This transcript has been edited for clarity.
Sarah L. Sammons, MD: Hello, everyone. My name is Dr Sarah Sammons, and I am a breast medical oncologist at Dana-Farber Cancer Institute, Harvard Medical School in Boston, Massachusetts.
I serve as the associate director of our metastatic breast cancer program, and I'm very excited to be here today and have a discussion with Dr Olivia Pagani. Dr Pagani, please introduce yourself.
Olivia Pagani, MD: Hi, everyone. Thank you, Sarah. I am Olivia Pagani. I was the director of the breast unit of the Institute of Oncology of Southern Switzerland and the director of the breast program of the European School of Oncology. I'm still a professor at University of Lugano and Geneva in Switzerland.
Sammons: Wonderful. I think we will have a really lively discussion today about one of my favorite topics. We're going to be speaking about new therapies and treatment strategies in patients with metastatic hormone receptor–positive or estrogen receptor–positive and HER2-negative breast cancer. It's becoming a more complex topic as the years go on. We have more and more therapy options for these patients.
First, let's talk about a patient with metastatic estrogen receptor–positive or hormone receptor–positive, HER2-negative breast cancer and the first line of therapy that we might think about for them. What kind of treatments are you thinking about in the first line for most patients? How are you selecting their treatments, Dr Pagani?
Pagani: Nowadays, at least in first-world countries, we tend to give our patients endocrine therapy together with cyclin-dependent kinase (CDK)–4/6 inhibitors. This is the best option in all patients except in those who have a visceral crisis, of whom there are luckily very few. This, I think, is the standard of care.
Of course, the issue of availability of these drugs is a problem worldwide; not in our countries, but in many countries, they are available but they need to be paid out-of-pocket by patients. Maybe later on, we will address this kind of situation.
The standard of care nowadays in first line is endocrine therapy plus CDK4/6 inhibitors, and don't forget ovarian function suppression in premenopausal women.
Sammons: Excellent. Very similarly, for the vast majority of patients who are in the first line, I'm going to offer them endocrine therapy. If they're considered endocrine-sensitive, then an aromatase inhibitor. If they progress on an aromatase inhibitor or within 12 months of stopping, then we're going to think about fulvestrant. I'm generally adding a CDK4/6 inhibitor for the vast majority of patients.
In my clinic, I tend to favor ribociclib nowadays just because we have three first-line clinical trials that have shown an overall survival benefit. It's a controversial topic, but do you have any preference on choice of CDK4/6 inhibitor?
Pagani: I participated in the palbociclib trials because they were the first. Nowadays, ribociclib is the only one with very strong overall survival benefits. Unless there is any cardiac contraindication, this is the best choice despite the fact that they were not compared nor will ever be compared. We really do not have their head-to-head comparison; I think that it seems reasonable to me to choose ribociclib as the first option.
Sammons: I feel similarly. If I have a patient with very heavy visceral liver disease or brain metastasis, I tend to actually choose abemaciclib. If I have an older patient or a patient with a history of cardiac or liver disease who's still a candidate for palbociclib, I will certainly still use palbociclib.
You brought up a great point, access equity, the ability to get a CDK4/6 inhibitor in the first-line setting is a challenge in some countries. There are some older patients who we worry about their performance status, who we worry about their candidacy of a CDK4/6 inhibitor.
I'm setting you up. Do we have any data to hold off on a CDK4/6 inhibitor in the first line, give single-agent endocrine therapy, and then bring the CDK4/6 inhibitor in the second line?
Pagani: I don't think we have such data, but I think that we discussed this several times at the Advanced Breast Cancer Conference— the Lisbon one.
Apart from older patients, it can be reasonable in patients who have low-volume disease or who had a very long disease-free interval. This could be reasonable to discuss in this limited portion of patients.
For the rest of the patients, the combination is provided. For the first time in metastatic breast cancer, CDK4/6 inhibitors provided an overall survival benefit. This was a great improvement for the control of this disease. We live in an era with really brilliant results, which very much changed the story of these patients. We were really lucky.
Sammons: I agree. Patients live quite well on endocrine therapy and a CDK4/6 inhibitor in terms of their quality of life. There are caveats for sure, but once we find the right dose and management strategies, patients can do really well on these therapies for years. That's certainly our goal.
