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Post-Adjuvant Breast Cancer Treatment

Panelists:Adam M. Brufsky, MD, University of Pittsburgh; Sara A. Hurvitz, MD, David Geffen School of Medicine; Joyce A. O'Shaugnessy, MD, Baylor Charles A. Sammons Cancer Center; Hope S. Rugo, MD, University of California; Christy A. Russell, MD, University of Southern California
Published Online: Wednesday, Apr 13, 2016


Transcript:

Adam M. Brufsky, MD:
So, let’s end this section with post-adjuvant therapy. So do we do anything after say TCH or ACTH? A year of trastuzumab? Do we do anything else? So that gets us to the ExteNET study.

Christy A. Russell, MD: The ExteNET trial is an interesting trial because it’s using neratinib, which has been a difficult drug for people to use because of the severe diarrhea that occurs. It’s interesting now with all these trials that have been done; now we’re getting into the trials to figure out how to prevent the diarrhea. And we also have the HERA trial, which looked at one versus two years of trastuzumab, showing no benefit of the second year of trastuzumab. It’s interesting that they ran this trial.

Adam M. Brufsky, MD: And the 10-year HERA results were actually just presented, which showed no benefit even at 10 years. But go ahead.

Christy A. Russell, MD: Exactly, there’s nothing there. It’s interesting that you would now use a different class of drugs in this setting. You’re using a tyrosine kinase inhibitor (TKI) rather than trastuzumab, and so you’re [looking at] high-risk patients, either those patients who did not get a pathologic complete response with neoadjuvant therapy or who are lymph node-positive breast cancer who get standard chemotherapy with trastuzumab and then are randomized to neratinib or no further therapy. The overall trial results were fairly unimpressive, but there are now some subgroups that have reported.

Adam M. Brufsky, MD: Like 2%.

Joyce A. O’Shaughnessy, MD: It was statistically significant, though.

Christy A. Russell, MD: Right. It was statistically significant. Now there are subgroups that are very interesting. One is a third of the patients who are not centrally HER2-positive.

Sara A. Hurvitz, MD: Right.

Christy A. Russell, MD: So you’ve got to get rid of those patients and not even consider them in the statistics. And what was more fascinating to me was that the ER-negative HER2-positive patients don’t seem to be the patients benefitting from the neratinib.

Adam M. Brufsky, MD: Yes, which is strange.

Christy A. Russell, MD: It’s the ER-positives.

Hope S. Rugo, MD: But see, to me that made perfect sense. I thought, ‘Okay, this is what HERA should really have been powered to look at,’ which was very difficult. Maybe it’s better to change therapies and get a non-cross–resistant treatment; we don’t know. But we know already that we improve response to hormone therapy by adding in HER2 targeting. So it makes a lot of sense that you’re somehow going to change. Now we’ve got to see the six-year, eight-year data, you know. We don’t know yet…

Adam M. Brufsky, MD: And it’s really the late recurrences; that’s what we’re seeing now. The triple positives have that late recurrence.

Hope S. Rugo, MD: Right.

Christy A. Russell, MD: Right, but they did look at it in HERA. I mean, they did look at the ER-positives and there’s nothing.

Hope S. Rugo, MD: And there’s no benefit.

Sara A. Hurvitz, MD: I have a different theory. I think it’s the crosstalk between EGFR and ER in these tumors that is actually pretty important. And when you’re hitting the EGFR receptor—and neratinib is a great, it’s an irreversible inhibitor, very potent—that may be the difference between HERA and ExteNET.

Hope S. Rugo, MD: And maybe you get these luminal B[-like] tumors, and you get a better effect [with neratinib]. There are data on the GBG trial that looked at lapatinib and trastuzumab, and they looked at disease-free survival. And it was superior in the group that got lapatinib in front and then got a year of trastuzumab out back, which was really interesting. It was good in the ER-positive subgroup. They presented those data at ESMO, and obviously we have to see those published. But the results suggest that maybe there is something in that ER-positive group that we’re going to see.

Adam M. Brufsky, MD: Yeah, but did the ALTTO study show anything? No, right?

