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Adjuvant T-DM1 Therapy in HER2+ Breast Cancer

Panelists: Joyce O Shaughnessy, MD, Baylor University Medical Center; Kevin Kalinsky, MD, MS NewYork-Presbyterian Hospital; Elizabeth Mittendorf Dana-Farber; Ruth O Regan, MD, University of Wisconsin Carbone Cancer Center; Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center
Published: Friday, May 03, 2019



Transcript: 

Joyce O’Shaughnessy, MD:
Tell us about how you approach the T1cN0 patients. What do you treat them with preoperatively?

Hope S. Rugo, MD: Some of it depends on ER [estrogen receptor] status and the age of the patient. But I find that some of these patients just don’t tolerate carboplatin well, and I don’t know how much it really adds. So in those kinds of patients, I treat with more of an APT [adjuvant paclitaxel and trastuzumab]–like regimen. If I really want them to be done with that, I might add pertuzumab because the path CR [pathologic complete response] rates were higher in NeoSphere when pertuzumab was given, even though those patients received anthracyclines postoperatively. And then if they have a path CR [pathologic complete response, I’d just continue with trastuzumab to complete a year. So they’ve only gotten 12 weeks of taxane therapy. I’ve actually even used that in some older patients who have bigger tumors, who really could never have tolerated TCHP [docetaxel, carboplatin, trastuzumab, and pertuzumab] or any kind of anthracycline-based regimen.

It was fascinating, to me, to see that in KATHERINE, 70% of the patients had ER-positive disease, because we knew they didn’t get pCRs [pathologic complete responses] as much. But then we thought that the hormone therapy plus continued trastuzumab would be good enough. Clearly, it wasn’t. You could make such a big difference by giving T-DM1 [ado trastuzumab emtansine] with hormone therapy. I still think it’s quite intriguing that there’s that difference because we know there’s a biological difference between those subsets of cancer. I also think KATHERINE has a big impact on the use of anthracyclines, so I’m really interested in what everybody is thinking about that. If you gave a nonanthracycline regimen like TCHP [docetaxel, carboplatin, trastuzumab, and pertuzumab] and they had residual disease, then you gave T-DM1 [ado trastuzumab emtansine], you forget. Are anthracyclines out the door?

Kevin Kalinsky, MD, MS: We also have randomized data with TRAIN-2, which was either everybody got Herceptin/Perjeta, anthracycline-based versus nonanthracycline-based, and we saw similar pCR rates. Hope, I think your comment is very well taken. I think part of what is also very impressive about KATHERINE was that as we perseverate about these subsets, there were similar hazard ratios independent of hormone receptor status. That wasn’t always the case with Perjeta, with the APHINITY data and with the ExteNET data; we would perseverate over the hormone receptor status. Clearly, we see that everybody is benefiting from T-DM1 [ado trastuzumab emtansine].

Ruth O’Regan, MD: Even the patients who have very little residual disease as well.

Hope S. Rugo, MD: Which is really interesting.

Joyce O’Shaughnessy, MD: A really small amount left. We switch over, right? We should be switching over based on the KATHERINE data, right?

Ruth O’Regan, MD: I think the ER data was a little bit surprising. I agree with you completely. I do think they are, within themselves, heterogeneous. We know there’s a luminal A subtype in there. So I think the bigger question is, what do you do after the year? I don’t think that using T-DM1 [ado trastuzumab emtansine] in that setting indicates using neratinib afterward. I do think there are some of these cancers…

Joyce O’Shaughnessy, MD: I was going to ask about that.

Hope S. Rugo, MD: That’s a great point.

Ruth O’Regan, MD: That really need continued blocking of ER and HER2 [human epidermal growth factor receptor 2] for a longer duration.

Hope S. Rugo, MD: I agree.

Joyce O’Shaughnessy, MD: Impressive. It was interesting. Beth?