Let's talk about strategies after a patient has progression on CDK4/6 inhibitor. This is also a space that's rapidly evolving. You have a patient, maybe they've been on their CDK4/6 inhibitor for two, 3 years or so, and now, they're having some progression in a bone, one new liver lesion. What would your next steps be in that patient? Would you do any further workup to help you decide what treatment that you would want to use?
Pagani: Maybe this should be done at the beginning. We need to have, before first line, the information about mutations such as PI3KCA and AKT1 because this can, of course, change our decision.
It's better to have this information from the beginning in order not to lose time when the patient is progressing. Of course, if the patient has a PI3KCA mutation, I think alpelisib is a very important tool to use. Now, we have some data with anti-AKT drugs but in later lines, and the results are not yet very good.
Then, we have some recent data that we can switch the CDK4/6 inhibitor from the SONIA trial, for example. We have many options. According to the individual situation, we can make a plan that is much better than what we could do in the past. What do you think?
Sammons: Absolutely. When a patient has progression on their CDK4/6 inhibitor, I'm usually sending—in the US, we can send their circulating tumor DNA, and we can get a wide panel variety of genomic alterations. Post CDK4/6, I would be looking for an ESR1 mutation, a PI3KCA mutation, or AKT1 alteration.
Of course, we'd also want to know if the patient had a germline BRCA1/2 mutation. That would also be very important because that would make a second-line poly (ADP-ribose) polymerase inhibitor a very viable strategy.
For my patients who have a PI3KCA mutation, I am going to be thinking about either a combination with capivasertib-fulvestrant or alpelisib-fulvestrant. Now, we have capivasertib in the US that's approved for patients with PI3KCA, AKT1, or PTEN alterations.
For my patients without a mutation in the second-line setting, now, we really have two options to think about. I still think everolimus combinations are very reasonable for the wild-type patients. If they received an aromatase inhibitor in the first line, I would give them everolimus with fulvestrant.
At the American Society of Clinical Oncology meeting just a couple of days ago, we saw Dr Kevin Kalinsky present the results of the postMONARCH clinical trial, and that was the first phase 3 clinical trial to look at CDK4/6 inhibitor after CDK4/6 inhibitor.
Most of the patients had received prior ribociclib and/or palbociclib with an aromatase inhibitor, and they were randomized to abemaciclib with fulvestrant vs endocrine monotherapy. We did see a statistically significant improvement in the progression-free survival with the use of abemaciclib and fulvestrant after palbociclib, ribociclib, or an endocrine therapy.
Either abemaciclib-fulvestrant or everolimus-fulvestrant are options for our wild-type patients. We also have elacestrant, which could be an option for select patients who have ESR1 mutations after CDK4/6.
The studies that have really shown elacestrant subgroup patients that might benefit are those who had a long duration on their first-line CDK4/6 inhibitor and have an ESR1 mutation. We have that as an option for them as well.
This area is getting a little bit crowded, but the good news for our patients is that we have options. We can talk to them about those options, talk to them about the side effect profile and the advantages, and decide together which treatment might be best.
Pagani: This is really important, and the postMONARCH is a very important piece of information, especially for those patients who have progression but not a huge extensive progression. I think it's a pity to throw away such a potent class of drugs. This is quite an important clinical practice.
They are available. Many drugs are not yet available in Europe, and Switzerland is a different country because it's not within the European community. For example, we do not have anti-ATK drugs yet. They will come, but the European Medicines Agency and the Swiss Regulatory are a little bit slower than the FDA. I think the postMONARCH is a very important piece of information.
Also, what is important, I would like to hear your opinion. It is very difficult, mostly in these days, when we have such an important amount of drugs to be used, knowing when to switch to chemo. It was much easier in the past because after one or two lines, there was nothing else.
Sammons: They didn't have any options.
Pagani: Now, they also put chemo inside all these pathways. It's really very complicated. I would like to know when you switch to chemo, is there a particular situation or is it a case-by-case decision?
Sammons: It's a really great question. It comes down to when we feel that a patient is endocrine-resistant. When do we feel like they're not going to respond to any more endocrine therapies? Then, at that point, we recommend moving on to chemotherapy.
I have found in my practice that patients are pretty unlikely to respond to more than two lines of endocrine therapy. But I do think that it's very patient-dependent. If you have a patient that's had a very long interval on their first-line CDK, and then a decently long interval on their second line with CDK, everolimus, or PIK3 inhibitor, then maybe I might try a third line of endocrine therapy if I have an option.
