At the 2022 San Antonio Breast Cancer Symposium, Sara Tolaney, MD, MPH, Dana-Farber Cancer Institute, Boston, Massachusetts makes the case that HER2 low should not be considered a new breast cancer subtype.

In the debate session, "HER2 Low: A Separate Entity?", Dr Tolaney argued that HER2 low status should not be considered a new subtype of breast cancer. She went on to explain the potential benefit of HER2 low as a biomarker within breast cancer.

Transcript:

My name is Sara Tolaney. I'm a breast medical oncologist at Dana-Farber Cancer Institute, and at San Antonio Breast Cancer Symposium this year I participated in a debate on HER2 low breast cancer with the question being, HER2 low a new subtype of breast cancer? My stance on this is no, it is not a new subtype. And I think the reason for this is really multifold. We've really thought of breast cancer subtypes as distinct groups within breast cancer that are associated with different biology and different outcome. We've really grouped breast cancer generally into 3 groups: hormone receptor-positive, HER2-positive, triple-negative. And we know that these subtypes are biologically distinct with unique gene expression profiles.

However, with HER2 low positive disease, we've seen that this is not the case. We know that HER2 low positive tumors compared to HER2-0 tumors do not have unique clinical pathologic features, when you correct them for ER status. That's really critical because we do see that HER2 low expression does increase as ER expression increases. If you do not correct for the degree of ER positivity, you could see that there seem to be differences between HER2 low and HER2-0. But again, when correcting for ER, these do tend to go away.

Another reason I think HER2 low is not a new subtype, it is not associated with a different prognosis compared to HER2-0 tumors. In fact, we're seeing a lot of data at San Antonio specifically looking at outcomes and there was a very large retrospective analysis from the National Cancer Database with over a million patients. When you look at survival outcomes by stage and by ER status, you really see the curves are largely overlapping — not really seeing distinct outcome differences from HER2 low and HER2-0.

Another reason I think HER2 low tumors are not a new subtype is because they're not biologically distinct. If we look, for example, at intrinsic subtypes, you can see that intrinsic subtypes are differentially distributed between HER2 low and HER2-0 tumors. But these differences in distribution are really driven by ER status, not by HER2 low status. Additionally, when you look at individual gene expression profiles, you'll also see the differences, for example, that you may see between HER2 low and HER2-0 tumors, such as proliferation genes, are driven by ER. So again, not truly biologically distinct.

And finally I think it's not a new subtype because it's not biologically consistent or stable. So for one, with HER2 testing, we see large amounts of discordance with central and local testing. We also see that HER2 low status can change over time. So it's quite dynamic. You can see a person can have a HER2 low, and a recurrence can be HER2-0, and then upon a subsequent biopsy in the metastatic setting could be HER2 low again. So you see it changes a lot over time. And at this San Antonio Breast Cancer Symposium, we did see data from a really interesting rapid autopsy series where they actually looked at tissue at different locations within an individual person suggesting heterogeneity and HER2 low status at the same time point and even in the same organ. So if you looked at someone's liver for example and looked at different locations in the liver, you could see some areas are HER2-0, some areas are HER2 low, so quite discordant there.

I think for all of these reasons, HER2 low is not a new subtype of breast cancer, but I do think it is a biomarker because it's allowing us to identify a target for delivery of a very potent cytotoxic payload that really does result in robust clinical benefit for patients. That being said, I do think we do need to refine this biomarker because we do need to develop novel quantitative assays because I think in the future our definition of HER2 low is going to continue to evolve.

Source:

Tolaney S. "HER2 Low: A Separate Entity? - Con." Presented at: San Antonio Breast Cancer Symposium; December 6 - 10; San Antonio, Texas.