Elizabeth A. Mittendorf, MD, PhD: I was just going to ask you all a question. I have a fair number of patients who are going to get just THP, and then they’ll come back and I’ll note that they still have what appears to be significant residual disease. Maybe they haven’t converted to a lumpectomy candidate, or maybe I’m still concerned that they might have positive nodal disease. My inclination has been to ask my medical oncology colleague to consider putting the anthracycline in. What do you guys think of that?

Ruth O’Regan, MD: I think that sounds completely reasonable, although you wonder if you could get it paid for, because you could just switch to trastuzumab-DM1 [ado trastuzumab emtansine] now.

Elizabeth A. Mittendorf, MD, PhD: Well, I’m talking about in the preoperative setting.

Ruth O’Regan, MD: No, I understand that, but I’m saying that if it’s so effective in that adjuvant setting, maybe if you did that.

Hope S. Rugo, MD: But those patients who were on KATHERINE got anthracycline-based neoadjuvant therapy. A smaller percentage got TCH [docetaxel, carboplatin, and trastuzumab] because there wasn’t so much P. So they got TCH [docetaxel, carboplatin, and trastuzumab]—a smaller percentage. And most people got anthracyclines because much of the world is still using anthracyclines as a standard. And again, that, I think, is changing for us. But in those patients, if you chose to give them THP [docetaxel, carboplatin, and pertuzumab] and they’re not in a pathologic CR, we do also go on to AC [doxorubicin hydrochloride and cyclophosphamide]. But now the question for me comes up: Should everybody be getting TCHP [docetaxel, carboplatin, trastuzumab, and pertuzumab] instead?

Joyce O’Shaughnessy, MD: Get a DNA-damaging agent up-front?

Hope S. Rugo, MD: In the metastatic setting, carboplatin added to TH [docetaxel and carboplatin] in the first-line metastatic setting didn’t change outcome. So are we just buying a lot of toxicity because the carboplatin with the pertuzumab increases diarrhea so much? I struggle with it a little. I think we’re kind of stuck with what we have.

Kevin Kalinsky, MD, MS: I think in that scenario that you’re mentioning, I guess I would use an anthracycline. I’m trying to come up with a patient who has experienced that. I haven’t had that experience, but that certainly could exist. But I do think that subsequently the patient would go and get T-DM1 [ado trastuzumab emtansine].

Elizabeth A. Mittendorf, MD, PhD: I just think in the HER2-positive patients, it’s such a fascinating space, at least from my standpoint or a surgeon’s standpoint. If we’re thoughtful about our therapies, this is really the space where we’re best able to personalize the treatment for our patients.

Joyce O’Shaughnessy, MD: Yes, the preoperative setting makes it so useful. I was interested, at [the 2018] San Antonio [Breast Cancer Symposium], in the ExteNET study. About one-third of patients received preoperative therapy. If they had residual disease—so again, enriching for a higher-risk population—they were randomized to the neratinib for a year versus not in the ER-positive population. There was a bigger benefit, heading toward 10% absolute benefit in that population. So the T-DM1 [ado trastuzumab emtansine]: We don’t know for sure that the neratinib would have the same level of benefit after T-DM1 [ado trastuzumab emtansine]. But I agree with you, Ruth. This double blockade of the pan-HER family plus the ER just makes so much biological sense.

Ruth O’Regan, MD: The HER2-directed therapy is trastuzumab, so I don’t know why it would make any difference.

Joyce O’Shaughnessy, MD: Right. If they have a high enough risk, you just finish up the year of the T-DM1 and go on to the neratinib afterward. Are you doing that at all, Hope?

Hope S. Rugo, MD: We haven’t had enough time to do that yet. That was just December, but I would do that. I think if somebody has substantial residual disease in ER-positive breast cancer, I would consider neratinib after T-DM1 [ado trastuzumab emtansine]. I actually think that’s quite reasonable. And then, of course there are still patients who go to surgery up front. That’s a very different issue, and we have no data to support T-DM1 [ado trastuzumab emtansine] and would use neratinib. So I completely agree with all of you on that. I think 1 of the things in the neoadjuvant setting is, if you gave THP [docetaxel, carboplatin, and pertuzumab], and after 3 or 4 cycles they’re not responding, then I think you need to think about adding in the platinum, or maybe you’re going to do something else. Because most of the studies that we’ve done have shown that the early responders are, to whatever regimen you’ve put them on, the people who tend to get pCRs. So maybe we should be following them a little more closely. I-SPY 2, the next iteration of I-SPY, which Kevin is also very much involved with, will do that sort of approach. So if you’re not getting a good response to a treatment, you’ll go on to something else before surgery in an effort to get a pCR.

