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Brain Metastases in HER2-Positive Breast Cancer

Panelists: Adam M. Brufsky, MD, PhD, University of Pittsburgh Cancer Institute; Carlos L. Arteaga, MD, Vanderbilt University; Jose Baselga, MD, PhD, Memorial Sloan Kettering Cancer Center; Kimberly Blackwell, MD, Duke Cancer Institute; Debu Tripathy, MD, University of Texas MD Anderson Cancer Center; Denise A. Yardley, MD, Sarah Cannon Research Institute; Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center
Published: Wednesday, Jul 19, 2017



Transcript:

Adam M. Brufsky, MD, PhD:
So, one last thing about HER2-positive disease—and then we’ll go to triple-negative—is the treatment of brain metastases. I think in everybody’s experience, that seems to be the big unmet need here. Most people, when they die of this disease, tend to die with brain metastases, and the issue is, what can we do? What is everybody’s approach? I’ll start with Carlos. What’s your approach now to brain metastasis? You had a fabulous paper in Science about the intertype switch. You were part of it. There’s a subtype switch to HER3 overexpression or something like that in those tumors?

Carlos L. Arteaga, MD: No, no. We think that the brain is very rich in heregulin, so that actually drives the activation of HER3, and those tumors require dual therapy. Again, I use capecitabine and lapatinib for the most part, and stereotactic radiation.

Adam M. Brufsky, MD, PhD: Kim—same thing?

Kimberly L. Blackwell, MD: My big soapbox right now is that I do anything within my power to avoid whole brain radiation.

Adam M. Brufsky, MD, PhD: Yes.

Kimberly L. Blackwell, MD: And I just think we have data from 2 large studies from 2016: one in non–small cell lung cancer, and one in a variety of tumors where you don’t improve survival by whole brain radiotherapy over supportive care. It’s always that moment of panic where the patient presents to the ER, they have been throwing up for 3 days, they do the CT scan, and everyone has a freakout. And then the radiation oncology person comes in and wants to do whole brain radiation. I

n this HER2 space where the disease is controlled so well from the neck down, we need to do everything we can, when clinically safe, to avoid that happening, because these women do quite well for a period of time. And we know from Bachelot’s study that there is some activity of lapatinib and capecitabine prior to whole brain radiation therapy. Dr. Freedman and the TBCRC now have data looking at the combination of capecitabine and neratinib with a volumetric objective response rate greater than 40% in patients progressing. And that will come out at this year’s ASCO.

So, I think I’m with Carlos. I’ve seen responses even in the non-HER2 setting with capecitabine in the brain, and the small molecule inhibitors also offer a lot of promise in this space. Certainly, if neratinib becomes regulatorily available, I think that that will never have a randomized study of progressive brain metastases—capecitabine versus capecitabine plus neratinib. That will be my go-to agent if the drug becomes commercially available, based on the data that the TBCRC generated.

Carlos L. Arteaga, MD: Neratinib has already beaten lapatinib in the brain.

Kimberly L. Blackwell, MD: Right.

José Baselga, MD, PhD: I think there’s something very important about the biology of brain metastases in HER2-positive disease. It’s a very different situation than in the triple-negative setting. Oh yes, these patients live quite longer.

Adam M. Brufsky, MD, PhD: We are participating in the registry, and those women live a long time.

José Baselga, MD, PhD: It’s important not to give them, if you can prevent it, as Kim is saying, whole brain RT—these patients will live. Use, if you can, localized therapy, and then just use your strategies well, because these patients can live a long time.

Adam M. Brufsky, MD, PhD: What are the most brain metastases that your radiotherapist will do SRS, or stereotactic radiosurgery, on? What's the maximum?

Debu Tripathy, MD: It depends on the location of it, but up to 10.

Adam M. Brufsky, MD, PhD: Up to 10?

Kimberly L. Blackwell, MD: And volume, too.

Debu Tripathy, MD: And volume.

Kimberly L. Blackwell, MD: Obviously, 1 big tumor could have just as much radio dose as 3 little ones. But I think the more important thing is to have a dialogue with the radiation oncologist, because they’re seeing multiple tumor types. So if they see 7 new brain metastases in lung cancer, not to pick on our lung cancer colleagues, that’s a bad thing. In HER2-positive breast cancer, those patients can do well for some time, especially if that’s their initial presentation of recurrent disease. I have probably 15 women right now with no disease outside of the brain, whose lungs are good, hearts are good, livers are good, and bones are good, so we really have to minimize the long-term toxicity.

