• The first targeted treatment for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, trastuzumab (Herceptin), was approved in 1998.
• Since then, researchers have continued to find new and better ways to combine trastuzumab with other therapies.
• These discoveries have significantly improved the once poor survival rate, helping people with early-stage HER2-positive breast cancer live longer, healthier lives.

As doctors and researchers learn more about breast cancer, they continue to develop new ways to treat it. The treatment of HER2-positive breast cancer has significantly improved since the 1990s, with new advances made nearly every year.

Before the U.S. Food and Drug Administration (FDA) approved trastuzumab (Herceptin) in 1998, many people with HER2-positive breast cancer, a subtype of breast cancer, had a poor prognosis (outlook). Now, new therapies help many people reach remission (when the disease is less active or not detectable) and live longer, healthier lives. These treatments have become more effective and convenient as well as safer in recent years.

In this article, we’ll discuss the discovery of the HER2 protein and how the development of targeted therapies has changed how we treat early-stage HER2-positive breast cancer, making it easier to target and fight the disease more effectively.

If you’re unsure about your HER2 status, ask your oncologist if you are HER2-positive or HER2-negative, as that information will affect your treatment options.

History of HER2 in Breast Cancer

In 1987, Dennis Slamon, M.D., and his colleagues reported that high levels of the HER2 protein were seen in around 30 percent of breast cancers. (A 2020 study places this figure at around 20 percent.) HER2 sends signals to cells, telling them to grow and divide. In HER2-positive breast cancer, tumor cells have too much of this protein, so they receive too many signals. As a result, the cells grow and divide uncontrollably, creating a fast-growing tumor.

Researchers found that HER2-positive breast cancer was more likely to recur (return after treatment) and metastasize (spread to other parts of the body). It was also associated with higher death rates. As a result, they concluded that the HER2 protein was important in breast cancer development and progression. Researchers began working on new treatments to block HER2 and stop breast cancer cells from growing and dividing.

1992-2006: Development and Approval of Trastuzumab

In 1992, the antibody trastuzumab was developed. Antibodies are proteins made by the immune system. In this case, trastuzumab is a laboratory-engineered antibody, also known as a monoclonal antibody. This was the first targeted treatment for HER2-positive breast cancer. Trastuzumab attaches to the HER2 protein, preventing it from sending signals to cells.

Clinical trials showed that combining trastuzumab with chemotherapy slowed metastatic HER2-positive cancer growth better than chemotherapy alone. The FDA approved trastuzumab in 1998.

Later, clinical trials showed the same results in people with early-stage HER2-positive breast cancer. In 2006, the FDA approved trastuzumab as an adjuvant therapy for treating early-stage HER2-positive breast cancer. Adjuvant therapy is given after surgery to kill any remaining cancer cells. According to the National Cancer Institute, trastuzumab has improved early-stage HER2-positive breast cancer survival rates by more than 30 percent.

Trastuzumab Treatment Today

Trastuzumab is a common choice for treating early-stage HER2-positive breast cancer. This drug may be combined with chemotherapy before surgery as a neoadjuvant therapy to help shrink tumors, used after surgery as an adjuvant therapy, or both.

Trastuzumab is given intravenously (IV, through a vein) at an infusion center or a hospital for 30 to 90 minutes. It can be given with several chemotherapy regimens, such as:

• Cyclophosphamide (Cytoxan)
• Anthracyclines, including doxorubicin (Adriamycin)
• Carboplatin (Paraplatin)
• Taxanes, including docetaxel (Taxotere) and paclitaxel (Abraxane; previously sold as Taxol in the U.S.)

Researchers continue to find new and better ways to use trastuzumab and combine it with other therapies to improve responses. Not only are these combinations more effective, but some formulations are also now available as injections. These therapies are more convenient and tend to be better tolerated.

2017-2020: Additional Targeted Therapies

From 2017 to 2020, scientists developed additional targeted therapies for treating HER2-positive breast cancer.

Pertuzumab

Pertuzumab (Perjeta), another monoclonal antibody, works in a slightly different way than trastuzumab does. This newer drug blocks HER2 from sending growth signals. Pertuzumab was originally approved in 2012 for treating HER2-positive metastatic breast cancer in combination with trastuzumab and docetaxel.

Later, researchers ran studies investigating the same drug combo in people with early-stage HER2-positive breast cancer who were at a higher risk of recurrence. Many of these people had hormone receptor-negative breast cancer, meaning their cancer cells didn’t have progesterone or estrogen receptors. These cancers are harder to treat compared to hormone receptor-positive breast cancers because they have fewer receptors to block with different therapies.

The clinical trials showed that treatment with pertuzumab, trastuzumab, and chemotherapy prevented recurrence better than trastuzumab and chemotherapy. In 2017, the FDA approved the triplet therapy for treating early-stage HER2-positive breast cancer.

