Dr Adam Brufsky Describes the Evolution of Treatment Options for HER2-Low Breast Cancer

Human epidermal growth factor receptor 2 (HER2)-low breast disease has a number of new treatments available, and more providers need to be aware of how it differs from other forms of breast cancer, according to Adam Brufsky, MD, PhD, University of Pittsburgh, at the San Antonio Breast Cancer Symposium.

The human epidermal growth factor receptor 2 (HER2)-positive (HER2+) breast cancer space is constantly evolving, and more providers need to pay attention to the growing data on therapies being used in HER2-low breast cancer, said Adam Brufsky, MD, PhD, professor of medicine, associate chief of the Division of Hematology/Oncology, co-director of the Comprehensive Breast Cancer Center, and associate director of clinical investigation at the University of Pittsburgh.


How has the treatment space for HER2+ breast cancer evolved over time, especially in the HER2-low space?

Brufsky: The treatment of HER2+ breast cancer really has changed now with the introduction of 2 things. The first thing is antibody-drug conjugates, as well as HER2 tyrosine kinase inhibitors.

In terms of antibody-drug conjugates, TDM1 [trastuzumab emtansine], the first one we had, it's been around for a little over a decade. And it's really changed the management of progressive second-line HER2+ metastatic breast cancer.

And now, especially at this meeting in San Antonio, we have even more evidence that the HER2 anybody-drug conjugate trastuzumab deruxtecan is far superior to TDM1 in a HER2+ group of patients, in metastatic HER2+ breast cancer. The progression-free survival with third-line therapy is 17 months, with second-line therapy, 28 months—with survival benefit. A quadrupling of progression-free survival vs TDM1 in HER2+ positive disease really has just changed the landscape.

We also now have data from DESTINY-Breast04 that was initially announced at ASCO [the annual meeting of the American Society of Clinical Oncology]—and I think it is going to be updated in this meeting as well—where there's a substantial progression-free and overall survival benefit in patients with HER2-low disease. That's HER2+ 1+ or 2+ by immunohistochemistry. In fact, there may be even benefit for people with ultra low amounts of HER2. There's a trial called DESTINY-Breast06, where patients are really being studied with as low HER2 expression as you possibly can get.

That data may show that trastuzumab deruxtecan works in even those patients. It's really dramatically changed the management of HER2+ metastatic breast cancer. It clearly has the potential to be drastically altered. People now are going to probably live a lot longer with HER2+ breast cancer.

I think the problem with a lot of these drugs is that women may still develop brain metastases. For that, we have the development of a lot of HER2 tyrosine kinase inhibitors, such as tucatinib and neratinib. Although there are kind of second-generation molecules beyond lapatinib that get into the blood-brain barrier and have the potential to prevent the onset of brain metastases.

But back to the HER2-low space. I think that we're realizing that you don't have to have a lot of expression. In fact, one of the things that came out, we had a session on what is HER2 low—is it a separate entity?—during San Antonio this year. During that special session, one of the comments that came out was that all you have to do is have 1 test that's HER2 1+ or 2+ and trastuzumab deruxtecan will likely have benefits. We don't know 100% for sure, but at least from analysis for the trials, it appears that that may be the case.

So, I think that truly the landscape has changed for the better. Now, these drugs do have toxicity. Trastuzumab deruxtecan does have pneumonitis that has to be washed out, that has to be kind of carefully observed. But if enough attention is paid to it and enough caution is paid to it, I think this is something that really will change the landscape not only for HER2 overexpressed patients but also patients with HER2 1+ or 2+.

What are some of the challenges of treating patients with HER2-low breast cancer, and what do you wish more providers understood about this breast cancer subtype?

Brufsky: We're not sure that HER2-low is a specific subtype per se. We do know that HER2-low disease defines a group of patients that are eligible to receive trastuzumab deruxtecan, and the question is kind of how to define that HER2 subtype. How low can you go? What are your assays? There are now ultrasensitive assays for this that have developed. Some of which are still in the research form, others are kind of at the cusp of being able to be used clinically.

But the bottom line is that, one challenge is who to treat. Again, if you just have a little bit of HER2 expression, like 1 specimen, it may be enough to be able to treat these patients and get a beneficial result. We don't know 100% if it will still work.

The other thing that I wish more people knew is that, again, you do have nausea with these drugs. With trastuzumab deruxtecan, you do have a little bit of neutropenia, not a ton. But the big one is interstitial lung disease [ILD], and you also do get some left ventricular ejection fraction dysfunction. Uncommonly, very uncommon. ILD is about 10%. The rule of thumb is about 1 in 10 to 1 in 8 will have some ILD. The key is to catch it quickly and just have an education, understand you're likely as a medical oncologist to use these drugs in a lot of people now because there's a lot of indications for it. When roughly 70% of all your patients with metastatic disease will be HER2-expressed, either low or 3+, you're gonna be using this a lot.

So, just getting familiarity with interstitial lung disease, understanding that you may have to stop the drugs early if there's cough or shortness of breath, get pulmonologists involved. That's what I think physicians need to know about this, other than the fact that they seem to work really well.

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