Establishing the Paradigm of HER2-Low Breast Cancer


Expert perspectives on the advent of HER2-low disease and how it has been historically managed since its emergence as a subset of breast cancer.

Andrew Seidman, MD:
It was about 25 years ago that I first heard the term triple negative. It was a new term that had no meaning before HER2 [human epidermal growth factor receptor 2] was around. And now at this year’s ASCO [American Society of Clinical Oncology] meeting, we have a new category of breast cancer we call HER2-low. VK, what is the consensus if there is one amongst oncologists about what is HER2-low breast cancer?

Vijayakrishna Gadi, MD, PhD: I am still forming my opinions on this and trying to unpack it after these extraordinary data. I think about HER2 as a driver, and for it to be a driver, it really has to be there and that kinase has to be engaged, and it has to be talking downstream. That’s a pretty solid definition. That’s the 3+ [immunohistochemistry tumor score] and amplifieds. Then we have this category where you see HER2, you can see it there, 1+, 2+, whatever terms we want to use, and in that situation it’s not to our understanding a driver of the disease, it is now a convenience target. If you have a drug that can find it, like trastuzumab, and you stick a very potent payload on it like deruxtecan, it’ll get internalized and kill it on the basis of that target being present. Those concepts of receptor density, how much HER2 do you have, etc., all of those things become important. This is an interesting drug because of the mechanism of action, this bystander killing, which I am sure we’re going to talk about. That’s how I am framing this molecule in my thinking.

The thing that matters now is how we test in the metastatic setting. In the early stage setting, the convention is you do immunohistochemistry, if it’s 2+, you go and get FISH [fluorescence in situ hybridization] reflexively, you’ve called it HER2+. That’s appropriate. In the metastatic setting, where you don’t have control tissue and it’s hard to know what a 2+, or 1+, or even a 3+ is, we’re really supposed to do FISH. We find HER2s, and then on everybody else we need to now know are they 2+ and 1+? And if so, we have another agent available to us. I am going to be careful about saying we have a new disease; I am not sure we do.

Andrew Seidman, MD: Is it fair to say that until we have more sophisticated technologies for quantitative HER2 assessment, that if you’re 1+ or 2+ and FISH-negative, regardless of hormone receptor status, that’s a HER2-low patient?

Vijayakrishna Gadi, MD, PhD: This comes back to your comment earlier, the limbo, how low can you go? I am not certain that attomolar concentration on the cell surface is going to be enough, but there has to be a threshold where we’re going to see a nice engagement and enough engagement that enough drug gets into these cells and does what it is supposed to do.

Andrew Seidman, MD: Did you want to take us through the data that were published recently on this subject?

Vijayakrishna Gadi, MD, PhD: In regard to…?

Andrew Seidman, MD: In regard to the [Carsten] Denkert, [MD,] paper in Lancet Oncology, and the [Paolo] Tarantino, [MD,] paper.

Vijayakrishna Gadi, MD, PhD: I am less familiar with those.

Andrew Seidman, MD: As I am.

Tiffany Traina, MD: I think they’re just prevalence.

Vijayakrishna Gadi, MD, PhD: Honestly I don’t know because I think the technologies are changing enough in how we measure in terms of the prevalence. I am just not sure, and this is a dynamic measure as well. These things might change.

Stephanie Graff, MD: I think they are both saying that there are about 60% of our patients who may meet these definitions. It’s a large population of patients that are going to meet the definition of being HER2-low.

Andrew Seidman, MD: What’s been your historical treatment for the typical DESTINY-Breast04 patient who may have had hormone receptor-positive disease, exhausted endocrine therapies, and she has had 1 or 2 prior chemotherapy regimens? What has been the historical standard of care for these patients we now call HER2-low for which there is another treatment option?

Stephanie Graff, MD: The historical context was that HER2-low wasn’t a thing. Historically we have either thought of these patients as having hormone receptor-positive metastatic breast cancer or triple-negative metastatic breast cancer, and we would be following those paradigms. These are patients who were enrolled on the DESTINY-Breast04 trial who were pretreated. In the hormone receptor-positive trial, they were pretreated with hormone therapy and emerging into the chemotherapy space. So you’re looking at your standard chemotherapy regimens for them, things like eribulin, capecitabine, taxane, maybe even something like sacituzumab. And in the triple-negative space, you’re looking at that arsenal of chemotherapeutics we use in triple-negative breast cancer.

Andrew Seidman, MD: At the plenary session on Sunday, Shanu Modi, [MD], who is our colleague and friend, received a standing ovation. I really believe the ovation was very much driven by the data and happiness for women to see a PFS [progression-free survival] benefit and overall survival benefit. I couldn’t help feeling, and I don’t think I was alone, in that some of that ovation was for Shanu herself. She is truly a bright, humble, and authentic person who we were lucky to extract from the mosquito-infested plains of Edmonton, Alberta, [Canada] about 30 years ago, bring to MSK [Memorial Sloan Kettering Cancer Center], and she decided to stay with us. We’re very proud of her. Those data I think are the biggest practice-changing data for me, and it has taken us away from the old choices of capecitabine, gemcitabine, eribulin, vinorelbine, and recycling taxanes, for 60%, which is a significant group of patients.

Transcript edited for clarity.

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