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ESR Mutations and Resistance to Endocrine Therapy in Breast Cancer

Panelists:Adam M. Brufsky, MD, PhD, University of Pittsburgh Cancer Institute;Carlos L. Arteaga, MD, Vanderbilt University;Kimberly L. Blackwell, MD, Duke University Medical Center;Joyce A. O’Shaughnessy, MD, Baylor Charles A. Sammons Cancer Center;Sunil Verma, MD, MSEd, FRCPC, University of Calgary
Published: Thursday, Jun 23, 2016


Transcript:

Adam M. Brufsky, MD, PhD:
Hello, and thank you for joining us today for this OncLive Peer Exchange discussion on the management of advanced breast cancer. Today, I’ll be joined by a panel of leading experts in the field of breast cancer research for a very informative discussion on the latest advances in treatment. My colleagues and I will be covering the data that has come out over the last few months, including information from ASCO 2016, and adding important perspective on how you can use this information in clinical practice.

I am Dr. Adam Brufsky and I am a professor of Medicine at the University of Pittsburgh and associate director for Clinical Investigation at the University of Pittsburgh Cancer Institute. Participating today on our distinguished panel are: Dr. Carlos Arteaga, professor of medicine and cancer biology, director of the Center for Cancer Targeted Therapies, director of the Breast Cancer Program at Vanderbilt University in Nashville, Tennessee; Dr. Kimberly Blackwell, professor of medicine in the Division of Oncology at Duke University Medical Center in Durham, North Carolina; Dr. Joyce O’Shaughnessy, chair of breast cancer research at Baylor Charles A. Sammons Cancer Center, Texas Oncology and U.S. Oncology in Dallas, Texas; and finally Dr. Sunil Verma, professor and head of the Department of Oncology at the University of Calgary and medical director at the Tom Baker Cancer Centre in Calgary, Canada. Thank you so much for joining us, and let’s begin.

The first thing we really want to talk about is hormone receptor advanced and metastatic, hormone receptor-positive breast cancer. And, really, the first thing I think to talk about is a little bit more on a basic science topic. This actually has clinical relevance, and that is, mechanisms of resistance. I think there’s been a lot of excitement recently about estrogen receptor (ER) mutations, and I’ll start with Carlos. What do you think of ER mutations, what’s been discussed at ASCO, and where do you think that’s going?

Carlos L. Arteaga, MD: Well, I think ER mutations are probably a major discovery in that they are a real mechanism of resistance to estrogen deprivation with aromatase inhibitors. Mechanistically, I think this makes a lot of sense. They are mutations in the ER that dispense of that need of estradiol. Therefore, these tumors progress on aromatase inhibitors, but fortunately they seem to be sensitive to other interventions like ER downregulators—like fulvestrant—and suggest that these new ER downregulators that are we developing may be very effective against them. I think what is remarkable is that up to 30% of patients that progress on aromatase inhibitors in the metastatic setting have these alterations, and suggests that we should deploy these ER downregulators, and we can find them, actually, in plasma without the need of a tissue biopsy. We may need to start thinking of incorporating, eventually, into our standard of care, measuring these mutations in plasma in patients that progress on an aromatase inhibitor.

Adam M. Brufsky, MD, PhD: So, Sunil, at this year’s ASCO there were two abstracts that actually looked at ER mutations and prognosis, as well as response to various therapies. Can you tell us a little bit about those?