Joyce O’Shaughnessy, MD: That personalized approach that Beth was talking about.

Hope S. Rugo, MD: Which speaks directly to what you said.

Ruth O’Regan, MD: I think the patients I really struggle with are the ones who are kind of equivocal but are HER2-positive. How do you manage those patients? I’m seeing a patient this week. She had triple-positive cancer, but the ratio on the HER2 is 2:1 and she’s being sent over for, essentially, TCHP [docetaxel, carboplatin, trastuzumab, and pertuzumab]. I’d just be interested in hearing everybody else talk about that patient because I don’t think she’s going to get a lot of benefit.

Joyce O’Shaughnessy, MD: Yeah, it’s such a spectrum of biology, but I’m always redoing HER2, IHC, and FISH [fluorescence in situ hybridization] to make sure I have the right diagnosis.

Hope S. Rugo, MD: The issue that comes up with a patient like that for me: I’m worried a little bit less if they have ER-positive disease, but if they’re ER-negative and they have this borderline HER2, you think they’re really triple-negative. So maybe I should give AC [doxorubicin hydrochloride and cyclophosphamide], and ACT [Adriamycin, cyclophosphamide, and Taxol] as opposed to TCHP [docetaxel, carboplatin, trastuzumab, and pertuzumab], or even add the HP [trastuzumab and pertuzumab] but still give the anthracycline because of the ABC [early breast cancer] trial showing the benefit of the anthracycline. That’s where I get nervous.

Ruth O’Regan, MD: In the adjuvant setting, I would sometimes give them docetaxel-Cytoxan with trastuzumab if I’m not exactly sure.

Hope S. Rugo, MD: That’s interesting.

Ruth O’Regan, MD: I’ve done that a few times as well.


Transcript Edited for Clarity

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Transcript: 

Joyce O’Shaughnessy, MD:
Tell us about how you approach the T1cN0 patients. What do you treat them with preoperatively?

Hope S. Rugo, MD: Some of it depends on ER [estrogen receptor] status and the age of the patient. But I find that some of these patients just don’t tolerate carboplatin well, and I don’t know how much it really adds. So in those kinds of patients, I treat with more of an APT [adjuvant paclitaxel and trastuzumab]–like regimen. If I really want them to be done with that, I might add pertuzumab because the path CR [pathologic complete response] rates were higher in NeoSphere when pertuzumab was given, even though those patients received anthracyclines postoperatively. And then if they have a path CR [pathologic complete response, I’d just continue with trastuzumab to complete a year. So they’ve only gotten 12 weeks of taxane therapy. I’ve actually even used that in some older patients who have bigger tumors, who really could never have tolerated TCHP [docetaxel, carboplatin, trastuzumab, and pertuzumab] or any kind of anthracycline-based regimen.

It was fascinating, to me, to see that in KATHERINE, 70% of the patients had ER-positive disease, because we knew they didn’t get pCRs [pathologic complete responses] as much. But then we thought that the hormone therapy plus continued trastuzumab would be good enough. Clearly, it wasn’t. You could make such a big difference by giving T-DM1 [ado trastuzumab emtansine] with hormone therapy. I still think it’s quite intriguing that there’s that difference because we know there’s a biological difference between those subsets of cancer. I also think KATHERINE has a big impact on the use of anthracyclines, so I’m really interested in what everybody is thinking about that. If you gave a nonanthracycline regimen like TCHP [docetaxel, carboplatin, trastuzumab, and pertuzumab] and they had residual disease, then you gave T-DM1 [ado trastuzumab emtansine], you forget. Are anthracyclines out the door?

