HER2-positive, HER2-low, and HER2-ultralow metastatic breast cancer
- Medical Review: Sara Hurvitz, MD
In metastatic breast cancer, or stage IV disease, the cancer cells have spread from the breast and nearby lymph nodes to tissues or organs far away from the breast.
When breast cancer has too many copies of a gene called HER2 (human epidermal growth factor receptor 2), the cancer develops too many HER2 receptors. Receptors are proteins on the surface of the cancer cells. The receptors receive signals that tell the cancer cells to grow and divide out of control.
Too many copies of the HER2 gene and too much HER2 protein expressed is called HER2 overexpression or HER2 gene amplification. This is also known as HER2-positive breast cancer. Fifteen to 20% of breast cancer is HER2-positive. It’s important to know that there are many effective treatment options for HER2-positive metastatic breast cancer.
Recently, researchers found that metastatic breast cancers with lower levels of HER2 — known as HER2-low and HER2-ultralow — may benefit from a targeted therapy called trastuzumab deruxtecan (Enhertu).
Below, you can learn more about diagnosis, treatments, and research on new treatments.
Diagnosing the cancer
To confirm a diagnosis of metastatic HER2-positive, HER2-low, or HER2-ultralow breast cancer, your care team will use imaging tests, blood tests, and/or tests on cancerous tissue.
Immunohistochemistry (IHC) tests, sometimes in combination with FISH tests, can confirm the cancer’s HER2 status.
Metastatic breast cancer with any level of HER2 can be:
- HER2-positive: the IHC score is 3+
- HER2-low: the IHC score is 1+, or, it is 2+ followed by a negative FISH test
- HER2-ultralow: the IHC score is greater than 0 and less than 1
Over half of HER2 positive metastatic breast cancer also tests positive for hormone receptors. If the cancer is HER2-positive and hormone receptor-positive, it is called triple-positive.
You can learn about HER2 testing, triple-positive breast cancer, and more on the HER2-positive or HER2-low breast cancer page.
Getting a new biopsy
If you were treated for early-stage HER2-positive breast cancer in the past and now have a metastatic diagnosis, it is important to talk with your medical oncologist about having a new biopsy of any abnormal finding from an imaging test. This is because cancer biomarkers, including HER2 and hormone receptors, can change. A different biomarker status can mean choosing different treatment options.
The biopsy helps to:
- Confirm the diagnosis
- Confirm the presence or absence of hormone receptors or HER2 to check for any changes since your original diagnosis
Biomarker testing
HER2 and hormone receptors are biomarkers (proteins, gene mutations, and other substances in the cancer). Biomarker testing is an important part of finding the most effective treatment for the cancer. These blood and tissue tests can help match a cancer to a treatment.
New biomarkers can develop in cancer over time, so it’s important to talk with your doctor about getting tested after a metastatic diagnosis and any time you are considering new treatments.
Learn more about biomarker testing and other tests for metastatic breast cancer.
Treatment options
Metastatic breast cancer that tests positive for HER2 can be treated with targeted therapy, chemotherapy, and in some cases, radiation therapy. Surgery is not usually part of a treatment plan for metastatic breast cancer, but it may be used in rare cases.
If the cancer is also hormone receptor-positive, hormonal therapy may be used in combination with HER2-targeted therapies and chemotherapy.
Targeted therapy
Treatment of HER2-positive breast cancer that has spread to organs other than the brain usually includes medicines called targeted therapies that are directed against the HER2 protein. These therapies block signals that tell the cancer to grow.
Here are the FDA-approved targeted therapies for metastatic breast cancer that tests positive for HER2:
- Trastuzumab (Herceptin) is a treatment that can attach to HER2 proteins and block signals that tell cancer cells to multiply. It is often given with chemotherapy. Trastuzumab is also available in biosimilar form — similar and equally effective to trastuzumab, and in some cases, less expensive. Learn more on the trastuzumab page.
- Ado-trastuzumab emtansine (Kadcyla) is an antibody drug conjugate, a medicine that combines a targeted therapy with chemotherapy. It sends the chemotherapy medicine directly to the cancer cells to reduce the risk of affecting healthy cells.
