HER2-positive or HER2-low breast cancer

Knowing what makes breast cancer cells grow and multiply helps you and your doctors choose treatments that can work effectively against the cancer. In HER2-positive breast cancer, mutations in a gene called HER2 (human epidermal growth factor receptor 2) trigger breast cancer cells to grow and multiply. Between 15-20% of breast cancers are found to be HER2-positive. An additional 50-60% of breast cancers test positive for small amounts of HER2 — not enough to be HER2-positive. These breast cancers are considered HER2-low.

Normally, the HER2 gene makes HER2 proteins, sometimes called HER2/neu proteins, that can be found on the surfaces of all healthy breast cells. The proteins are receptors that can be activated from outside the cell, which results in HER2 gene signaling. Normal HER2 gene signaling tells HER2 proteins to grow, multiply, or repair damage in a healthy way.

But in HER2-positive breast cancer, the HER2 gene’s DNA has a mutation, or a mistake, that causes the gene to make too many copies of itself. Too many copies of the gene cause too many receptors to be created. The extra receptors result in more incoming signals. The signals tell the breast cells to grow and divide out of control, which can lead to the development of breast cancer.

While HER2-positive breast cancer often grows and spreads faster than HER2-negative breast cancer, there are many effective treatments available that work by targeting the HER2 protein.

What causes HER2-positive or HER2-low breast cancer?

The gene amplification that leads to HER2-positive or HER2-low breast cancer is somatic. This means that the mutations are not inherited: they cannot be passed down to you by your parents, nor can you pass them on to your children.

Right now, doctors don’t know what causes the HER2 gene to mutate and start making too many HER2 proteins in some breast cells. But researchers are exploring whether a person’s environment and lifestyle, or factors contained within the tumor itself, may play a role.

Video: Ask the expert: Early-stage HER2-positive breast cancer

Adrienne Waks, MD addresses audience questions on symptoms, side effects, treatment options and more related to early-stage HER2-positive breast cancer.

Listen to the recording or read the transcript.

Testing for HER2 in breast cancer

After a breast biopsy, the removed tissue sample is analyzed under a microscope. If cancer cells are present, tests are performed to learn more about them. One or more of those tests checks the cancer cells’ HER2 status. Your doctor will share the test results with you in a document called a pathology report. The test results help you and your doctor choose treatment options.

There are two types of tests that can check HER2 status:

• Immunohistochemistry (IHC) tests measure how many HER2 proteins are on the surface of the breast cancer cells.
• In situ hybridization (ISH) tests look for extra copies of HER2 genes in cancer cells. ISH tests use different kinds of microscopes to look at the cancer. Although there are several kinds available, the most commonly used ISH test is the fluorescence in situ hybridization (FISH) test.

IHC test results are shown as a numeric range that describes how many HER2 proteins are on the surface of the breast cancer cells. The results of an ISH test will be either positive or negative.

When testing is complete, the breast cancer will be described as HER2-positive, HER2-negative, or HER2-low. HER2-low is a newer designation. It is identified based on the results of IHC testing, sometimes with a follow-up ISH test. Right now, treatment for HER2-low breast cancer is available for metastatic breast cancer, but not early-stage breast cancer. That may change in the future.

In the next section, we’ll explain what HER2 test results mean.

It’s important to know that research has shown differences in how individual labs or pathologists interpret IHC test results. This is because the middle range, called borderline, could be HER2-positive or HER2-low. The American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) have issued guidelines and updates for medical professionals to help interpret borderline results.

HER2 testing is the subject of continued research as scientists work to create even more sensitive tests.

The meaning of the test results

In most cases, the cancer’s HER2 status will first be checked using the IHC test. Possible results from the IHC test include:

• HER2-negative: an IHC score of 0. HER2-targeted therapy will not be effective. Your treatment will be based on other characteristics of the cancer, such as the hormone receptor status.
• HER2-low: an IHC score of 1+ or an IHC score of 2+ followed by a negative ISH test. The HER2-targeted therapy trastuzumab deruxtecan may be effective.
• HER2-positive: an IHC score of 3+. HER2-targeted therapies are very effective in treating this cancer.