Kevin Kalinsky, MD, MS: We also have randomized data with TRAIN-2, which was either everybody got Herceptin/Perjeta, anthracycline-based versus nonanthracycline-based, and we saw similar pCR rates. Hope, I think your comment is very well taken. I think part of what is also very impressive about KATHERINE was that as we perseverate about these subsets, there were similar hazard ratios independent of hormone receptor status. That wasn’t always the case with Perjeta, with the APHINITY data and with the ExteNET data; we would perseverate over the hormone receptor status. Clearly, we see that everybody is benefiting from T-DM1 [ado trastuzumab emtansine].

Ruth O’Regan, MD: Even the patients who have very little residual disease as well.

Hope S. Rugo, MD: Which is really interesting.

Joyce O’Shaughnessy, MD: A really small amount left. We switch over, right? We should be switching over based on the KATHERINE data, right?

Ruth O’Regan, MD: I think the ER data was a little bit surprising. I agree with you completely. I do think they are, within themselves, heterogeneous. We know there’s a luminal A subtype in there. So I think the bigger question is, what do you do after the year? I don’t think that using T-DM1 [ado trastuzumab emtansine] in that setting indicates using neratinib afterward. I do think there are some of these cancers…

Joyce O’Shaughnessy, MD: I was going to ask about that.

Hope S. Rugo, MD: That’s a great point.

Ruth O’Regan, MD: That really need continued blocking of ER and HER2 [human epidermal growth factor receptor 2] for a longer duration.

Hope S. Rugo, MD: I agree.

Joyce O’Shaughnessy, MD: Impressive. It was interesting. Beth?

Elizabeth A. Mittendorf, MD, PhD: I was just going to ask you all a question. I have a fair number of patients who are going to get just THP, and then they’ll come back and I’ll note that they still have what appears to be significant residual disease. Maybe they haven’t converted to a lumpectomy candidate, or maybe I’m still concerned that they might have positive nodal disease. My inclination has been to ask my medical oncology colleague to consider putting the anthracycline in. What do you guys think of that?

Ruth O’Regan, MD: I think that sounds completely reasonable, although you wonder if you could get it paid for, because you could just switch to trastuzumab-DM1 [ado trastuzumab emtansine] now.

Elizabeth A. Mittendorf, MD, PhD: Well, I’m talking about in the preoperative setting.

Ruth O’Regan, MD: No, I understand that, but I’m saying that if it’s so effective in that adjuvant setting, maybe if you did that.

Hope S. Rugo, MD: But those patients who were on KATHERINE got anthracycline-based neoadjuvant therapy. A smaller percentage got TCH [docetaxel, carboplatin, and trastuzumab] because there wasn’t so much P. So they got TCH [docetaxel, carboplatin, and trastuzumab]—a smaller percentage. And most people got anthracyclines because much of the world is still using anthracyclines as a standard. And again, that, I think, is changing for us. But in those patients, if you chose to give them THP [docetaxel, carboplatin, and pertuzumab] and they’re not in a pathologic CR, we do also go on to AC [doxorubicin hydrochloride and cyclophosphamide]. But now the question for me comes up: Should everybody be getting TCHP [docetaxel, carboplatin, trastuzumab, and pertuzumab] instead?

Joyce O’Shaughnessy, MD: Get a DNA-damaging agent up-front?

Hope S. Rugo, MD: In the metastatic setting, carboplatin added to TH [docetaxel and carboplatin] in the first-line metastatic setting didn’t change outcome. So are we just buying a lot of toxicity because the carboplatin with the pertuzumab increases diarrhea so much? I struggle with it a little. I think we’re kind of stuck with what we have.

Kevin Kalinsky, MD, MS: I think in that scenario that you’re mentioning, I guess I would use an anthracycline. I’m trying to come up with a patient who has experienced that. I haven’t had that experience, but that certainly could exist. But I do think that subsequently the patient would go and get T-DM1 [ado trastuzumab emtansine].

