this question a little bit more. We have data about the use of extending hormone therapy, either with tamoxifen or aromatase inhibitors, and we have data on the natural history of patients who have hormone receptor–positive disease. If you think about all of this information together, I think what it suggests is that hormone receptor–positive disease—a fact we’ve known for a long time, but we’re really understanding much better now—is a chronic disease.

Recurrences can occur out past 20 years, even for relatively low-risk disease. About half of the recurrence risk occurs after 5 years, so for patients who have a high-risk disease when they start, their risk after 5 years is still much higher than the women who had tiny cancers. So, a stage I cancer that is low-risk, by all other features, I will likely treat for 5 years. For a woman who has a higher-stage cancer, I tend to extend therapy as long as they can tolerate it, for longer than 5 years, usually out to 10 years. Again, really, we have to individualize therapy based on the patient themselves. And, I tend to not talk about that duration when they start with treatment because I found that that can lead to a sense of less hopefulness about outcome. We discuss it over time, as new data is obtained, but also as we see how the patient is tolerating treatment themselves. If a patient starts with tamoxifen because they’re perimenopausal, I will switch to an aromatase inhibitor after 2 or 3 years when they are menopausal, and then continue that treatment usually for 5 years.

Transcriped Edited for Clarity
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