Sunil Verma, MD, MSEd, FRCPC: Yes. There were two very important abstracts. The first one looking at what the frequency of ESR (estrogen receptor) gene mutations is, and there was about a 30% or so frequency rate. And they found, as Carlos mentioned, that they were seen only in those patients who had prior aromatase inhibitor therapy, looking at cell-free DNA. And they didn’t see any of those in patients who had prior tamoxifen. So, it is a very treatment-dependent effect. They also saw, interesting enough, that they were more likely to occur in patients who had bone metastases—versus visceral metastases,—again, telling us that maybe the biology of disease may tell us a little bit about what type of resistance and how this natural history will evolve. PALOMA-3 presented by Nick Turner, which is a study looking at palbociclib plus fulvestrant versus fulvestrant plus placebo, looked at patients who had ESR1 mutations. And they found that despite these mutations, there was a benefit favoring palbociclib, i.e. ESR1 mutation was not resistant to CDK4/6 inhibitors. So, this was, I think, one of the key data points to come out of this study, showing that they are still effective in patients with ESR mutation.

Carlos L. Arteaga, MD: Also, there was an interesting biological insight in that presentation, that the patients that had had prior response to endocrine therapy that showed some evidence of being luminal and hormone-dependent were those that developed acquired ER mutations, whereas those that did not, did not develop ER mutations. So, that’s fascinating. Tumors are going to be using whatever they know works. The fact that they did not respond to endocrine therapy to begin with means that they were not using the ER, maybe. Hence, they’re not going to mutate that pathway because they may have other ways…

Adam M. Brufsky, MD, PhD: Of coming around.

Carlos L. Arteaga, MD: Of progressing.

Sunil Verma, MD, MSEd, FRCPC: And they showed that patients who had PI3 kinase mutations, one-third of the patients, also had ESR mutations as well. So, they’re not mutually exclusive.

Adam M. Brufsky, MD, PhD: Wasn’t PI3 kinase more related to the more luminal low aggressive subtypes?

Carlos L. Arteaga, MD: I’m not sure yet.

Adam M. Brufsky, MD, PhD: Joyce, would you use ER mutations now in your practice at all? Will you subtype patients? Will you do an ER assay since it’s available?

Joyce A. O’Shaughnessy, MD: No, I don’t think it’s really specifically actionable right now. I think that it’s very important and may have potentially some implications when we have choices in the adjuvant setting. I think that’s a really important question for us to work out because most of these, as Carlos said, have been emerging in metastatic aromatase inhibitor therapy. I don’t think we know yet about adjuvant AI (aromatase inhibitor) therapy. But, no, we’re not going to change our practice patterns because we’re going to use the CDK4/6 inhibitors. There were also data—correct me if I’m wrong—with regard to the BOLERO-2 trial and ESR1 mutations and everolimus and it didn’t make any difference there either. So, the everolimus is going to work no matter which way patients have them or not. I think we’re just going to continue to treat patients as we do anyway, so I don’t think we need to check for it.

Kimberly L. Blackwell, MD: Yes. I agree with Carlos though. The way I’m using it is in patients who haven’t had fulvestrant, if I see this on a Foundation One or some other type of genomic sequencing assay, certainly, fulvestrant goes higher on my list. In general, at ASCO this year, it was shown that the presence of these mutations, the patients’ overall survival, is worsened if you see these mutations in their tumor. So, I think that’s a reflection of that they’re no longer eligible for the endocrine therapy because they develop these mutations in the setting of chronic therapy more so than a worse kind of biology of this disease. That was the largest series ever presented at this year’s meeting of ER mutations.

Carlos L. Arteaga, MD: I agree. But, however, for the patient who is seeking a clinical trial, I think that there are trials now that enroll based on these mutations. These are, trials with ER downregulators that I believe, eventually, maybe would become standard of care.

Kimberly L. Blackwell, MD: I agree with you.

Carlos L. Arteaga, MD: So, I think for that setting, for those patients, I think it’s probably important that they know that there are options for them.

Adam M. Brufsky, MD, PhD: In other words, if you have an ESR mutation, you should probably get something like fulvestrant as opposed to a SERM (selective estrogen receptor modulator) or a SERD (selective estrogen receptor degrader). Is that kind of what you were going?

Carlos L. Arteaga, MD: I would say in the absence of a clinical trial rather than to a new SERD, fulvestrant would be a better choice based on the data we have seen, and the data in the laboratory, too.