Neratinib

Other medications used to treat many types of cancer include tyrosine kinase inhibitors (TKIs). This class of drugs prevents certain proteins known as tyrosine kinases from sending growth signals to cancer cells. HER2 is one example of a tyrosine kinase.

Neratinib (Nerlynx) is a TKI that blocks HER2 and other proteins. The FDA approved neratinib in 2017 to prevent recurrence in people with HER2-positive early breast cancer that had been treated with surgery and trastuzumab for at least one year. Neratinib is typically prescribed to be taken for one year.

Ado-Trastuzumab Emtansine

Researchers have also discovered in recent years that monoclonal antibodies can deliver other medications directly to tumor cells. These pairings of a delivery antibody and a drug are known as antibody-drug conjugates (ADCs), and they’re used to treat several types of cancer.

The ADC ado-trastuzumab emtansine (Kadcyla), also known as T-DM1, combines trastuzumab with the chemotherapy drug emtansine (DM1). This medication blocks HER2 from sending growth signals and delivers chemotherapy directly to breast cancer cells.

The FDA approved ado-trastuzumab emtansine in 2019 for treating early-stage HER2-positive breast cancer. Specifically, this drug is used as an adjuvant treatment, whereas trastuzumab and chemotherapy are given before surgery to help shrink the tumor. ADCs tend to be better tolerated, leading to fewer side effects, than traditional chemotherapy drugs.

Trastuzumab/Hyaluronidase-Oysk

Trastuzumab/hyaluronidase-oysk (Herceptin Hylecta) is a form of trastuzumab given by subcutaneous injection (underneath the skin) rather than IV infusion. Hyaluronidase is an enzyme that thins the connective tissue where the drug is injected, which helps the body better absorb the medication. Every three weeks, this treatment plus chemotherapy is given for two to five minutes. This is much faster than an IV infusion of trastuzumab, which can take up to an hour and a half.

Results from clinical trials show that the injectable form of trastuzumab is as safe and effective as IV trastuzumab. In 2019, the FDA approved trastuzumab/hyaluronidase-oysk for treating HER2-positive breast cancer that either has spread to the lymph nodes (node-positive) or hasn’t spread (node-negative) but has a high risk of recurrence. Injectable therapies continue to be an effective and simpler treatment option for early-stage breast cancer.

Pertuzumab, Trastuzumab, and Hyaluronidase-Zzxf

A combination of pertuzumab, trastuzumab, and hyaluronidase-zzxf given with chemotherapy can shrink a tumor before surgery or kill the remaining cancer cells after surgery. This combination of drugs was initially given intravenously in an infusion clinic — like chemotherapy — and receiving a dose could take as long as eight hours.

In 2020, the FDA approved Phesgo, an injectable combination of pertuzumab, trastuzumab, and hyaluronidase-zzxf, for treating early-stage or metastatic HER2-positive breast cancer. With this new formulation, the combination drug can be given at home by a health care professional in minutes as a subcutaneous injection. It no longer requires a trip to an infusion center lasting several hours. Clinical studies have found that this therapy is as safe and effective as IV pertuzumab and trastuzumab.

Other Therapies for HER2-Positive Breast Cancer

Several other targeted therapies are available to treat HER2-positive breast cancer. Some are approved for treating cancer that has spread to other parts of the body, and others may be used when surgery isn’t possible. If your early-stage breast cancer progresses or returns, you may receive one of these therapies. Examples include:

• Fam-trastuzumab deruxtecan-nxki (Enhertu) — An ADC that’s used to treat metastatic HER2-positive breast cancer or early-stage cancer that returned within six months of completing treatment
• Tucatinib (Tukysa) — A TKI that’s used to treat HER2-positive breast cancer that can’t be treated with surgery or has metastasized
• Lapatinib (Tykerb) — A TKI that’s used to treat advanced HER2-positive breast cancer, usually given with the chemotherapy drugs capecitabine and trastuzumab
• Margetuximab-cmkb (Margenza) — A monoclonal antibody similar to trastuzumab that’s used with chemotherapy in metastatic HER2-positive breast cancer

New therapies for treating HER2-positive breast cancer continue to be studied in clinical trials. Doctors and researchers specializing in oncology hope these advances will keep improving overall survival rates with even more tolerable and easily administered treatments.

If you have questions about HER2 therapy or your HER2 status, schedule a follow-up appointment with your oncologist.

Talk With Others Who Understand

MyBCTeam is the social network for people with breast cancer and their loved ones. On MyBCTeam, more than 69,000 members come together to ask questions, give advice, and share their stories with others who understand life with breast cancer.

What types of therapies have you received for HER2-positive breast cancer? Do you still have questions about how early-stage HER2-positive breast cancer is treated? Start a conversation by posting on your Activities page.