Understanding HER2 Expression in Metastatic Breast Cancer

Vijayakrishna Gadi, MD, PhD: Being sensitive to time and everything else, let’s go on to the next concept. Mylin, you were going to lead us on this strange concept of HER2-low.

Mylin A. Torres, MD: We’ve spoken extensively about the HER2-positive metastatic breast cancer landscape. We can all acknowledge that there are many patients who don’t completely fit within the enrollment criteria for these landmark studies that we’ve been describing. There’s a lot of talk about the HER2-low patient population. VK and Neil, what’s your general approach for patients like these?

Vijayakrishna Gadi, MD, PhD: I briefly mentioned before the idea that you’re seeing not just HER2-low but HER2 heterogeneity, uneven expression, whatever the driver of that is. Our classic immunotherapy agents of trastuzumab, pertuzumab, and those others work best when you have strong or robust expression of these. In fact, a molecule like Kadcyla, or T-DM1 [trastuzumab emtansine], doesn’t work that well on HER2 heterogeneous disease. It’s valuable that you have payloads associated with these molecules that can cross the barriers that exist and get into nearest neighbors and kill those. We’re obviously going to see some focus studies on these populations. Here, it’s not that the cancers are HER2-driven. We’re using HER2 as a marker of convenience to attack them, and that’s the distinction. A lot of the clever biologic things we’ve done to understand HER2 disease as an entity don’t apply here. But we have to prove that some of the same molecules we’re looking at could have value. Neil, I’ll give it back to you.

Neil M. Iyengar, MD: I completely agree, and I’d take this question as an opportunity to reiterate that when we can re-phenotype the disease, we should. What I mean by that is if it’s possible to obtain tissue at a time of progression and re-evaluate HER2 status, that might completely shift or even open up new treatment options for your patients because we know, either due to tumor heterogeneity or clonal evolution, that the receptor status or receptor expression can change. That’s a bit tangential to the HER2-low concept, but it all ties together in that we’re now recognizing HER2 expression as a heterogeneous entity.

The data in HER2-low are very exciting, partly due to the bystander effect that VK very nicely outlined. Eventually, we’re likely going to define a new subgroup or a subpopulation of HER2-expressive breast cancer that will benefit from a HER2-directed approach, particularly with these agents that have a bystander effect, several of which are in the pipeline as well. This is an area that we’re going to see rapidly evolving and defining a new treatment category, not just in breast cancer but other cancers, like gastric cancers, as well.

Transcript edited for clarity.