What is HER2-low? Insights from Dr. Sara Hurvtiz
During our recent webinar on the evolution of breast cancer testing, Dr. Sara Hurvitz of Fred Hutch Cancer Center provided a helpful explanation of HER2-low.
Q: What are the latest therapies specific for HER2-low breast cancer? Is this important to know in early-stage breast cancer or just metastatic breast cancer (mBC)?
A: It’s a great question, and there has been a lot of press, so I can understand the confusion and eagerness to know more. Up until, I would say 2023 or 2022, when we spoke about HER2–which stands for human epidermal growth factor receptor number two–we spoke about it only as:
- Is it a yes or no?
- Is it overexpressed?
- Is the gene amplified in the tumor, or is it not?
If you had HER2-positive, meaning amplified, or HER2-overexpressing breast cancer, you needed HER2-targeted therapy like Herceptin, Perjeta, or Kadcyla. If it was not, then you just never received a HER2-targeted therapy.
Well, there is a drug that was developed called T-DXd or Trastuzumab deruxtecan, also known as Enhertu. This is essentially an antibody, so it’s Herceptin or Trastuzumab–which target HER2–and it’s loaded up (like wearing a backpack with chemotherapy). We call it an antibody-drug conjugate. It’s like a Trojan horse. So the antibody goes and finds the cells with overexpression of HER2 on the cell surface, binds to the HER2, and is taken up into the cell, and the bomb goes off. Well, in this particular antibody-drug conjugate, the bomb itself is able to leave the cancer cell that it killed and kill neighboring tumor cells that may not have HER2 high expression. And so scientists began noticing this. This was approved in 2019 for HER2-positive mBC and studies started going on to look at, “Will this work in breast cancers that have normal expression of HER2, which is called HER2-low?”
Because back in the 90s when HER2 was discovered, and there was writing about it, my former boss Dennis Slayman and his colleague Mike Press at USC, wrote a paper that is now famous in Oncogene, looking at HER2 levels, and every cell in our body has some HER2 on it. And all breast cancer [cells] have HER2 on [them]. It’s just when it’s overexpressed, it’s a lot, a lot more. So the scientists showed that T-DXd actually is beneficial in HER2-low or normal expressing cancer cells, that it actually is able to deliver enough of the chemo to the cancer cells, which have a little more than normal cells.
And so that led to clinical trials in what is called HER2-low breast cancer. This means they can see a little bit or a medium amount of HER2 expression on the cancer cells with a standard test called immunohistochemistry (IHC), which is just like a stain of a tumor sample to look for HER2. T-DXd is now only approved for metastatic, HER2-low breast cancer. Two-thirds or more of hormone receptor-positive breast cancer is HER2-low and about a third of triple-negative breast cancer is HER2-low.
Now, I just told you that all breast cancer has some level of HER2 expressed on it, and in fact, a recent study showed that even if there is 0 expression of HER2 in hormone receptor-positive breast cancer, you can use T-DXd. And…the FDA approved it for HER2-0 as long as there is up to 9% of the cells showing HER2 hormone receptor-positive metastatic breast cancer.
There have been studies done to look at:
- Is this a distinct disease?
- Do cancers that have some expression of HER2 detected on it behave differently than cancers that don’t?
And there’s no difference in prognosis, because this is just a laboratory artifact: our ability to detect it on the cell. And, in fact, our current assay is really not very good at quantifying HER2 expression levels. IHC was never developed by Mike Press and colleagues to quantify the amount of HER2 on the cell. So I think T-DXd probably will work, to some level, in everybody with breast cancer. But it’s approved in these particular indications, and only in metastatic breast cancer. There are ongoing studies in early breast cancer. So, it’s only important to know if you have HER2-low breast cancer, if you’re being evaluated for a clinical trial in early-stage disease. At this point, there is nothing available in early-stage disease that targets HER2-low.
Have questions about HER2-low? Reach out to one of our oncology nurse practitioners using the Ask Outcomes4Me feature in our app.
