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HER2-Targeted Therapy for HER2 Low-Expressing Breast Cancer

Panelists:Adam M. Brufsky, MD, PhD, FACP, University of Pittsburgh School of Medicine; Francisco Esteva, MD, PhD, Langone Medical Center; Komal Jhaveri, MD, FACP, Memorial Sloan Kettering Cancer Center; Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Lee Schwartzberg, MD, FACP, The University of Texas Health Science Center
Published: Wednesday, Mar 21, 2018



Transcript: 

Adam M. Brufsky, MD, PhD, FACP: There’s one last thing I want to talk about before we end this segment, and that’s the B-47 trial, which had a great idea. We saw in a subset analysis of B-31 that there were patients who apparently had a HER2 that was 1+ or 2+, or a ratio less than 1.8, who had benefit with adjuvant trastuzumab. Because that was an unplanned subset analysis, a retrospective study as we’re talking about, they went ahead in B-47 and did a very large randomized trial of women receiving standard of care with a HER2 of 1+ and 2+. You could have a ratio of less than 2, I think that is what they did; 2 was their cutoff. And they gave patients chemotherapy with or without trastuzumab. As we all know, there was no benefit. What do you guys think of that trial?

Lee Schwartzberg, MD, FACP: I think you can learn things from negative trials.

Adam M. Brufsky, MD, PhD, FACP: You can, very much so.

Lee Schwartzberg, MD, FACP: I was actually happy about that result because it would have rocked my world if we thought that we knew the target—we had a test to identify the target—but then we didn’t. That would really set back a lot of precision medicine, so I actually think that’s very positive. We understand that. I also think that there have been refinements in both local and central technology about testing HER2 from the time of B-31 and N9831.

Adam M. Brufsky, MD, PhD, FACP: You think that’s the reason why they had the targeted issue?

Lee Schwartzberg, MD, FACP: Yes, I think it was a technical issue about that. I also think that the important thing to use B-47 for is what happened to those patients: 90% 5-year disease-free survival.

Hope S. Rugo, MD: Which is incredible.

Lee Schwartzberg, MD, FACP: Which is incredible. That’s the number. They were mostly ER-positive, but there was a third or so who were triple-negative.

Adam M. Brufsky, MD, PhD, FACP: That’s the criticism of that trial: They were mostly ER-positive. They would have done well no matter what you put them on.

Hope S. Rugo, MD: Also, Sherene Loi has shown that if you have a low level and low ratio—2.2 up to 3.2 or so—the benefit from trastuzumab is definitely muted. So, you still see a benefit, but it’s much less. It actually makes sense as you keep going down, but those data, of course, way postdated the development of B-47 and even came out after accrual had been finished. So, it made a lot of sense to us, and I think it’s what we see in the neoadjuvant setting. The ER-positive patients with low ratios don’t respond as well.

Adam M. Brufsky, MD, PhD, FACP: Speaking of the ratio, do you use copy number or ratio for HER2?

Hope S. Rugo, MD: We use both, per ASCO guidelines.

Lee Schwartzberg, MD, FACP: We use both.

Adam M. Brufsky, MD, PhD, FACP: The same thing? Which do you use more?

Francisco Esteva, MD, PhD: The ratio.

Komal Jhaveri, MD, FACP: The ratio.

Lee Schwartzberg, MD, FACP: Ratio.

Adam M. Brufsky, MD, PhD, FACP: The ratio, not copy number?

Lee Schwartzberg, MD, FACP: Yes.

Hope S. Rugo, MD:  But if you have a copy number over 6…

Adam M. Brufsky, MD, PhD, FACP: What happens if the copy number is 4 and the ratio is 1.5?

Hope S. Rugo, MD: They’re negative.

Lee Schwartzberg, MD, FACP: Yes, it has to be over 4.

Adam M. Brufsky, MD, PhD, FACP: Per the ASCO guidelines. So, are we all comfortable with that?

Hope S. Rugo, MD: Copy number of 5, yes.

Adam M. Brufsky, MD, PhD, FACP: Because people are asking that question. This is a big question. In your clinical practice, which one do you use?

Komal Jhaveri, MD, FACP: None of the trials had eligibility criteria of just the copy number to call them positive, and I think that’s been a bigger issue. I think we’re probably expecting updated guidelines yet again for the HER2 testing, and we’ll see if this is further clarified or not in those updated guidelines.

Hope S. Rugo, MD: But it will still say a copy number over 6, and I think the issue is the indeterminate will maybe be a little bit clearer as opposed to muddy, but these patients who have a ratio of 1.5 and a copy number that’s around 4.2 are not amplified.

Komal Jhaveri, MD, FACP: Talking about HER2-negative disease and taking a tangential approach here, in the metastatic setting what we found very intriguing was an antibody drug conjugate trial for HER2 low expressers. Despite having activity not only in the HER2 expressers, it also had activity in the HER2 low expressers: the Daiichi compound, the antibody drug conjugate.