Hope S. Rugo, MD: But what’s interesting about the way they did this trial is that patients who had lapatinib in the neoadjuvant setting had [a] longer duration of trastuzumab exposure after surgery. And that’s obviously just inferential based on what we saw with neratinib. But maybe there is some difference in the ER-positive group. And it was just ER-positive where they saw that. So I think it’s fascinating.

Joyce A. O’Shaughnessy, MD: The thing that would be challenging…if the ExteNET trial leads to approval of neratinib.

Adam M. Brufsky, MD: Do you think it will?

Joyce A. O’Shaughnessy, MD: I really hope so. I want the tool.

Adam M. Brufsky, MD: To be used for other off-label uses. We shouldn’t be saying that.

Joyce A. O’Shaughnessy, MD: And I want it in the adjuvant setting for the higher-risk ER-positive patients.

Adam M. Brufsky, MD: Right, okay, fair enough. I’m just teasing.

O’Shaughnessy, MD: But what if APHINITY is positive?

Hope S. Rugo, MD: Right, then what do we do?

Joyce A. O’Shaughnessy, MD: Then what do we do with a year of pertuzumab and trastuzumab together?

Adam M. Brufsky, MD: That’s a good point.

Hope S. Rugo, MD: Then the patents are going to have diarrhea for two years.

Adam M. Brufsky, MD: Instead of one, correct? Right.

Hope S. Rugo, MD: So I don’t know. There are some studies that are looking at ways to try and prevent diarrhea outside of taking Imodium every day. I mean, if you’re taking drugs that prevent diarrhea every day, you’re going to have a lot of bloating and won’t feel great. Although you do reduce the rate of grade 3/4 diarrhea tremendously. So it seems to be a secretory diarrhea, and one of my colleagues is looking at using sort of an herbal-like preparation that reduces chloride-secretory diarrhea. It would be fascinating to see if you could really eliminate it with something that was relatively nontoxic.

Christy A. Russell, MD: And we are in San Francisco, so herbal therapy.

Adam M. Brufsky, MD: Yeah, peppermint oil, whatever.

Hope S. Rugo, MD: That doesn’t work.
                                                                                                                                                                                                                                                                                                               
Transcript Edited for Clarity
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Transcript:

Adam M. Brufsky, MD:
So, let’s end this section with post-adjuvant therapy. So do we do anything after say TCH or ACTH? A year of trastuzumab? Do we do anything else? So that gets us to the ExteNET study.

Christy A. Russell, MD: The ExteNET trial is an interesting trial because it’s using neratinib, which has been a difficult drug for people to use because of the severe diarrhea that occurs. It’s interesting now with all these trials that have been done; now we’re getting into the trials to figure out how to prevent the diarrhea. And we also have the HERA trial, which looked at one versus two years of trastuzumab, showing no benefit of the second year of trastuzumab. It’s interesting that they ran this trial.

Adam M. Brufsky, MD: And the 10-year HERA results were actually just presented, which showed no benefit even at 10 years. But go ahead.

Christy A. Russell, MD: Exactly, there’s nothing there. It’s interesting that you would now use a different class of drugs in this setting. You’re using a tyrosine kinase inhibitor (TKI) rather than trastuzumab, and so you’re [looking at] high-risk patients, either those patients who did not get a pathologic complete response with neoadjuvant therapy or who are lymph node-positive breast cancer who get standard chemotherapy with trastuzumab and then are randomized to neratinib or no further therapy. The overall trial results were fairly unimpressive, but there are now some subgroups that have reported.

Adam M. Brufsky, MD: Like 2%.

Joyce A. O’Shaughnessy, MD: It was statistically significant, though.

Christy A. Russell, MD: Right. It was statistically significant. Now there are subgroups that are very interesting. One is a third of the patients who are not centrally HER2-positive.

Sara A. Hurvitz, MD: Right.

Christy A. Russell, MD: So you’ve got to get rid of those patients and not even consider them in the statistics. And what was more fascinating to me was that the ER-negative HER2-positive patients don’t seem to be the patients benefitting from the neratinib.

Adam M. Brufsky, MD: Yes, which is strange.

Christy A. Russell, MD: It’s the ER-positives.