Kimberly L. Blackwell, MD: And for those patients who maybe got a dose or two of fulvestrant and for whatever reason didn’t get it—those are few and far between—I’d certainly consider recycling it when I see these ESR mutations.

Transcript Edited for Clarity
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Transcript:

Adam M. Brufsky, MD, PhD:
Hello, and thank you for joining us today for this OncLive Peer Exchange discussion on the management of advanced breast cancer. Today, I’ll be joined by a panel of leading experts in the field of breast cancer research for a very informative discussion on the latest advances in treatment. My colleagues and I will be covering the data that has come out over the last few months, including information from ASCO 2016, and adding important perspective on how you can use this information in clinical practice.

I am Dr. Adam Brufsky and I am a professor of Medicine at the University of Pittsburgh and associate director for Clinical Investigation at the University of Pittsburgh Cancer Institute. Participating today on our distinguished panel are: Dr. Carlos Arteaga, professor of medicine and cancer biology, director of the Center for Cancer Targeted Therapies, director of the Breast Cancer Program at Vanderbilt University in Nashville, Tennessee; Dr. Kimberly Blackwell, professor of medicine in the Division of Oncology at Duke University Medical Center in Durham, North Carolina; Dr. Joyce O’Shaughnessy, chair of breast cancer research at Baylor Charles A. Sammons Cancer Center, Texas Oncology and U.S. Oncology in Dallas, Texas; and finally Dr. Sunil Verma, professor and head of the Department of Oncology at the University of Calgary and medical director at the Tom Baker Cancer Centre in Calgary, Canada. Thank you so much for joining us, and let’s begin.

The first thing we really want to talk about is hormone receptor advanced and metastatic, hormone receptor-positive breast cancer. And, really, the first thing I think to talk about is a little bit more on a basic science topic. This actually has clinical relevance, and that is, mechanisms of resistance. I think there’s been a lot of excitement recently about estrogen receptor (ER) mutations, and I’ll start with Carlos. What do you think of ER mutations, what’s been discussed at ASCO, and where do you think that’s going?

Carlos L. Arteaga, MD: Well, I think ER mutations are probably a major discovery in that they are a real mechanism of resistance to estrogen deprivation with aromatase inhibitors. Mechanistically, I think this makes a lot of sense. They are mutations in the ER that dispense of that need of estradiol. Therefore, these tumors progress on aromatase inhibitors, but fortunately they seem to be sensitive to other interventions like ER downregulators—like fulvestrant—and suggest that these new ER downregulators that are we developing may be very effective against them. I think what is remarkable is that up to 30% of patients that progress on aromatase inhibitors in the metastatic setting have these alterations, and suggests that we should deploy these ER downregulators, and we can find them, actually, in plasma without the need of a tissue biopsy. We may need to start thinking of incorporating, eventually, into our standard of care, measuring these mutations in plasma in patients that progress on an aromatase inhibitor.

Adam M. Brufsky, MD, PhD: So, Sunil, at this year’s ASCO there were two abstracts that actually looked at ER mutations and prognosis, as well as response to various therapies. Can you tell us a little bit about those?

Sunil Verma, MD, MSEd, FRCPC: Yes. There were two very important abstracts. The first one looking at what the frequency of ESR (estrogen receptor) gene mutations is, and there was about a 30% or so frequency rate. And they found, as Carlos mentioned, that they were seen only in those patients who had prior aromatase inhibitor therapy, looking at cell-free DNA. And they didn’t see any of those in patients who had prior tamoxifen. So, it is a very treatment-dependent effect. They also saw, interesting enough, that they were more likely to occur in patients who had bone metastases—versus visceral metastases,—again, telling us that maybe the biology of disease may tell us a little bit about what type of resistance and how this natural history will evolve. PALOMA-3 presented by Nick Turner, which is a study looking at palbociclib plus fulvestrant versus fulvestrant plus placebo, looked at patients who had ESR1 mutations. And they found that despite these mutations, there was a benefit favoring palbociclib, i.e. ESR1 mutation was not resistant to CDK4/6 inhibitors. So, this was, I think, one of the key data points to come out of this study, showing that they are still effective in patients with ESR mutation.