Adam M. Brufsky, MD, PhD, FACP: Which we’ll get to. We’re going to get to that in the next section.

Transcript Edited for Clarity 

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Transcript: 

Adam M. Brufsky, MD, PhD, FACP: There’s one last thing I want to talk about before we end this segment, and that’s the B-47 trial, which had a great idea. We saw in a subset analysis of B-31 that there were patients who apparently had a HER2 that was 1+ or 2+, or a ratio less than 1.8, who had benefit with adjuvant trastuzumab. Because that was an unplanned subset analysis, a retrospective study as we’re talking about, they went ahead in B-47 and did a very large randomized trial of women receiving standard of care with a HER2 of 1+ and 2+. You could have a ratio of less than 2, I think that is what they did; 2 was their cutoff. And they gave patients chemotherapy with or without trastuzumab. As we all know, there was no benefit. What do you guys think of that trial?

Lee Schwartzberg, MD, FACP: I think you can learn things from negative trials.

Adam M. Brufsky, MD, PhD, FACP: You can, very much so.

Lee Schwartzberg, MD, FACP: I was actually happy about that result because it would have rocked my world if we thought that we knew the target—we had a test to identify the target—but then we didn’t. That would really set back a lot of precision medicine, so I actually think that’s very positive. We understand that. I also think that there have been refinements in both local and central technology about testing HER2 from the time of B-31 and N9831.

Adam M. Brufsky, MD, PhD, FACP: You think that’s the reason why they had the targeted issue?

Lee Schwartzberg, MD, FACP: Yes, I think it was a technical issue about that. I also think that the important thing to use B-47 for is what happened to those patients: 90% 5-year disease-free survival.

Hope S. Rugo, MD: Which is incredible.

Lee Schwartzberg, MD, FACP: Which is incredible. That’s the number. They were mostly ER-positive, but there was a third or so who were triple-negative.

Adam M. Brufsky, MD, PhD, FACP: That’s the criticism of that trial: They were mostly ER-positive. They would have done well no matter what you put them on.

Hope S. Rugo, MD: Also, Sherene Loi has shown that if you have a low level and low ratio—2.2 up to 3.2 or so—the benefit from trastuzumab is definitely muted. So, you still see a benefit, but it’s much less. It actually makes sense as you keep going down, but those data, of course, way postdated the development of B-47 and even came out after accrual had been finished. So, it made a lot of sense to us, and I think it’s what we see in the neoadjuvant setting. The ER-positive patients with low ratios don’t respond as well.

Adam M. Brufsky, MD, PhD, FACP: Speaking of the ratio, do you use copy number or ratio for HER2?

Hope S. Rugo, MD: We use both, per ASCO guidelines.

Lee Schwartzberg, MD, FACP: We use both.

Adam M. Brufsky, MD, PhD, FACP: The same thing? Which do you use more?

Francisco Esteva, MD, PhD: The ratio.

Komal Jhaveri, MD, FACP: The ratio.

Lee Schwartzberg, MD, FACP: Ratio.

Adam M. Brufsky, MD, PhD, FACP: The ratio, not copy number?

Lee Schwartzberg, MD, FACP: Yes.

Hope S. Rugo, MD:  But if you have a copy number over 6…

Adam M. Brufsky, MD, PhD, FACP: What happens if the copy number is 4 and the ratio is 1.5?

Hope S. Rugo, MD: They’re negative.

Lee Schwartzberg, MD, FACP: Yes, it has to be over 4.

Adam M. Brufsky, MD, PhD, FACP: Per the ASCO guidelines. So, are we all comfortable with that?

Hope S. Rugo, MD: Copy number of 5, yes.

Adam M. Brufsky, MD, PhD, FACP: Because people are asking that question. This is a big question. In your clinical practice, which one do you use?

Komal Jhaveri, MD, FACP: None of the trials had eligibility criteria of just the copy number to call them positive, and I think that’s been a bigger issue. I think we’re probably expecting updated guidelines yet again for the HER2 testing, and we’ll see if this is further clarified or not in those updated guidelines.

Hope S. Rugo, MD: But it will still say a copy number over 6, and I think the issue is the indeterminate will maybe be a little bit clearer as opposed to muddy, but these patients who have a ratio of 1.5 and a copy number that’s around 4.2 are not amplified.

Komal Jhaveri, MD, FACP: Talking about HER2-negative disease and taking a tangential approach here, in the metastatic setting what we found very intriguing was an antibody drug conjugate trial for HER2 low expressers. Despite having activity not only in the HER2 expressers, it also had activity in the HER2 low expressers: the Daiichi compound, the antibody drug conjugate.

Adam M. Brufsky, MD, PhD, FACP: Which we’ll get to. We’re going to get to that in the next section.

Transcript Edited for Clarity 
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