Human epidermal growth factor receptor 2 (HER2) is a protein that’s found on the surface of breast cells. Its normal function is to promote cellular growth and division.

Some breast cancers have higher-than-normal levels of HER2. These are called HER2-positive breast cancers. However, only a low percentage of breast cancers are HER2-positive.

Most breast cancers are HER2-negative. According to the National Cancer Institute (NCI), an estimated 78 percent of breast cancers are HER2-negative and don’t produce too much HER2.

Continue reading below as we explore what it means to have HER2-negative breast cancer. We’ll cover the different HER2-negative subtypes, as well as diagnosis, treatment, and outlook.

HER2-negative breast cancer has a couple of different subtypes. Let’s take a look at these now.

HER2-negative, hormone receptor-positive

In addition to having a HER2 status, breast cancer cells also have a hormone receptor (HR) status. Estrogen and progesterone hormone receptors can be found on breast cancer cells. It’s worth noting that these receptors can also be found on healthy breast cells.

A breast cancer is HR-positive when it has receptors for estrogen, progesterone, or both. Estrogen receptor-positive cancers are more common and are estimated to occur in about 75 percent of all breast cancers.

In HR-positive cancers, estrogen or progesterone can bind to the hormone receptors on breast cancer cells, helping to promote their growth and spread. As such, treatments for HR-positive breast cancers often targets hormone receptors.

Overall, HER2-negative, HR-positive breast cancers are the most common subtype of breast cancer. The NCI estimates that between 2014 and 2018, 68 percent of breast cancers in the United States were this subtype.

HER2-negative, hormone receptor-negative

It’s also possible for a breast cancer to be negative for both HER2 and for hormone receptors. A breast cancer that’s HER2-negative, HR-negative is called triple-negative breast cancer.

This subtype of breast cancer is less common. The NCI estimates that between the years of 2014 and 2018, only 10 percent of breast cancers were this subtype.

Because triple-negative breast cancer lacks both HER2 and hormone receptors, it doesn’t respond to treatments that target these factors. Additionally, it tends to recur more often than other subtypes of breast cancer.

If you’ve been newly diagnosed with breast cancer, the HER2 status of your tumor will be determined. This is performed on a tissue sample collected from a biopsy or surgery.

HER2 status can be tested in two ways:

  1. Immunohistochemistry (IHC): An IHC test uses a dye to stain HER2 protein on the surface of the tissue sample.
  2. Fluorescence in situ hybridization (FISH): A FISH test uses special labeling molecules that bind to HER2 proteins. When they attach to HER2 proteins in a tissue sample, they glow in the dark.

Generally speaking, testing HER2 status with FISH can take longer and be more expensive. Because of this, IHC is often used initially. The results of this test are reported as a number value from 0 to 3+:

  • 0 or 1+: Low or normal levels of HER2 are detected. The cancer is considered to be HER2-negative.
  • 2+: The HER2 status of the cancer can’t be determined. It’s likely that your doctor will recommend retesting with FISH to determine the cancer’s HER2 status.
  • 3+: High levels of HER2 are found. The cancer is considered to be HER2-positive.

If a FISH test is done, the results are reported as either positive or negative. A test that comes back FISH negative is considered to be HER2-negative.

The treatment of HER2-negative breast cancer can also depend on HR status. Let’s examine some of the potential treatment options for each subtype of HER2-negative breast cancer.

Hormone receptor-positive treatments

HER2-negative breast cancer that’s HR-positive can be treated with hormone therapy. This blocks the actions of hormones, stopping the cancer from growing.

Most of the drugs that are used in hormone therapy target estrogen. Some examples include:

  • tamoxifen (Soltamox) or toremifene (Fareston): selective estrogen receptor modulators (SERMs) that block estrogen receptors on breast cancer cells
  • fulvestrant (Faslodex): a selective estrogen receptor degrader (SERD) that both blocks and decreases levels of estrogen receptors throughout the body
  • aromatase inhibitors: lower estrogen levels in the body, and include:

Another way to block the action of estrogen is to reduce or shut down the ovaries’ activity. This is called ovarian suppression and can be accomplished by:

  • luteinizing hormone-releasing hormone (LHRH) analogs, which shut down the ovaries (often called chemical or medical menopause)
  • surgical removal of the ovaries (oophorectomy or surgical menopause)
  • chemotherapy drugs, which may reduce or end ovarian production of estrogen

Some types of targeted therapy may also be used in HER2-negative, HR-positive breast cancer. Targeted therapy drugs bind to specific proteins on or in cancer cells. Some that may be used for this subtype of breast cancer are:

  • CDK4/6 inhibitors, which can be used along with hormone therapy and block the activity of growth-promoting proteins called cyclin-dependent kinases (CDKs). They include drugs like:
    • ribociclib (Kisqali)
  • the PI3K inhibitor alpelisib (Piqray), which is used with fulvestrant to inhibit cancer cell growth in individuals with mutations in the PIK3CA gene
  • the mTOR inhibitor everolimus (Afinitor), which can help block cancer cell and blood vessel growth
  • PARP inhibitors, which block the DNA repair process in cancer cells with BRCA1 or BRCA2 mutations, causing them to die, and include the drugs olaparib (Lynparza) and talazoparib (Talzenna)