Adam M. Brufsky, MD, PhD: And women are living long enough that you’re beginning to see the toxicity of nonhippocampal sparing in whole brain RT. When people live 2, 3, or 4 years now with brain metastases, you’re starting to see the long-term side effects, which are worse than the disease. I agree with you. So, I think we’re all saying in general that trying to do less whole brain radiation in these women is probably the right thing to do, but we don’t have any good drugs at this point in time.

Transcript Edited for Clarity

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Transcript:

Adam M. Brufsky, MD, PhD:
So, one last thing about HER2-positive disease—and then we’ll go to triple-negative—is the treatment of brain metastases. I think in everybody’s experience, that seems to be the big unmet need here. Most people, when they die of this disease, tend to die with brain metastases, and the issue is, what can we do? What is everybody’s approach? I’ll start with Carlos. What’s your approach now to brain metastasis? You had a fabulous paper in Science about the intertype switch. You were part of it. There’s a subtype switch to HER3 overexpression or something like that in those tumors?

Carlos L. Arteaga, MD: No, no. We think that the brain is very rich in heregulin, so that actually drives the activation of HER3, and those tumors require dual therapy. Again, I use capecitabine and lapatinib for the most part, and stereotactic radiation.

Adam M. Brufsky, MD, PhD: Kim—same thing?

Kimberly L. Blackwell, MD: My big soapbox right now is that I do anything within my power to avoid whole brain radiation.

Adam M. Brufsky, MD, PhD: Yes.

Kimberly L. Blackwell, MD: And I just think we have data from 2 large studies from 2016: one in non–small cell lung cancer, and one in a variety of tumors where you don’t improve survival by whole brain radiotherapy over supportive care. It’s always that moment of panic where the patient presents to the ER, they have been throwing up for 3 days, they do the CT scan, and everyone has a freakout. And then the radiation oncology person comes in and wants to do whole brain radiation. I

n this HER2 space where the disease is controlled so well from the neck down, we need to do everything we can, when clinically safe, to avoid that happening, because these women do quite well for a period of time. And we know from Bachelot’s study that there is some activity of lapatinib and capecitabine prior to whole brain radiation therapy. Dr. Freedman and the TBCRC now have data looking at the combination of capecitabine and neratinib with a volumetric objective response rate greater than 40% in patients progressing. And that will come out at this year’s ASCO.

So, I think I’m with Carlos. I’ve seen responses even in the non-HER2 setting with capecitabine in the brain, and the small molecule inhibitors also offer a lot of promise in this space. Certainly, if neratinib becomes regulatorily available, I think that that will never have a randomized study of progressive brain metastases—capecitabine versus capecitabine plus neratinib. That will be my go-to agent if the drug becomes commercially available, based on the data that the TBCRC generated.

Carlos L. Arteaga, MD: Neratinib has already beaten lapatinib in the brain.

Kimberly L. Blackwell, MD: Right.

José Baselga, MD, PhD: I think there’s something very important about the biology of brain metastases in HER2-positive disease. It’s a very different situation than in the triple-negative setting. Oh yes, these patients live quite longer.

Adam M. Brufsky, MD, PhD: We are participating in the registry, and those women live a long time.

José Baselga, MD, PhD: It’s important not to give them, if you can prevent it, as Kim is saying, whole brain RT—these patients will live. Use, if you can, localized therapy, and then just use your strategies well, because these patients can live a long time.

Adam M. Brufsky, MD, PhD: What are the most brain metastases that your radiotherapist will do SRS, or stereotactic radiosurgery, on? What's the maximum?

Debu Tripathy, MD: It depends on the location of it, but up to 10.

Adam M. Brufsky, MD, PhD: Up to 10?

Kimberly L. Blackwell, MD: And volume, too.

Debu Tripathy, MD: And volume.

Kimberly L. Blackwell, MD: Obviously, 1 big tumor could have just as much radio dose as 3 little ones. But I think the more important thing is to have a dialogue with the radiation oncologist, because they’re seeing multiple tumor types. So if they see 7 new brain metastases in lung cancer, not to pick on our lung cancer colleagues, that’s a bad thing. In HER2-positive breast cancer, those patients can do well for some time, especially if that’s their initial presentation of recurrent disease. I have probably 15 women right now with no disease outside of the brain, whose lungs are good, hearts are good, livers are good, and bones are good, so we really have to minimize the long-term toxicity.

Adam M. Brufsky, MD, PhD: And women are living long enough that you’re beginning to see the toxicity of nonhippocampal sparing in whole brain RT. When people live 2, 3, or 4 years now with brain metastases, you’re starting to see the long-term side effects, which are worse than the disease. I agree with you. So, I think we’re all saying in general that trying to do less whole brain radiation in these women is probably the right thing to do, but we don’t have any good drugs at this point in time.

Transcript Edited for Clarity
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