I think the vast majority of patients are probably going to receive two lines of endocrine therapy before we move on to chemotherapy. Would you agree? How do you think about that?
Pagani: Absolutely. I think that it's really patient-dependent. I would like to stress the fact that when chemotherapy is given, a single agent is the preferred choice unless you really need to have a very quick response. This is, I think, still not common practice.
Sammons: When thinking about which first chemotherapy to give a patient, I totally agree that single-agent chemotherapy is the way to go for the vast majority of patients.
We just saw data a few days ago for the DESTINY-Breast06 clinical trial that took patients with hormone receptor–positive, HER2-low, or - ultralow breast cancer and as the first line of chemotherapy, compared trastuzumab deruxtecan with a single agent, either capecitabine or a taxane.
We saw that trastuzumab deruxtecan had a profoundly longer progression-free survival of 13 months compared with 8 months with chemotherapy — so really, a substantial benefit. We haven't seen overall survival data for that yet.
The general sentiment was that in DESTINY-Breast06, most of the patients had heavy visceral disease and they had two lines of endocrine therapy. I certainly would consider trastuzumab deruxtecan for a patient with a large amount of visceral disease.
Pagani: Then, of course, we have all these new drugs we do not have time to address, such as sacituzumab. We have so many lines also after one or two lines of chemotherapy. The spectrum is really expanding, and this is very good for our patients.
We have, I think, a different approach when we speak with a patient with metastatic breast cancer than we had 5-6 years ago. It's a really very exciting period.
Sammons: Absolutely. We're doing better every year, and that's what I tell my patients. It's really a balance of disease control for as long as possible, but also with optimal quality of life. We have more options now than ever before.
Pagani: It's really very interesting. The future will be even more interesting and exciting than the present.
Sammons: Absolutely. Thank you so much, Dr Pagani, for joining me. Thank you for listening to us today. We hope that you have a lovely day.
COMMENTARY
New Approaches in the Treatment of HR+ Metastatic Breast Cancer
Olivia Pagani, MD; Sarah L. Sammons, MD
DISCLOSURES
| July 10, 2024This transcript has been edited for clarity.
Sarah L. Sammons, MD: Hello, everyone. My name is Dr Sarah Sammons, and I am a breast medical oncologist at Dana-Farber Cancer Institute, Harvard Medical School in Boston, Massachusetts.
I serve as the associate director of our metastatic breast cancer program, and I'm very excited to be here today and have a discussion with Dr Olivia Pagani. Dr Pagani, please introduce yourself.
Olivia Pagani, MD: Hi, everyone. Thank you, Sarah. I am Olivia Pagani. I was the director of the breast unit of the Institute of Oncology of Southern Switzerland and the director of the breast program of the European School of Oncology. I'm still a professor at University of Lugano and Geneva in Switzerland.
Sammons: Wonderful. I think we will have a really lively discussion today about one of my favorite topics. We're going to be speaking about new therapies and treatment strategies in patients with metastatic hormone receptor–positive or estrogen receptor–positive and HER2-negative breast cancer. It's becoming a more complex topic as the years go on. We have more and more therapy options for these patients.
First, let's talk about a patient with metastatic estrogen receptor–positive or hormone receptor–positive, HER2-negative breast cancer and the first line of therapy that we might think about for them. What kind of treatments are you thinking about in the first line for most patients? How are you selecting their treatments, Dr Pagani?
Pagani: Nowadays, at least in first-world countries, we tend to give our patients endocrine therapy together with cyclin-dependent kinase (CDK)–4/6 inhibitors. This is the best option in all patients except in those who have a visceral crisis, of whom there are luckily very few. This, I think, is the standard of care.
Of course, the issue of availability of these drugs is a problem worldwide; not in our countries, but in many countries, they are available but they need to be paid out-of-pocket by patients. Maybe later on, we will address this kind of situation.
The standard of care nowadays in first line is endocrine therapy plus CDK4/6 inhibitors, and don't forget ovarian function suppression in premenopausal women.