If the tumor is sent for ISH testing, the results reflect the number of extra copies of HER2 genes found in the breast cancer cells and whether the cells have more than one chromosome 17, shown as HER2/CEP17 ratio. Chromosome 17 is where the HER2 gene is located. The results of the ratio as well as the number of HER2 genes will help your doctor decide whether the tumor is ultimately considered HER2-positive or HER2-negative. A tumor with an IHC score of 2+ that tests negative with an ISH test will be considered HER2-low.

If you previously had early-stage breast cancer and it comes back (either in your breast or elsewhere in your body), or if metastatic breast cancer progresses, talk with your doctor about the possibility of a new biopsy to re-confirm HER2 receptor status. Research has shown that HER2 test results can change if the cancer recurs or progresses. For example, a tumor that was originally determined to be HER2-positive can change to HER2-negative (or vice versa) when it recurs or progresses. Knowing the cancer’s current HER2 and hormone receptor status helps you and your care team choose the treatments that can work as effectively as possible.

HR-positive, triple-positive, HER2-low, and triple-negative breast cancer

The IHC test used to check HER2 status also checks the cancer’s hormone receptor status. The test shows whether the cancer cells have receptors for the hormones estrogen, progesterone, or both. Here are the different designations:

• Hormone receptor-positive: If the cells have receptors for either hormone, the cancer is considered hormone receptor-positive, or HR-positive.
• Triple-positive: It’s possible to have breast cancer that is both HER2-positive and hormone receptor-positive. Some people, including doctors, refer to this informally as triple-positive breast cancer.
• HER2-low: HER2-low is a new designation that may be found in breast cancers that are either HR-positive or HR-negative. Doctors estimate that about 30-50% of triple-negative breast cancers are HER2-low.
• Triple-negative: If the breast cancer tests negative for estrogen, progesterone, and HER2 receptors, the cancer is called triple-negative.

If you have triple-positive breast cancer or HR-positive breast cancer, your treatment will likely include medicines that target the HER2 receptors and medicines that target the hormone receptors.

Treatment options for HER2-positive and HER2-low breast cancer

Treatments for HER2-positive breast cancer may include targeted therapies (medicines that specifically target the HER2 receptor), surgery, radiation therapy, and chemotherapy. If the breast cancer is also hormone receptor-positive, hormonal therapy will likely be part of your plan. Targeted therapy is also an option for HER2-low breast cancer that is metastatic.

The types and order of treatments can be different from person to person depending on individual needs, so don’t worry if your treatment plan seems different than someone else’s. Usually, more than one treatment is given at a time to treat HER2-positive breast cancer.

If you have early-stage breast cancer, you may also be offered pre-surgery, or neoadjuvant, treatment. Usually, if your tumor size is 1 centimeter or greater and/or cancer has traveled to lymph nodes under your arm, you will be offered neoadjuvant therapy, which can include chemotherapy given with targeted therapy before surgery. This kind of treatment is also considered for smaller tumors, although it’s not routinely given. If you do have neoadjuvant treatment, your care team will evaluate how the cancer has responded to that treatment at the time of surgery. This information is then used to guide the treatment given after surgery. Receiving treatment before surgery can make surgery less extensive by shrinking the size of the tumor.

For people diagnosed with breast cancer in the underarm lymph nodes, receiving treatment before surgery, such as chemotherapy, can sometimes help avoid having to undergo more extensive lymph node surgery (axillary lymph node dissection).

Next, we’ll talk about the targeted therapies used to treat HER2-positive and HER2-low breast cancer.

Targeted therapy for HER2-positive and HER2-low breast cancer

Targeted therapy is a type of treatment that works in different ways to treat cancer. In HER2-positive breast cancer, targeted therapies can deliver other medicines directly to the cancer, or prevent cancer cells from receiving signals to grow and multiply.

At this time, only one treatment targeting HER2, trastuzumab deruxtecan (Enhertu), is approved to treat HER2-low breast cancer. If you have been diagnosed with HER2-low metastatic breast cancer or HER2-low breast cancer has returned within six months of completing treatment, you may be eligible for this medicine.

