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Neoadjuvant 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:
Thanks for the great discussion on the ER [estrogen receptor]-positive patients. Let’s go on to HER2 [human epidermal growth factor receptor 2]-positive disease now, which is one of the more gratifying things we get to treat. Should we be giving everybody with HER2-positive disease preoperative therapy, or close to everybody? Kevin, what do you think?

Kevin Kalinsky, MD, MS: At our institution, we work very closely with the surgeons. I think they have a very low threshold with a newly diagnosed HER2-positive patient to send them over to us just to see if we should be giving neoadjuvant therapy. I think generally, although not always, for those that are greater than 2 cm and are node-positive, we’re giving neoadjuvant HER2-targeted therapy with chemotherapy, at least at our institution. Where things become a little bit more gray is for those patients who have T1c clinically node-negative disease, in which case if somebody is 1.9 cm it’s a different discussion than somebody that’s 1.1 cm, in which case we would then likely have them go to surgery and then do something like the APT trial where patients got paclitaxel and trastuzumab. That’s generally how we approach things at our institution.

Joyce O’Shaughnessy, MD: So a lot of neoadjuvant, but not 100%. How about you, Beth? What do you think of this?

Elizabeth A. Mittendorf, MD, PhD: I agree with Kevin. At our institution, broadly speaking, if the tumor is less than 1 cm we’ll take them to surgery first, because there’s little chance that it’s going to make breast conservation more easy, which of course, as a surgeon, is a reason to consider neoadjuvant therapy. And then they would get Taxol/Herceptin in the adjuvant setting. With respect to all of the other patients, for a long time, as surgeons, we thought that the importance of giving neoadjuvant therapy was to downsize the tumor so that I could do a lumpectomy. And now, of course, based on our surgical literature, it also is likely downsizing the amount of axillary surgery they may need. So certainly, for the node-positive patients, the HER2-positive folks, they can have pathologic complete response rates in the axilla that are approaching 70%-plus. We know from the Z1071, the Canadian trial, that perhaps we can give them preoperative systemic therapy, get a complete response, and do a sentinel node procedure as opposed to a fully axillary lymph node dissection.

So I think most surgeons are on board with literature as it relates to doing smaller surgery on the breast, less surgery on the axilla. But one thing that I’ve become a champion of when I’m talking to my surgical colleagues is just how important neoadjuvant therapy is now for you all for your adjuvant therapy decisions. I’m assuming we’ll be talking a bit about the KATHERINE trial, but as a surgeon, I now almost feel a little bit responsible for considering neoadjuvant therapy so that patients can get that trastuzumab or pertuzumab up front and get their optimal response. And we can determine whether you all need to do a different treatment on that other side.

Joyce O’Shaughnessy, MD: Yes, that’s been a game-changer—the KATHERINE data. I think you were going to tell us about the KATHERINE data, Ruth?

Ruth O'Regan, MD: Yes. To Beth’s point, I think you wonder if KATHERINE will drop our threshold for giving preoperative treatment even lower than it was. Because I think most of us would do over 2 cm, as you said, but I think the 1 to 2 cm....

Hope S. Rugo, MD: I like the 1 cm myself. I use that because I like the response.

Ruth O'Regan, MD: The KATHERINE study essentially addressed this issue. Patients had at least 6 cycles of chemotherapy and HER2-directed therapy and would go to surgery and then would have residual disease left. They had to have at least 1 cm of residual disease with or without positive nodes. They were randomized to 14 cycles of T-DM1 [ado-trastuzumab emtansine] or to trastuzumab. There was really a markedly improved outcome in the patients who got T-DM1. I believe it was an invasive disease-free survival benefit of about 11%. It was one of the most positive adjuvant trials we’ve seen in a long time. So this was very exciting. There were some toxicities, certainly. More patients stopped the T-DM1 than the trastuzumab. It was the typical things we’d see in the metastatic setting. So I think it was really exciting. I think it makes a lot of sense because the residual disease is probably trastuzumab-resistant and you’re giving a different drug in that scenario. So that makes sense.

Also, what was pointed out was that it really shows that HER2 does remain active, even in this residual disease, because obviously it wouldn’t work very well if we don’t have HER2. So these are very exciting results. I think they were totally practice-changing, and I think for people who were being a little bit more conservative about preoperative treatment, like Beth was saying, we’re probably going to start seeing more of that being done.