Sammons: Excellent. Very similarly, for the vast majority of patients who are in the first line, I'm going to offer them endocrine therapy. If they're considered endocrine-sensitive, then an aromatase inhibitor. If they progress on an aromatase inhibitor or within 12 months of stopping, then we're going to think about fulvestrant. I'm generally adding a CDK4/6 inhibitor for the vast majority of patients.
In my clinic, I tend to favor ribociclib nowadays just because we have three first-line clinical trials that have shown an overall survival benefit. It's a controversial topic, but do you have any preference on choice of CDK4/6 inhibitor?
Pagani: I participated in the palbociclib trials because they were the first. Nowadays, ribociclib is the only one with very strong overall survival benefits. Unless there is any cardiac contraindication, this is the best choice despite the fact that they were not compared nor will ever be compared. We really do not have their head-to-head comparison; I think that it seems reasonable to me to choose ribociclib as the first option.
Sammons: I feel similarly. If I have a patient with very heavy visceral liver disease or brain metastasis, I tend to actually choose abemaciclib. If I have an older patient or a patient with a history of cardiac or liver disease who's still a candidate for palbociclib, I will certainly still use palbociclib.
You brought up a great point, access equity, the ability to get a CDK4/6 inhibitor in the first-line setting is a challenge in some countries. There are some older patients who we worry about their performance status, who we worry about their candidacy of a CDK4/6 inhibitor.
I'm setting you up. Do we have any data to hold off on a CDK4/6 inhibitor in the first line, give single-agent endocrine therapy, and then bring the CDK4/6 inhibitor in the second line?
Pagani: I don't think we have such data, but I think that we discussed this several times at the Advanced Breast Cancer Conference— the Lisbon one.
Apart from older patients, it can be reasonable in patients who have low-volume disease or who had a very long disease-free interval. This could be reasonable to discuss in this limited portion of patients.
For the rest of the patients, the combination is provided. For the first time in metastatic breast cancer, CDK4/6 inhibitors provided an overall survival benefit. This was a great improvement for the control of this disease. We live in an era with really brilliant results, which very much changed the story of these patients. We were really lucky.
Sammons: I agree. Patients live quite well on endocrine therapy and a CDK4/6 inhibitor in terms of their quality of life. There are caveats for sure, but once we find the right dose and management strategies, patients can do really well on these therapies for years. That's certainly our goal.
Let's talk about strategies after a patient has progression on CDK4/6 inhibitor. This is also a space that's rapidly evolving. You have a patient, maybe they've been on their CDK4/6 inhibitor for two, 3 years or so, and now, they're having some progression in a bone, one new liver lesion. What would your next steps be in that patient? Would you do any further workup to help you decide what treatment that you would want to use?
Pagani: Maybe this should be done at the beginning. We need to have, before first line, the information about mutations such as PI3KCA and AKT1 because this can, of course, change our decision.
It's better to have this information from the beginning in order not to lose time when the patient is progressing. Of course, if the patient has a PI3KCA mutation, I think alpelisib is a very important tool to use. Now, we have some data with anti-AKT drugs but in later lines, and the results are not yet very good.
Then, we have some recent data that we can switch the CDK4/6 inhibitor from the SONIA trial, for example. We have many options. According to the individual situation, we can make a plan that is much better than what we could do in the past. What do you think?
Sammons: Absolutely. When a patient has progression on their CDK4/6 inhibitor, I'm usually sending—in the US, we can send their circulating tumor DNA, and we can get a wide panel variety of genomic alterations. Post CDK4/6, I would be looking for an ESR1 mutation, a PI3KCA mutation, or AKT1 alteration.
Of course, we'd also want to know if the patient had a germline BRCA1/2 mutation. That would also be very important because that would make a second-line poly (ADP-ribose) polymerase inhibitor a very viable strategy.
For my patients who have a PI3KCA mutation, I am going to be thinking about either a combination with capivasertib-fulvestrant or alpelisib-fulvestrant. Now, we have capivasertib in the US that's approved for patients with PI3KCA, AKT1, or PTEN alterations.
For my patients without a mutation in the second-line setting, now, we really have two options to think about. I still think everolimus combinations are very reasonable for the wild-type patients. If they received an aromatase inhibitor in the first line, I would give them everolimus with fulvestrant.
At the American Society of Clinical Oncology meeting just a couple of days ago, we saw Dr Kevin Kalinsky present the results of the postMONARCH clinical trial, and that was the first phase 3 clinical trial to look at CDK4/6 inhibitor after CDK4/6 inhibitor.
