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HER2 Mutations in Breast Cancer

Panelists: Adam M. Brufsky, MD, University of Pittsburgh Cancer Institute; Ahmad Awada, MD, PhD, Jules Bordet Institute; Wolfgang J. Janni, MD, PhD, University of Ulm; Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Michael Untch, MD, Helios Klinikum Berlin-Buch
Published: Thursday, Jan 05, 2017


Transcript:

Adam M. Brufsky, MD, PhD:
There is another mutation that we’re just starting to talk about in the ER-positive HER2-negative setting. Apparently there’s a certain percentage, a low frequency, probably under 10%, but we’re not sure, of HER2 mutations.

Hope S. Rugo, MD: It’s 3%.

Adam M. Brufsky, MD, PhD: Well, it’s 3%, but some people think it’s more. You have Matt Ellis’s data that says 3%.

Hope S. Rugo, MD: Not Matt.

Adam M. Brufsky, MD, PhD: Oh, your data?

Hope S. Rugo, MD: No, not Matt Ellis and Cynthia Ma who are doing that trial. I think they think it’s still really low, 3%.

Adam M. Brufsky, MD, PhD: But, who knows? It could be higher. I think that we don’t know. Anyway, be that as it may, assume it’s 3%. For example, for lung, ALK is 4%, so this is significant.

Hope S. Rugo, MD: I don’t think 3% makes it not significant. The Foundation data suggest it’s really low, too.

Adam M. Brufsky, MD, PhD: Assuming it’s 3%, will there, do you think, be a role for anti-HER2 therapy, tyrosine kinase inhibitors or the like in these patients?

Ahmad Awada, MD, PhD: I think it depends on the magnitude of the effect of the drug. If the drug made a major difference, like in an ALK-translocated tumor, I agree. If we have, let’s say, 10% to 12% objective response rate…

Hope S. Rugo, MD: It’s actually, I think, becoming a more and more interesting area to study because it turns out that these mutations are primarily seen in ER-positive and in lobular cancer. And we’ve all seen this subset of lobular cancers that seem to be very resistant to therapy, ER-positive. They relapse, they don’t do well, they get visceral disease early. And so, it may be that those patients represent the larger percentage of HER2-mutated tumors. There are plenty of, now, case reports of very nice and durable responses to neratinib as an oral tyrosine kinase inhibitor. And that was modeled in the preclinical setting. So, actually, I think it’s an interesting area. Maybe in the future we’re going to be focusing more and more on these very small subsets.

Michael Untch, MD: Two drops of water into the wine. Before flying to the stars and going for these exciting new biomarkers, which we have to do and we have translational programs in all of our studies, I think we have to go back and do some homework in our local pathology. In the ALTTO trial, 8000 patients, GeparQuattro study, more than 600 patients, and including ExteNET trial, the rates of locally HER2-positive, centrally HER2-negative, is between 15% and 20%.

Ahmad Awada, MD, PhD: It’s huge.

Michael Untch, MD: Now, in the setting of early treatment, these patients receive chemotherapy and trastuzumab. At least they don’t receive the wrong treatment. But, for T-DM1, it is crucial to be HER2-positive.

Adam M. Brufsky, MD, PhD: I agree with you.

Michael Untch, MD: Because T-DM1 is the only treatment. So, if you treat them with placebo, then they have a problem. So, again, please, homework. Local pathology, we have to improve.

Adam M. Brufsky, MD, PhD: Do people in Europe use copy number like they do in the United States now for HER2? Copy number FISH?

Michael Untch, MD: Not in all patients. We still have the algorithm, IHC3+, you have to believe it. IHC2+, then we do CISH or FISH.

Ahmad Awada, MD, PhD: That was basically accepted. In our countries, with a few possible exceptions, we are doing both.

Adam M. Brufsky, MD, PhD: And do you guys treat equivocals, say you have a copy number greater than 4 or ratio 1.8?

Michael Untch, MD: That is the problem.

Hope S. Rugo, MD: I don’t.

Michael Untch, MD: I don’t.

Hope S. Rugo, MD: Do you?

Adam M. Brufsky, MD, PhD: I do, yes.

Hope S. Rugo, MD: I don’t treat equivocals because I don’t think there are any data to support it, but we do treat patients who have a copy number greater than 6 who don’t have a ratio over 2.