Like all medicines, targeted therapies are categorized into classes, which describe how the medicine works. For example, HER2-targeted therapies fall into three classes:

• Monoclonal antibodies, such as trastuzumab (Herceptin) and pertuzumab (Perjeta), are molecules that attach to HER2 receptors on the outside of the cell and block signals that tell breast cancer cells to multiply and grow.
  • There are also trastuzumab biosimilars approved to treat HER2-positive breast cancer. These drugs are structurally and functionally similar to trastuzumab and work in the same way. And like trastuzumab, they are given through an IV infusion line. The benefit in some cases is that biosimilars may be more widely available and cost less. The trastuzumab biosimilars below are approved to treat all stages of HER2-positive breast cancer:
    • Trastuzumab-anns (Kanjinti)
    • Trastuzumab-dkst (Ogivri)
    • Trastuzumab-dttb (Ontruzant)
    • Trastuzumab-qyyp (Trazimera)
    • Trastuzumab-pkrb (Herzuma)
    • Trastuzumab-strf (Hercessi)

• Tyrosine kinase inhibitors (TKIs), which include lapatinib (Tykerb), tucatinib (Tukysa), and neratinib (Nerlynx), are smaller molecules that work from inside the cell, and block proteins called tyrosine kinases from telling cancer cells to grow.
• Antibody-drug conjugates, which include ado-trastuzumab emtansine (Kadcyla) and trastuzumab-deruxtecan (Enhertu), pair a targeted therapy with a chemotherapy. The targeted therapy delivers or "chauffeurs" the chemotherapy directly to breast cancer cells. This helps limit chemotherapy’s effects on healthy cells.

The FDA-approved targeted therapies for HER2-positive breast cancer are:

Each targeted therapy has unique side effects that you should discuss with your doctors. The most common are:

• Anemia
• Low white blood cell counts
• Low platelet counts (platelets are cells that help blood to clot and help wound healing)
• Chills
• Fatigue
• Headache
• Nausea
• Vomiting
• Diarrhea
• Rash

Some targeted therapies may cause heart issues. If your doctor recommends treatment with a medicine that could impact your heart health, they will also recommend you have regular heart screenings (such as an echocardiogram) to make sure you’re receiving treatment as safely as possible.

Trastuzumab deruxtecan (Enhertu) can cause serious lung side effects. If you experience breathing difficulty, let your doctor know right away.

If chemotherapy has been recommended together with targeted therapy, talk with your care team about the kinds of side effects you can expect, and how to manage them.

Learn more about targeted therapies for HER2-positive breast cancer.

Risk of recurrence

In the past, HER2-positive breast cancer was associated with a higher risk of recurrence and a higher risk of death. But the development of HER2-targeting therapies in the late 1990s and many research advances since then have significantly lowered the risk of recurrence and death. One 2021 study found that adding trastuzumab to chemotherapy for early-stage, HER2-positive breast cancer lowered both the risk of recurrence and of death by about 30%.

“With the new staging system that now includes a prognostic stage along with the anatomic stage, when breast cancer is HER2-positive, it often actually improves prognostic stage. This is a recognition of how effective the anti-HER2 treatments have been for so many people, ostensibly taking HER2+ out of the bad bucket and putting into the good bucket,” says Pallav Mehta, MD, medical oncologist at MD Anderson Cancer Center at Cooper.

If you were treated for early-stage breast cancer, it’s normal to have concerns about your long-term health after you finish treatment. As you get closer to the end of treatment, make a list of questions about your post-treatment needs and follow-up care. These questions may include:

• How often will I see you for follow-up appointments?
• Are there any other doctors or nurses I should see as part of my follow-up?
• What kinds of tests will I need after treatment is finished? How often will I need them?
• How long will it be before I start to feel like myself again?
• Are there any side effects that can arise later that I should know about?
• What kinds of things can I do to reduce my risk of recurrence?
• What new symptoms should I report to you?
• How should I let you know about new symptoms?
• What medical records should I keep after treatment is over?
• Are there any support groups you can recommend?

You can also ask about creating a survivorship care plan. This is a written document that includes information about your diagnosis, treatment, tests for monitoring your health, insurance resources, nutrition and exercise tips, and more. Your healthcare providers are there to help you understand how breast cancer affects your life, including your life after treatment ends.