Most of the patients had received prior ribociclib and/or palbociclib with an aromatase inhibitor, and they were randomized to abemaciclib with fulvestrant vs endocrine monotherapy. We did see a statistically significant improvement in the progression-free survival with the use of abemaciclib and fulvestrant after palbociclib, ribociclib, or an endocrine therapy.
Either abemaciclib-fulvestrant or everolimus-fulvestrant are options for our wild-type patients. We also have elacestrant, which could be an option for select patients who have ESR1 mutations after CDK4/6.
The studies that have really shown elacestrant subgroup patients that might benefit are those who had a long duration on their first-line CDK4/6 inhibitor and have an ESR1 mutation. We have that as an option for them as well.
This area is getting a little bit crowded, but the good news for our patients is that we have options. We can talk to them about those options, talk to them about the side effect profile and the advantages, and decide together which treatment might be best.
Pagani: This is really important, and the postMONARCH is a very important piece of information, especially for those patients who have progression but not a huge extensive progression. I think it's a pity to throw away such a potent class of drugs. This is quite an important clinical practice.
They are available. Many drugs are not yet available in Europe, and Switzerland is a different country because it's not within the European community. For example, we do not have anti-ATK drugs yet. They will come, but the European Medicines Agency and the Swiss Regulatory are a little bit slower than the FDA. I think the postMONARCH is a very important piece of information.
Also, what is important, I would like to hear your opinion. It is very difficult, mostly in these days, when we have such an important amount of drugs to be used, knowing when to switch to chemo. It was much easier in the past because after one or two lines, there was nothing else.
Sammons: They didn't have any options.
Pagani: Now, they also put chemo inside all these pathways. It's really very complicated. I would like to know when you switch to chemo, is there a particular situation or is it a case-by-case decision?
Sammons: It's a really great question. It comes down to when we feel that a patient is endocrine-resistant. When do we feel like they're not going to respond to any more endocrine therapies? Then, at that point, we recommend moving on to chemotherapy.
I have found in my practice that patients are pretty unlikely to respond to more than two lines of endocrine therapy. But I do think that it's very patient-dependent. If you have a patient that's had a very long interval on their first-line CDK, and then a decently long interval on their second line with CDK, everolimus, or PIK3 inhibitor, then maybe I might try a third line of endocrine therapy if I have an option.
I think the vast majority of patients are probably going to receive two lines of endocrine therapy before we move on to chemotherapy. Would you agree? How do you think about that?
Pagani: Absolutely. I think that it's really patient-dependent. I would like to stress the fact that when chemotherapy is given, a single agent is the preferred choice unless you really need to have a very quick response. This is, I think, still not common practice.
Sammons: When thinking about which first chemotherapy to give a patient, I totally agree that single-agent chemotherapy is the way to go for the vast majority of patients.
We just saw data a few days ago for the DESTINY-Breast06 clinical trial that took patients with hormone receptor–positive, HER2-low, or - ultralow breast cancer and as the first line of chemotherapy, compared trastuzumab deruxtecan with a single agent, either capecitabine or a taxane.
We saw that trastuzumab deruxtecan had a profoundly longer progression-free survival of 13 months compared with 8 months with chemotherapy — so really, a substantial benefit. We haven't seen overall survival data for that yet.
The general sentiment was that in DESTINY-Breast06, most of the patients had heavy visceral disease and they had two lines of endocrine therapy. I certainly would consider trastuzumab deruxtecan for a patient with a large amount of visceral disease.
Pagani: Then, of course, we have all these new drugs we do not have time to address, such as sacituzumab. We have so many lines also after one or two lines of chemotherapy. The spectrum is really expanding, and this is very good for our patients.
We have, I think, a different approach when we speak with a patient with metastatic breast cancer than we had 5-6 years ago. It's a really very exciting period.
Sammons: Absolutely. We're doing better every year, and that's what I tell my patients. It's really a balance of disease control for as long as possible, but also with optimal quality of life. We have more options now than ever before.
Pagani: It's really very interesting. The future will be even more interesting and exciting than the present.
Sammons: Absolutely. Thank you so much, Dr Pagani, for joining me. Thank you for listening to us today. We hope that you have a lovely day.
Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
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