Role of HER2 Explored in Breast Cancer

Erika P. Hamilton, MD: Hello, and thank you for joining this Targeted Oncology™ presentation titled, “Targeted Therapy in Early Stage HER2-positive Breast Cancer.”

The last few years have been quite exciting, in regard to the treatment of HER2-positive breast cancer, with new and improved targeted therapies. Today, we’re going to talk about the expanding role of treatment options in early HER2-amplified breast cancer. I’m Dr Erika Hamilton, and I’m the director of the breast cancer research program at the Sarah Cannon Research Institute. Joining me is Dr Stephanie Graff, director of the breast program at the Sarah Cannon Research Institute at HCA Midwest Health, and the associate director of the breast cancer research program at Sarah Cannon Research Institute. Thank you so much for joining us. Let us get started.

First, we’re going to talk a little about defining the role of HER2 positivity in breast cancer, in general.

Stephanie Graff, MD, FACP: I think there’s been a lot going on in the HER2 space, which is really exciting. I think we have some excitement and new drug development happening, so it’s a good and important time for us to be coming together and talking about this.

Right now, we have several wonderful drugs that have built on the trastuzumab story. We have pertuzumab, we have antibody-drug conjugates, and we have new-generation anti–HER2-directed therapy emerging. One of the first things that we want to explore, though, Erika, is the background of how we got here. Can you tell us how HER2 gene amplification drives the breast cancer story?

Erika P. Hamilton, MD: Yes, absolutely. HER2 is human epidermal growth factor receptor 2, and it helps control healthy cell division, growth, and repair. And overexpression of this in tumor cells really increases the growth rate. We know that HER2-amplified cancers tend to be aggressive cancers, and they tend to be cancers that grow quite rapidly. This is important to recognize. This cancer used to have a poor prognosis. Now we have very effective therapies that help improve this quite a bit.

Stephanie Graff, MD, FACP: I think it’s important to recognize that not only is HER2 expression prognostic—historically, HER2-positive cancers of any type, not just breast, behave more poorly—but it’s also predictive. Obviously, we know that these medicines that target HER2 improve outcomes when they’re given, and the story extends beyond what we see in breast oncology, which is our focus today. We see HER2 positivity in GI [gastrointestinal] malignancies, including colorectal and gastric cancers. We see it in other rare tissue types. ERBB2 expression is pretty commonly found when we do more sophisticated genomic profiling across metastatic cancer types or early stage cancer types. So there is definitely a role to expand some of the drugs we’re talking about today to other spaces beyond the breast cancer space.

Erika P. Hamilton, MD: Absolutely. Let’s talk a little about the role of not HER2 amplifications or overexpression, but somatic mutations.

Stephanie Graff, MD, FACP: A somatic mutation is a mutation on the cancer itself, not a germline mutation. My genes are what’s passed down parent to child. We find those somatic mutations across tumor types, and the various HER2 mutations ultimately end up having a role in resistance. They also have a role in how these medicines work together, in terms of which portion of the HER2 entity is being bound by the antibody or the antibody-drug conjugate. So there is a lot of detail at play when we’re talking about HER2. It’s easy to think of it as a nice, clean, 1-piece solution, but ultimately there’s a bunch of different isoforms and different mutations and ligands that can change over time as patients gain exposure to the various compounds.

In particular, in terms of resistance, we’ve seen alternate isoforms that develop. We’ve seen tumors that develop increased ligand production, so we see a higher ratio of HER2 expression overcome the antibody expression. And then we also see mutations in the intracellular signaling process through the HER2 compound. So there are a lot of different opportunities to improve care for patients who have developed resistance to trastuzumab as we continue moving forward with drug development.

Erika P. Hamilton, MD: Absolutely. Is there any prognostic or predictive value? What about other tumor subtypes outside of breast? Do you think this is going to be actionable and something that we’re going to be thinking more about in the future?

Stephanie Graff, MD, FACP: Yes, definitely. Again, HER2 has turned out to be both prognostic and predictive in a variety of tumor types. We see that not only are HER2-amplified tumors doing more poorly without HER2-directed therapy, but the expression of HER2 in a variety of different strategies, regardless of whether that’s immunohistochemical staining or FISH [fluorescence in situ hybridization] or identification of a genomic or somatic mutation, predicts a response to HER2-targeted therapy. So I think better stratifying and understanding the HER2 landscape across cancer types, not just breast, is going to be vital as we continue to better define and explore rare cancer subtypes.

What about in your practice? What percentage of tumors have you seen, Dr Hamilton, that have HER2 alterations?

Erika P. Hamilton, MD: In the breast cancer world, we commonly think that this is probably around 15%, and that’s stayed pretty steady over time. We also see a higher rate of HER2 amplifications in GI tumors, like gastric, even colorectal; and to a smaller degree, lung and other cancers. We’ve had trastuzumab since the 1990s for breast cancer, and we also have approvals for trastuzumab in GI malignancies. But now that we’re getting more agents in the HER2 space, trastuzumab deruxtecan comes to mind. Some of the tyrosine kinase inhibitors have had recent reports of activity in colorectal cancer, etc. I think we’re going to see more options for these tumor types outside of breast. Trastuzumab deruxtecan is certainly expanding into other tumor types and has presented some great results. We see the same with tucatinib in colorectal cancer. I think this is really an emerging field. In 2020, sometimes we’re worrying a bit less about where the cancer came from, and instead, we are asking the question of, what makes this particular cancer tick, and how can we stop it from growing?

Stephanie Graff, MD, FACP: Yes, that precision medicine storyline was on display at ASCO [the American Society of Clinical Oncology annual meeting] 2020. We saw an entire clinical science symposium dedicated to genomic profiling and how it can help us define cancer types. I definitely think that’s the direction that our field, and oncology, globally, is taking to figure out what is going on biologically with the tumor to try to best address it with targeted therapy.

Erika P. Hamilton, MD: Absolutely.

Transcript edited for clarity.