Hope S. Rugo, MD: But see, to me that made perfect sense. I thought, ‘Okay, this is what HERA should really have been powered to look at,’ which was very difficult. Maybe it’s better to change therapies and get a non-cross–resistant treatment; we don’t know. But we know already that we improve response to hormone therapy by adding in HER2 targeting. So it makes a lot of sense that you’re somehow going to change. Now we’ve got to see the six-year, eight-year data, you know. We don’t know yet…

Adam M. Brufsky, MD: And it’s really the late recurrences; that’s what we’re seeing now. The triple positives have that late recurrence.

Hope S. Rugo, MD: Right.

Christy A. Russell, MD: Right, but they did look at it in HERA. I mean, they did look at the ER-positives and there’s nothing.

Hope S. Rugo, MD: And there’s no benefit.

Sara A. Hurvitz, MD: I have a different theory. I think it’s the crosstalk between EGFR and ER in these tumors that is actually pretty important. And when you’re hitting the EGFR receptor—and neratinib is a great, it’s an irreversible inhibitor, very potent—that may be the difference between HERA and ExteNET.

Hope S. Rugo, MD: And maybe you get these luminal B[-like] tumors, and you get a better effect [with neratinib]. There are data on the GBG trial that looked at lapatinib and trastuzumab, and they looked at disease-free survival. And it was superior in the group that got lapatinib in front and then got a year of trastuzumab out back, which was really interesting. It was good in the ER-positive subgroup. They presented those data at ESMO, and obviously we have to see those published. But the results suggest that maybe there is something in that ER-positive group that we’re going to see.

Adam M. Brufsky, MD: Yeah, but did the ALTTO study show anything? No, right?

Hope S. Rugo, MD: But what’s interesting about the way they did this trial is that patients who had lapatinib in the neoadjuvant setting had [a] longer duration of trastuzumab exposure after surgery. And that’s obviously just inferential based on what we saw with neratinib. But maybe there is some difference in the ER-positive group. And it was just ER-positive where they saw that. So I think it’s fascinating.

Joyce A. O’Shaughnessy, MD: The thing that would be challenging…if the ExteNET trial leads to approval of neratinib.

Adam M. Brufsky, MD: Do you think it will?

Joyce A. O’Shaughnessy, MD: I really hope so. I want the tool.

Adam M. Brufsky, MD: To be used for other off-label uses. We shouldn’t be saying that.

Joyce A. O’Shaughnessy, MD: And I want it in the adjuvant setting for the higher-risk ER-positive patients.

Adam M. Brufsky, MD: Right, okay, fair enough. I’m just teasing.

O’Shaughnessy, MD: But what if APHINITY is positive?

Hope S. Rugo, MD: Right, then what do we do?

Joyce A. O’Shaughnessy, MD: Then what do we do with a year of pertuzumab and trastuzumab together?

Adam M. Brufsky, MD: That’s a good point.

Hope S. Rugo, MD: Then the patents are going to have diarrhea for two years.

Adam M. Brufsky, MD: Instead of one, correct? Right.

Hope S. Rugo, MD: So I don’t know. There are some studies that are looking at ways to try and prevent diarrhea outside of taking Imodium every day. I mean, if you’re taking drugs that prevent diarrhea every day, you’re going to have a lot of bloating and won’t feel great. Although you do reduce the rate of grade 3/4 diarrhea tremendously. So it seems to be a secretory diarrhea, and one of my colleagues is looking at using sort of an herbal-like preparation that reduces chloride-secretory diarrhea. It would be fascinating to see if you could really eliminate it with something that was relatively nontoxic.

Christy A. Russell, MD: And we are in San Francisco, so herbal therapy.

Adam M. Brufsky, MD: Yeah, peppermint oil, whatever.

Hope S. Rugo, MD: That doesn’t work.
                                                                                                                                                                                                                                                                                                               
Transcript Edited for Clarity
View Conference Coverage
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TitleExpiration DateCME Credits
Medical Crossfire®: Leveraging New Evidence in the Context of Evolving Early-Stage Treatment Standards in HER2-Positive Breast CancerJan 30, 20181.5
14th Annual School of Breast Oncology® OnlineFeb 10, 201825
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