Other potential treatment options for HER2-negative, HR-positive breast cancers include:

  • Surgery. Many people that are diagnosed with breast cancer have some type of surgery, such as lumpectomy or mastectomy, to remove the cancer.
  • Immunotherapy. Immunotherapy helps your immune system to better respond to the cancer.
  • Chemotherapy. Chemotherapy uses strong drugs to kill cancer cells or stop them from dividing.
  • Radiation therapy. Radiation therapy uses high energy radiation to either kill cancer cells or slow their growth. It’s often used after surgery to help prevent the cancer from coming back.

Hormone receptor-negative treatments

Breast cancer that’s triple-negative won’t respond to some of the treatments used for HER2-negative, HR-positive breast cancer. This includes hormone therapy and many targeted therapies.

As with many breast cancers, the first potential treatment option for this subtype is surgery. This may or may not be followed by radiation therapy to help prevent the cancer from coming back.

If surgery isn’t possible or doesn’t remove all of the cancer, chemotherapy is the main systemic treatment option for triple-negative breast cancer. Chemotherapy may also be given along with the immunotherapy drug pembrolizumab (Keytruda).

Targeted therapy with PARP inhibitors (olaparib, talazoparib) may be used in people with triple-negative breast cancer and BRCA1 or BRCA2 mutations. This is typically given when cancer hasn’t responded to chemotherapy.

Another targeted therapy drug called sacituzumab govitecan (Trodelvy) may be used to treat triple-negative breast cancer that has metastasized, or spread, to other parts of the body.

In addition to HER2 and HR status, there are also several other factors that can impact breast cancer treatment. These include:

  • the specific type of breast cancer
  • the stage of the cancer
  • how quickly the cancer is growing
  • whether or not this is a new diagnosis or a cancer recurrence
  • which types of treatments have already been used, if any
  • if certain genetic changes are present, such as those in BRCA1 or BRCA2
  • your age and overall health
  • whether or not you’ve reached menopause
  • your personal preference

Your doctor will take all of these different factors into account when determining what type of treatment to recommend for your individual situation.

HER2-positive breast cancer cells have high levels of HER2 on their surface. This is in contrast to HER2-negative breast cancers, in which cells have low or normal levels of HER2.

The HER2 protein promotes cellular growth. Because of this, HER2-positive breast cancers tend to grow and spread more quickly than other types of breast cancers.

Breast cancers that are HER2-positive also have additional treatment options available. These are targeted therapies that specifically target the HER2 protein on cancer cells.

It’s also important to note that some research has found that breast cancers may switch HER2 and HR status over time. This is why it’s important to reassess these markers if a cancer recurs.

Is HER2-negative better than HER2-positive?

You may be wondering if having HER2-negative breast cancer is better than having HER2-positive breast cancer. There’s no straightforward answer to this question, as both types of breast cancer have their own upsides and downsides.

For example, HER2-positive breast cancer is likely to grow and spread more rapidly. However, it also has many available treatment options, particularly if it’s also HR-positive.

Meanwhile, HER2-negative breast cancer grows and spreads more slowly than HER2-positive breast cancer. However, it also has less potential treatment options, especially if it’s HR-negative (triple-negative).

Further, other additional factors besides HER2 and HR status play into breast cancer outlook. Some of these include individual factors like your age and overall health. Other factors that are used in staging are also important, such as:

  • the size of the tumor
  • whether or not the cancer has spread to neighboring lymph nodes
  • whether or not the cancer has spread outside of the breast

Cancer survival statistics are typically reported using a 5-year survival rate. This is the percentage of individuals that are still living 5 years after their diagnosis.

Survival rates can vary based off of the subtype of breast cancer that you have. A publication from the American Cancer Society reports 5-year survival rates for HER2-negative breast cancers as:

  • 92 percent for HER2-negative, HR-positive breast cancer
  • 77 percent for triple-negative breast cancer

Keep in mind that HER2 and HR status aren’t the only factors that can influence outlook. Other important factors at diagnosis include:

  • the stage of the cancer
  • the specific type of breast cancer
  • your age and overall health

The outlook for HER2-negative breast cancer can depend on its HR status. HER2-negative breast cancers that are HR-positive typically have a better outlook than those that are triple-negative.

The stage of the cancer also plays an important role. For example, HER2-negative cancers that are localized to the breast have a better outlook than those that have spread to the lymph nodes or to more distant tissues.

Remember that statistics on outlook or survival are determined based off of the outcomes of a large amount of people with breast cancer over many years. They don’t take into account individual factors or very recent advances in treatment.

Your doctor will help you to better understand what your HER2-negative status means for you on an individual level. Don’t hesitate to voice any questions or concerns that you may have regarding your diagnosis or treatment options.