Adam M. Brufsky, MD, PhD: Right. It’s a really fascinating question.

Transcript Edited for Clarity
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Transcript:

Adam M. Brufsky, MD, PhD:
There is another mutation that we’re just starting to talk about in the ER-positive HER2-negative setting. Apparently there’s a certain percentage, a low frequency, probably under 10%, but we’re not sure, of HER2 mutations.

Hope S. Rugo, MD: It’s 3%.

Adam M. Brufsky, MD, PhD: Well, it’s 3%, but some people think it’s more. You have Matt Ellis’s data that says 3%.

Hope S. Rugo, MD: Not Matt.

Adam M. Brufsky, MD, PhD: Oh, your data?

Hope S. Rugo, MD: No, not Matt Ellis and Cynthia Ma who are doing that trial. I think they think it’s still really low, 3%.

Adam M. Brufsky, MD, PhD: But, who knows? It could be higher. I think that we don’t know. Anyway, be that as it may, assume it’s 3%. For example, for lung, ALK is 4%, so this is significant.

Hope S. Rugo, MD: I don’t think 3% makes it not significant. The Foundation data suggest it’s really low, too.

Adam M. Brufsky, MD, PhD: Assuming it’s 3%, will there, do you think, be a role for anti-HER2 therapy, tyrosine kinase inhibitors or the like in these patients?

Ahmad Awada, MD, PhD: I think it depends on the magnitude of the effect of the drug. If the drug made a major difference, like in an ALK-translocated tumor, I agree. If we have, let’s say, 10% to 12% objective response rate…

Hope S. Rugo, MD: It’s actually, I think, becoming a more and more interesting area to study because it turns out that these mutations are primarily seen in ER-positive and in lobular cancer. And we’ve all seen this subset of lobular cancers that seem to be very resistant to therapy, ER-positive. They relapse, they don’t do well, they get visceral disease early. And so, it may be that those patients represent the larger percentage of HER2-mutated tumors. There are plenty of, now, case reports of very nice and durable responses to neratinib as an oral tyrosine kinase inhibitor. And that was modeled in the preclinical setting. So, actually, I think it’s an interesting area. Maybe in the future we’re going to be focusing more and more on these very small subsets.

Michael Untch, MD: Two drops of water into the wine. Before flying to the stars and going for these exciting new biomarkers, which we have to do and we have translational programs in all of our studies, I think we have to go back and do some homework in our local pathology. In the ALTTO trial, 8000 patients, GeparQuattro study, more than 600 patients, and including ExteNET trial, the rates of locally HER2-positive, centrally HER2-negative, is between 15% and 20%.

Ahmad Awada, MD, PhD: It’s huge.

Michael Untch, MD: Now, in the setting of early treatment, these patients receive chemotherapy and trastuzumab. At least they don’t receive the wrong treatment. But, for T-DM1, it is crucial to be HER2-positive.

Adam M. Brufsky, MD, PhD: I agree with you.

Michael Untch, MD: Because T-DM1 is the only treatment. So, if you treat them with placebo, then they have a problem. So, again, please, homework. Local pathology, we have to improve.

Adam M. Brufsky, MD, PhD: Do people in Europe use copy number like they do in the United States now for HER2? Copy number FISH?

Michael Untch, MD: Not in all patients. We still have the algorithm, IHC3+, you have to believe it. IHC2+, then we do CISH or FISH.

Ahmad Awada, MD, PhD: That was basically accepted. In our countries, with a few possible exceptions, we are doing both.

Adam M. Brufsky, MD, PhD: And do you guys treat equivocals, say you have a copy number greater than 4 or ratio 1.8?

Michael Untch, MD: That is the problem.

Hope S. Rugo, MD: I don’t.

Michael Untch, MD: I don’t.

Hope S. Rugo, MD: Do you?

Adam M. Brufsky, MD, PhD: I do, yes.

Hope S. Rugo, MD: I don’t treat equivocals because I don’t think there are any data to support it, but we do treat patients who have a copy number greater than 6 who don’t have a ratio over 2.

Adam M. Brufsky, MD, PhD: Right. It’s a really fascinating question.

Transcript Edited for Clarity
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