Expert Perspectives on Defining HER2-Low Breast Cancer


Centered discussion on the advent of HER2-low breast cancer and how it is differentiated from HER2+ and HER2- disease.


Aditya Bardia, MD, MPH: Thank you for reviewing HER2+ metastatic breast cancer. Now let's move to HER2-low metastatic breast cancer, a new classification. We'll start with biomarker testing. Michelle, could you review how we measure HER2? And what is the HER2-low breast cancer subtype?

S. Michelle Shiller, DO, AP/CP, MGP: Yes. This is also a very hot topic in pathology because this is probably the first time in several years that we've looked at HER2 differently with a significantly radical change in how that impacts therapeutic decision making. And as a result, there's been a lot of internal discussion, which I've had the opportunity to participate in. HER2 is initially tested by immunohistochemistry. Right now in existence, we have the ASCO/CAP 2018 guidelines for interpreting that. And because we don't have a guideline update for us with respect to our reporting standards, we must follow those guidelines because there's nothing that has been updated—that becomes important momentarily. We have technically 4 interpretations. We have HER2 0, which is then ultimately called negative; HER2 1+, which is then ultimately rendered negative as well; HER2 2+, which then would need follow-up testing with FISH, fluorescence in situ hybridization, and then HER2 3+ interpretation. And that would be overexpressed. And that allows patient to have trastuzumab deruxtecan [T-DXd] in the traditional understanding of HER2.

Where it becomes complicated is that with the DESTINY-Breast04 trial and the FDA approval, this HER2 low and what that is. With immunohistochemical interpretation, they use the guidelines for interpreting and determining a score of 1+ or 2+, then ultimately that 1+ according to that trial is now considered HER2 low and it qualifies a patient in the metastatic setting for consideration of trastuzumab deruxtecan antibody-drug conjugate therapy. In a 2+ interpretation, you still need to do FISH to determine what that ultimate HER2 interpretation is. And when it's FISH negative, then that is ultimately rendered now HER2 low. And again, the patient can be considered for that therapy. With HER2 0, there was no impact on its interpretation. It's always still considered negative, though. We're just going to stay with the current approvals right now.

And then we have our HER2 overexpression. Those have been unimpacted, but it's this middle ground, but it's a very significant and important group of patients with breast cancer. And we have not conflicting but an additional layer of information that needs to be conveyed. As a result, until we see a guideline update, which I'm sure will integrate these things, right now from a reporting perspective for pathologies, it’s very important that we're clear as to what we're seeing underneath the microscope. And we specifically render 2 lines to our interpretation. One is the ASCO/CAP 2018 guideline. We would say HER2 1+ negative, then we'd have a new line for DESTINY-Breast04, and it would say HER2 low. That way, we're trying to be very clear as to what we're seeing. It also helps to convey what that expression looks like underneath the microscope, what we're seeing.

Aditya Bardia, MD, MPH: Absolutely. And I can imagine there's more to come as we have additional data. At SABCS 2022, there was a full session dedicated to HER2 low, where we saw several abstracts presented. Virginia, could you highlight some of the important developments that came out of SABC 2022 related to this new category of HER2-low breast cancer?

Virginia Kaklamani, MD: The debate had been whether this is a new prognostic category, besides the fact that we know it's predictive to T-DXd and potentially other agent benefit. There was a debate and there were several abstracts presented that looked at trying to molecularly characterize HER2 low compared with the HER2 0 breast cancers, whether they're ER+ or ER-. And the consensus is that it's probably not prognostically different, but there were some minor changes. For example, it looked like HER2 low seemed to have more AR expression, it had more expression of fatty acid and steroid metabolism genes. Regardless of whether it was ER+ or ER-, it seemed to have a higher rate of PIK3CA mutations. Whether that means anything, I don't know. But it looks like consensus wise, it's not prognostically any different than HER2-negative breast cancer.

One of the things for us to keep in mind—and it might make a difference with the molecular characteristics of the tumor—is how does HER2 evolve into being HER2 low? Is it starting as HER2 0, especially in the ER+ setting? And then it starts gaining for the HER2 expression, it starts increasing over time as the tumor becomes estrogen resistant, which we've seen, and we've seen a lot of data from Kent Osborne’s group looking at this as well. Or is it really HER2 low from the beginning? This is something that I didn't see much information on, but this definitely is different from just a HER2 low tumor from the get-go.

Aditya Bardia, MD, MPH: That's a good question, because we are talking about HER2 low as though it's a static category, but maybe it changes over time. And from a biology perspective, what drives HER2 low breast cancer? That’s an open question at this time.

Transcript edited for clarity.

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