- Lapatinib (Tykerb) treats metastatic breast cancer when the standard trastuzumab has stopped working. It is given in combination with capecitabine (Xeloda), trastuzumab, or, if the cancer is both HER2- and HR-positive, letrozole (Femara).
- Margetuximab (Margenza) is given with chemotherapy to treat metastatic, HER2-positive breast cancer after treatment with at least two previous lines of targeted therapy.
- Neratinib (Nerlynx) is given with the chemotherapy pill capecitabine (Xeloda) if the cancer grew despite treatment with at least two previous lines of targeted therapy treatment.
- Pertuzumab (Perjeta) works by blocking signals that tell breast cancer cells to multiply. It is given in combination with trastuzumab and chemotherapy.
- Trastuzumab deruxtecan (Enhertu) is an antibody-drug conjugate FDA approved to treat metastatic breast cancer that is HER2-positive, HER2-low, HER2-ultralow, hormone receptor-positive and HER2-low, and hormone receptor-positive and HER2-ultralow. For HER2-positive metastatic breast cancer, trastuzumab deruxtecan is FDA-approved as a first treatment in combination with pertuzumab.
- Tucatinib (Tukysa) is a tyrosine kinase inhibitor that is given with trastuzumab and the chemotherapy pill capecitabine to treat cancers that have grown after previous HER2-targeted treatments.
Chemotherapy
Chemotherapy is often used to treat metastatic breast cancer that tests positive for HER2. It is often combined with other therapies, such as trastuzumab. It can be given in different forms, including through a vein (intravenous, or IV) or orally as a pill.
Learn more about chemotherapy.
Radiation therapy
Radiation therapy can be used to manage symptoms or relieve pain caused by metastatic breast cancer.
Visit Radiation therapy to learn more.
Surgery
Surgery is rarely used in metastatic breast cancer treatment, but in some cases, it may be recommended. For example:
- If other treatments keep the cancer from growing for some time, your doctor might recommend removing the original breast tumor
- In rare cases, doctors may recommend surgically removing a metastatic lesion
- If you have pain or bleeding, your doctor may recommend surgical removal of the original breast tumor to help relieve symptoms.
Treatments for brain and spine metastasis
Metastatic HER2-positive breast cancers are more likely than some other types of breast cancer to spread to the brain and spinal cord, which with the spinal fluid make up the central nervous system or CNS. Up to half of people diagnosed with HER2-positive metastatic breast cancer develop metastases to the central nervous system.
There are local therapies available to treat these areas of metastases. These can include surgery and radiation therapy. Visit the brain metastases and bone metastases pages to learn more.
Research on treatment for HER2-positive brain metastasis
Many systemic, or whole-body, therapies have trouble reaching the brain. Medicines such as trastuzumab and pertuzumab are known as monoclonal antibodies. These are large molecules that have a harder time getting to the brain due to their size.
However, some targeted therapies are able to reach and treat metastasis in the brain.
The targeted therapies trastuzumab deruxtecan and ado-trastuzumab emtansine are large molecule drugs. Unlike other large molecule medicines, these drugs have been found to be effective in treating brain metastasis.
Researchers are studying small molecules, called tyrosine kinase inhibitors or TKIs, to see whether they can more easily cross the blood-brain barrier. Lapatinib, neratinib, and tucatinib are TKIs.
Tucatinib was specifically studied in people with brain metastases, and clinical trials suggest it can effectively get through the blood-brain barrier to treat the cancer.
Clinical trials
A clinical trial is a study that looks at how well new medical approaches work in people. Clinical trials offer access to new treatments that are not otherwise available and may prove to work better than standard treatments.
Participating in a clinical trial also helps researchers develop better treatments for people diagnosed in the future.
Visit Clinical trials for metastatic breast cancer for more information. You can also look for trials using the Metastatic trial search tool.
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Reviewed and updated: March 14, 2026
Reviewed by: Sara Hurvitz, MD
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