Transcript Edited for Clarity

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Transcript: 

Joyce O’Shaughnessy, MD:
Thanks for the great discussion on the ER [estrogen receptor]-positive patients. Let’s go on to HER2 [human epidermal growth factor receptor 2]-positive disease now, which is one of the more gratifying things we get to treat. Should we be giving everybody with HER2-positive disease preoperative therapy, or close to everybody? Kevin, what do you think?

Kevin Kalinsky, MD, MS: At our institution, we work very closely with the surgeons. I think they have a very low threshold with a newly diagnosed HER2-positive patient to send them over to us just to see if we should be giving neoadjuvant therapy. I think generally, although not always, for those that are greater than 2 cm and are node-positive, we’re giving neoadjuvant HER2-targeted therapy with chemotherapy, at least at our institution. Where things become a little bit more gray is for those patients who have T1c clinically node-negative disease, in which case if somebody is 1.9 cm it’s a different discussion than somebody that’s 1.1 cm, in which case we would then likely have them go to surgery and then do something like the APT trial where patients got paclitaxel and trastuzumab. That’s generally how we approach things at our institution.

Joyce O’Shaughnessy, MD: So a lot of neoadjuvant, but not 100%. How about you, Beth? What do you think of this?

Elizabeth A. Mittendorf, MD, PhD: I agree with Kevin. At our institution, broadly speaking, if the tumor is less than 1 cm we’ll take them to surgery first, because there’s little chance that it’s going to make breast conservation more easy, which of course, as a surgeon, is a reason to consider neoadjuvant therapy. And then they would get Taxol/Herceptin in the adjuvant setting. With respect to all of the other patients, for a long time, as surgeons, we thought that the importance of giving neoadjuvant therapy was to downsize the tumor so that I could do a lumpectomy. And now, of course, based on our surgical literature, it also is likely downsizing the amount of axillary surgery they may need. So certainly, for the node-positive patients, the HER2-positive folks, they can have pathologic complete response rates in the axilla that are approaching 70%-plus. We know from the Z1071, the Canadian trial, that perhaps we can give them preoperative systemic therapy, get a complete response, and do a sentinel node procedure as opposed to a fully axillary lymph node dissection.

So I think most surgeons are on board with literature as it relates to doing smaller surgery on the breast, less surgery on the axilla. But one thing that I’ve become a champion of when I’m talking to my surgical colleagues is just how important neoadjuvant therapy is now for you all for your adjuvant therapy decisions. I’m assuming we’ll be talking a bit about the KATHERINE trial, but as a surgeon, I now almost feel a little bit responsible for considering neoadjuvant therapy so that patients can get that trastuzumab or pertuzumab up front and get their optimal response. And we can determine whether you all need to do a different treatment on that other side.

Joyce O’Shaughnessy, MD: Yes, that’s been a game-changer—the KATHERINE data. I think you were going to tell us about the KATHERINE data, Ruth?

Ruth O'Regan, MD: Yes. To Beth’s point, I think you wonder if KATHERINE will drop our threshold for giving preoperative treatment even lower than it was. Because I think most of us would do over 2 cm, as you said, but I think the 1 to 2 cm....

Hope S. Rugo, MD: I like the 1 cm myself. I use that because I like the response.

Ruth O'Regan, MD: The KATHERINE study essentially addressed this issue. Patients had at least 6 cycles of chemotherapy and HER2-directed therapy and would go to surgery and then would have residual disease left. They had to have at least 1 cm of residual disease with or without positive nodes. They were randomized to 14 cycles of T-DM1 [ado-trastuzumab emtansine] or to trastuzumab. There was really a markedly improved outcome in the patients who got T-DM1. I believe it was an invasive disease-free survival benefit of about 11%. It was one of the most positive adjuvant trials we’ve seen in a long time. So this was very exciting. There were some toxicities, certainly. More patients stopped the T-DM1 than the trastuzumab. It was the typical things we’d see in the metastatic setting. So I think it was really exciting. I think it makes a lot of sense because the residual disease is probably trastuzumab-resistant and you’re giving a different drug in that scenario. So that makes sense.

Also, what was pointed out was that it really shows that HER2 does remain active, even in this residual disease, because obviously it wouldn’t work very well if we don’t have HER2. So these are very exciting results. I think they were totally practice-changing, and I think for people who were being a little bit more conservative about preoperative treatment, like Beth was saying, we’re probably going to start seeing more of that being done.


Transcript Edited for Clarity
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