Carlos L. Arteaga, MD: Also, there was an interesting biological insight in that presentation, that the patients that had had prior response to endocrine therapy that showed some evidence of being luminal and hormone-dependent were those that developed acquired ER mutations, whereas those that did not, did not develop ER mutations. So, that’s fascinating. Tumors are going to be using whatever they know works. The fact that they did not respond to endocrine therapy to begin with means that they were not using the ER, maybe. Hence, they’re not going to mutate that pathway because they may have other ways…

Adam M. Brufsky, MD, PhD: Of coming around.

Carlos L. Arteaga, MD: Of progressing.

Sunil Verma, MD, MSEd, FRCPC: And they showed that patients who had PI3 kinase mutations, one-third of the patients, also had ESR mutations as well. So, they’re not mutually exclusive.

Adam M. Brufsky, MD, PhD: Wasn’t PI3 kinase more related to the more luminal low aggressive subtypes?

Carlos L. Arteaga, MD: I’m not sure yet.

Adam M. Brufsky, MD, PhD: Joyce, would you use ER mutations now in your practice at all? Will you subtype patients? Will you do an ER assay since it’s available?

Joyce A. O’Shaughnessy, MD: No, I don’t think it’s really specifically actionable right now. I think that it’s very important and may have potentially some implications when we have choices in the adjuvant setting. I think that’s a really important question for us to work out because most of these, as Carlos said, have been emerging in metastatic aromatase inhibitor therapy. I don’t think we know yet about adjuvant AI (aromatase inhibitor) therapy. But, no, we’re not going to change our practice patterns because we’re going to use the CDK4/6 inhibitors. There were also data—correct me if I’m wrong—with regard to the BOLERO-2 trial and ESR1 mutations and everolimus and it didn’t make any difference there either. So, the everolimus is going to work no matter which way patients have them or not. I think we’re just going to continue to treat patients as we do anyway, so I don’t think we need to check for it.

Kimberly L. Blackwell, MD: Yes. I agree with Carlos though. The way I’m using it is in patients who haven’t had fulvestrant, if I see this on a Foundation One or some other type of genomic sequencing assay, certainly, fulvestrant goes higher on my list. In general, at ASCO this year, it was shown that the presence of these mutations, the patients’ overall survival, is worsened if you see these mutations in their tumor. So, I think that’s a reflection of that they’re no longer eligible for the endocrine therapy because they develop these mutations in the setting of chronic therapy more so than a worse kind of biology of this disease. That was the largest series ever presented at this year’s meeting of ER mutations.

Carlos L. Arteaga, MD: I agree. But, however, for the patient who is seeking a clinical trial, I think that there are trials now that enroll based on these mutations. These are, trials with ER downregulators that I believe, eventually, maybe would become standard of care.

Kimberly L. Blackwell, MD: I agree with you.

Carlos L. Arteaga, MD: So, I think for that setting, for those patients, I think it’s probably important that they know that there are options for them.

Adam M. Brufsky, MD, PhD: In other words, if you have an ESR mutation, you should probably get something like fulvestrant as opposed to a SERM (selective estrogen receptor modulator) or a SERD (selective estrogen receptor degrader). Is that kind of what you were going?

Carlos L. Arteaga, MD: I would say in the absence of a clinical trial rather than to a new SERD, fulvestrant would be a better choice based on the data we have seen, and the data in the laboratory, too.

Kimberly L. Blackwell, MD: And for those patients who maybe got a dose or two of fulvestrant and for whatever reason didn’t get it—those are few and far between—I’d certainly consider recycling it when I see these ESR mutations.

Transcript Edited for Clarity
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