Elizabeth A. Mittendorf, MD, PhD: I just think in the HER2-positive patients, it’s such a fascinating space, at least from my standpoint or a surgeon’s standpoint. If we’re thoughtful about our therapies, this is really the space where we’re best able to personalize the treatment for our patients.

Joyce O’Shaughnessy, MD: Yes, the preoperative setting makes it so useful. I was interested, at [the 2018] San Antonio [Breast Cancer Symposium], in the ExteNET study. About one-third of patients received preoperative therapy. If they had residual disease—so again, enriching for a higher-risk population—they were randomized to the neratinib for a year versus not in the ER-positive population. There was a bigger benefit, heading toward 10% absolute benefit in that population. So the T-DM1 [ado trastuzumab emtansine]: We don’t know for sure that the neratinib would have the same level of benefit after T-DM1 [ado trastuzumab emtansine]. But I agree with you, Ruth. This double blockade of the pan-HER family plus the ER just makes so much biological sense.

Ruth O’Regan, MD: The HER2-directed therapy is trastuzumab, so I don’t know why it would make any difference.

Joyce O’Shaughnessy, MD: Right. If they have a high enough risk, you just finish up the year of the T-DM1 and go on to the neratinib afterward. Are you doing that at all, Hope?

Hope S. Rugo, MD: We haven’t had enough time to do that yet. That was just December, but I would do that. I think if somebody has substantial residual disease in ER-positive breast cancer, I would consider neratinib after T-DM1 [ado trastuzumab emtansine]. I actually think that’s quite reasonable. And then, of course there are still patients who go to surgery up front. That’s a very different issue, and we have no data to support T-DM1 [ado trastuzumab emtansine] and would use neratinib. So I completely agree with all of you on that. I think 1 of the things in the neoadjuvant setting is, if you gave THP [docetaxel, carboplatin, and pertuzumab], and after 3 or 4 cycles they’re not responding, then I think you need to think about adding in the platinum, or maybe you’re going to do something else. Because most of the studies that we’ve done have shown that the early responders are, to whatever regimen you’ve put them on, the people who tend to get pCRs. So maybe we should be following them a little more closely. I-SPY 2, the next iteration of I-SPY, which Kevin is also very much involved with, will do that sort of approach. So if you’re not getting a good response to a treatment, you’ll go on to something else before surgery in an effort to get a pCR.

Joyce O’Shaughnessy, MD: That personalized approach that Beth was talking about.

Hope S. Rugo, MD: Which speaks directly to what you said.

Ruth O’Regan, MD: I think the patients I really struggle with are the ones who are kind of equivocal but are HER2-positive. How do you manage those patients? I’m seeing a patient this week. She had triple-positive cancer, but the ratio on the HER2 is 2:1 and she’s being sent over for, essentially, TCHP [docetaxel, carboplatin, trastuzumab, and pertuzumab]. I’d just be interested in hearing everybody else talk about that patient because I don’t think she’s going to get a lot of benefit.

Joyce O’Shaughnessy, MD: Yeah, it’s such a spectrum of biology, but I’m always redoing HER2, IHC, and FISH [fluorescence in situ hybridization] to make sure I have the right diagnosis.

Hope S. Rugo, MD: The issue that comes up with a patient like that for me: I’m worried a little bit less if they have ER-positive disease, but if they’re ER-negative and they have this borderline HER2, you think they’re really triple-negative. So maybe I should give AC [doxorubicin hydrochloride and cyclophosphamide], and ACT [Adriamycin, cyclophosphamide, and Taxol] as opposed to TCHP [docetaxel, carboplatin, trastuzumab, and pertuzumab], or even add the HP [trastuzumab and pertuzumab] but still give the anthracycline because of the ABC [early breast cancer] trial showing the benefit of the anthracycline. That’s where I get nervous.

Ruth O’Regan, MD: In the adjuvant setting, I would sometimes give them docetaxel-Cytoxan with trastuzumab if I’m not exactly sure.

Hope S. Rugo, MD: That’s interesting.

Ruth O’Regan, MD: I’ve done that a few times as well.


Transcript Edited for Clarity
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