HER2-Low and HER2-Ultralow Breast Cancer
Updated on February 16, 2026
Until recently, the only two results of HER2 status testing were HER2-positive or HER2-negative. Now, many doctors recognize two additional HER2 levels: HER2-low and HER2-ultralow. This is because more than half of breast cancers considered HER2-negative have some extra HER2 proteins on the surface of their cells. There just aren’t enough HER2 proteins for the cancer to be considered HER2-positive.
How are HER2-low and -ultralow breast cancers diagnosed?
While there are no official definitions for these categories, many doctors and researchers use these criteria to decide if a breast cancer is HER2-low or -ultralow.
HER2-low: an ImmunoHistoChemistry (IHC) test score of 1+ or 2+ with a negative Fluorescence In Situ Hybridization (FISH) test result
HER2-ultralow: an IHC score of 0 with 10% or fewer cancer cells showing faint HER2 protein staining on the cells’ outer boundaries
Why does the number of HER2 proteins matter for treatment?
Knowing whether a cancer is HER2-low or -ultralow matters because some newer treatments can work on these cancers even when older anti-HER2 medicines don’t.
HER2 proteins sit on the surface of breast cancer cells. If a breast cancer is HER2-positive, there are many HER2 proteins on the cancer cell packed closely together. When the HER2 proteins touch other HER proteins, they send signals that cause the cancer cells to multiply rapidly.
With HER2-low and HER2-ultralow cancer cells, there are far fewer HER2 proteins, so they’re spaced farther apart. This means the HER2 proteins are unlikely to touch other HER proteins and tell the cell to multiply.
Older anti-HER2 medicines like Herceptin (chemical name: trastuzumab) and Perjeta (chemical name: pertuzumab) cloak the HER2 proteins — like covering them in bubble wrap — which keeps the HER2 proteins from touching and stops the cancer cells from multiplying.
These medicines work well in HER2-positive breast cancer because HER2 proteins are close enough together for the drugs to be effective, which helps explain why they don’t work as well when HER2 levels are low.
The next generation of anti-HER2 drugs: antibody-drug conjugates
Antibody-drug conjugates (ADCs) are medicines that attach to specific proteins, like HER2, on a cancer cell. They also contain chemotherapy. Once attached to the cell, the chemotherapy enters and kills the cancer. One ADC, Enhertu (chemical name: fam-trastuzumab-deruxtecan-nxki), sometimes called T-DXd, attaches to HER2 proteins on a cancer cell. So doctors began wondering if Enhertu could work on breast cancers that had only a few HER2 proteins. Research shows that it does.
In 2022, results from the DESTINY-Breast04 study showed that Enhertu offered better progression-free survival and overall survival than chemotherapy in people diagnosed with previously treated metastatic HER2-low breast cancer.
In 2024, the DESTINY-Breast06 study found that Enhertu doubled progression-free survival compared to chemotherapy in people with hormone receptor-positive, HER2-low or -ultralow metastatic breast cancer that grew after they received one or more hormonal therapy medicines.
Listen to the episode of The Breastcancer.org Podcast featuring Aditya Bardia, MD, MPH, discussing the results of the DESTINY-Breast06 study.
Enhertu for HER2-Low and -Ultralow Metastatic Breast Cancer
Dec 12, 2024Are HER2-low and -ultralow considered breast cancer subtypes?
The short answer is: not right now. While HER2-low and -ultralow status can help doctors recommend treatments like Enhertu, there is controversy about whether HER2-low and -ultralow should be considered distinct subtypes of breast cancer.
The 2023 update to guidelines on breast cancer HER2 testing from the American Society of Clinical Oncology and the College of American of Pathologists say while it’s too early to create official test result categories for HER2-low and -ultralow, it’s important to know if a breast cancer has an IHC score of 0 or 1+ because this can affect treatment options.
In part, this is because IHC testing wasn’t designed to distinguish between HER2-low, HER2-ultralow, and HER2-zero (or null) breast cancers. The test was designed to tell the difference between very high and low levels of HER2 proteins — not between low and lower levels of HER2 proteins.
Also, HER2 levels can vary throughout a cancer tumor. So a biopsy of one part of the tumor may offer different HER2 IHC test results than a biopsy taken from a different area of the tumor.
Everyone agrees that more refined HER2 testing is needed and researchers are working to develop it.
How common is HER2-low and -ultralow breast cancer?
Studies that have looked at breast cancers previously classified as HER2-negative suggest that between 50% and 60% of breast cancers are HER2-low and between 10% and 20% are HER2-ultralow.
This means that a lot of people diagnosed with breast cancer, including people with metastatic disease, could benefit from a medicine like Enhertu.
If you’ve been diagnosed with HER2-negative breast cancer, you may want to talk to your doctor about the details of the HER2 test results and if the cancer could possibly be HER2-low or -ultralow.
Are there treatments specifically for HER2-low and -ultralow breast cancer?
At this time, Enhertu is the only medicine approved specifically for HER2-low or -ultralow breast cancer. Enhertu is used to treat:
unresectable (can’t be removed with surgery) or metastatic hormone receptor-positive, HER2-low or -ultralow breast cancer that has previously been treated with hormonal therapy
unresectable or metastatic HER2-low breast cancer that has previously been treated with chemotherapy