Emerging Therapies for HER2-Positive Metastatic Breast Cancer - Episode 2

Treatment for High- and Low-Risk HER2+ Breast Cancer

December 24, 2019

Ian E. Krop, MD, PhD:As mentioned, there are a number of large randomized adjuvant trials that help us guide our optimal management for patients with HER2-positive of early stage disease. I think the 1 that’s made the most impact in terms of changing our management plan is the KATHERINE trial, which as I mentioned is a study that looked at patients who received neoadjuvant HER2-directed therapy but had residual cancers. In that study, switching patients from adjuvant trastuzumab to adjuvant T-DM1 [ado-trastuzumab emtansine] had a large impact in reducing the risk of recurrence.

It’s clear that the standard of care should be T-DM1 [ado-trastuzumab emtansine] in those patients who had residual cancer after neoadjuvant therapy. However, the only way we’re going to know who has residual cancer, and thus who would benefit from T-DM1 [ado-trastuzumab emtansine], is if they received neoadjuvant therapy.

Based on the KATHERINE data, it is important to basically treat all patients with stage II or higher HER2-positive breast cancer with neoadjuvant therapy, so we can assess their responsiveness to that neoadjuvant therapy and decide who needs additional therapy with T-DM1 [ado-trastuzumab emtansine].

What type of neoadjuvant therapy you use is not that important. I think any of the currently standard approaches [is] reasonable. In the United States, I think a nonanthracycline regimen, such as docetaxel, carboplatin, trastuzumab, and pertuzumab, or TCHP, is appropriate. Or any anthracycline regimen, such as Adriamycin, Cytoxan, paclitaxel, trastuzumab, and pertuzumab, or ACTHP. Both of those regimens have been associated with very good [pathologic] complete response [PCR] rates and HER2-positive disease. I think there are some pros and cons to either one, but both are appropriate. In those patients who have residual disease after receiving those therapies, T-DM1 [ado-trastuzumab emtansine] is recommended.

Interestingly, in the KATHERINE trial the benefits of T-DM1 [ado-trastuzumab emtansine] were often also seen across the spectrum in terms of the amount of residual disease. Even patients with small—less than 1 cm—cancers at time of surgery that were node negative still had substantial benefit from the T-DM1 [ado-trastuzumab emtansine]. Starting with any neoadjuvant therapy, any patient with significant invasive residual disease should then receive T-DM1 [ado-trastuzumab emtansine].

Those patients who have a pathologic complete response from their neoadjuvant therapy can just continue with antibodies, either trastuzumab-pertuzumab or just trastuzumab. We do not have randomized data in that regard. Based on the APHINITY study—which, as I mentioned, for high-risk patients did show a substantial benefit to the inclusion of pertuzumab—that study did use the pertuzumab for 1 year. In my practice I continue pertuzumab along with trastuzumab in the patients who have a pathologic compete response if they started with reasonably high-risk cancer.

That’s the recommendation for patients who have stage II or higher HER2-positive cancers—that they be treated with neoadjuvant therapy and that the results of that therapy be used to decide whether a patient should continue with just trastuzumab and pertuzumab if they have a PCR or [switch] to T-DM1 [ado-trastuzumab emtansine] to complete the year of therapy.

For particularly high-risk patients, one could consider the use of neratinib after the completion of their first year of adjuvant therapy. That is with the caveat that in the neratinib study patients did not receive either pertuzumab or T-DM1 [ado-trastuzumab emtansine] in their first year of treatment. So we do not know with any degree of certainty whether the use of neratinib in the second year of treatment has efficacy in patients who received T-DM1 [ado-trastuzumab emtansine] or pertuzumab. That being said, I think it’s not an unreasonable extrapolation for particularly high-risk patients. What I mean by that is patients with multiple nodes positive after neoadjuvant therapy who have estrogen receptor—positive disease, because remember, that’s where the benefit of neratinib is. It’s worth considering using neratinib in that population, but I do think it’s worth cautioning patients that we do not have definitive data specifically in that situation.

Those are the recommendations for high-risk patients. What about low-risk patients? Here we have an interesting trial for patients who had low-risk disease. This was called the APT trial, and it defined low-risk cancers as those cancers that were either stage I, meaning a T1 cancer 2 cm or less that’s node negative, or patients up to 3 cm that were node negative, but there was only a relatively small percentage of cancers like that in this population. Mainly we would view this as a regimen for stage I cancers.

In that trial, which was a single-arm study, those patients with largely stage I cancers received just 12 weeks of weekly paclitaxel with a year of trastuzumab, with the trastuzumab started at the same time as the paclitaxel. That trial, which enrolled slightly more than 400 patients, showed excellent outcome with a 3-year disease-free survival of approximately 97%. There were very few recurrences in that trial. When patients with early stage disease were treated with the TH [paclitaxel, trastuzumab] regimen, that regimen in general is well tolerated. There is some alopecia, but most patients found the regimen quite tolerable, certainly better than one would expect with multiagent chemotherapy and trastuzumab.

For stage I HER2-positive cancers, their TH [paclitaxel, trastuzumab] regimen is associated with good outcome and good tolerability, and I think it’s the standard of care for these patients. There is really no reason to treat cancers that are felt to be stage I with neoadjuvant therapy, because we already know that those patients do very well with just TH [paclitaxel, trastuzumab]. So there’s no reason to think about adding T-DM1 [ado-trastuzumab emtansine] for such patients.

Transcript edited for clarity.