HER2 and Breast Cancer: Testing and Targeted Therapies

The treatment of breast cancer is evolving rapidly. The new classification of HER2 positive Vs HER2 negative breast cancer has a lot of clinical significance.

Generally, HER2-positive breast cancers are very aggressive and spread rapidly. However, with the new HER2-targeted therapies, especially trastuzumab (Herceptin), the mortality rates have markedly gone down.

Since October is the month of breast cancer awareness, it is essential to know about different types of breast cancer. Here we have a detailed discussion about HER2-positive breast cancer.

What is HER2 status?

HER2 stands for human epidermal growth factor receptor 2.

Approximately 15% to 20% of all breast cancers contain an enhanced level of this protein and such breast cancer cases are called HER2-positive breast cancer.

You may ask your physician about your HER2 status.

What Is HER2-Positive Breast Cancer?

HER2, also known as human epidermal growth factor receptor 2, is overexpressed in all breast cells and is tested for.

HER2 proteins are receptors that regulate how cells divide and proliferate. Breast cells can grow out of control when there are too many HER2 receptors present in the breast tissue (overexpression). However, uncontrolled growth might develop into a tumor.

Breast cancer that has been shown to be HER2-positive has the propensity to spread (metastatic breast cancer) and develop more quickly (recur).

Although HER2-positive breast cancer can be aggressive, it also responds better to HER2 protein-targeted therapies.

HER2-positive breast cancer is not related to any particular symptoms or breast cancer risk factors, while some research indicates that HER2-positive status is more prevalent in younger women.

HER2 testing

You might require this test if you have been told you have breast cancer in order to determine if it is HER2-positive or HER2-negative.

You might require this test if you have HER2-positive breast cancer and are already receiving treatment for it to:

• Check to see whether your therapy is effective. You may be responding to therapy if your HER2 levels are normal. High levels might indicate that the therapy is ineffective.
• Check to see if the cancer has returned after therapy.

Taking a sample

The majority of HER2 tests require performing a biopsy to get a sample of tumor tissue. There are three primary categories of biopsy techniques:

• Fine Needle Aspiration (FNA) of the Breast

The FNA will be performed while you are lying on your back, and you must remain motionless during that time.

You can experience some discomfort from the ultrasound wand and when the needle is inserted if ultrasonography is utilized.

The physician will employ the syringe to extract a little quantity of tissue or fluid after the needle is in the proper location.

There may be several instances of this. Following the treatment, a sterilized dressing or bandage is placed over the region.

Each biopsy sample typically requires 15 seconds to get. If ultrasonography is utilized, the complete operation typically takes between 20 and 30 minutes.

• Core needle biopsy

Any form of CNB will begin with a tiny needle being used to inject a local anesthetic, a numbing agent, into the region to be biopsied.

The breast is then occasionally chopped just a little bit—about a quarter inch. Through this opening, the biopsy needle is inserted into the breast tissue to extract a sample of the tissue.

As the needle is inserted, you can feel pressure. Again, an imaging examination could be performed to direct the needle to the proper location.

• Surgical Breast Biopsy

In most cases, you will also get an intravenous (IV) sedative to make you sleepy combined with local anesthesia (numbing medication).

Another choice is to have general anesthesia (when you are given medication to put you in a deep slumber and not experience discomfort) while the biopsy is being performed.

The doctor makes an incision on the breast and removes the problematic region. After a surgical biopsy, you’ll probably require sutures, and bleeding may be stopped temporarily with pressure. A sterile dressing is then applied to the region.

After a sample is taken through biopsy, the following tests may be performed.

Immunohistochemistry (IHC) test

The most popular test to determine if cancer cells in a tumor have an excessive amount of the HER2 receptor protein on their surface is IHC.

The cells get too many signals instructing them to expand and divide when there are too many HER2 receptors.

IHC identifies the overexpression of HER2-positive breast cancer cells. The CAP recommends testing via the FISH method if the IHC result is indeterminate.

​Fluorescence In Situ Hybridization (Fish)

Fluorescence in situ hybridization, often known as FISH, is a laboratory-based test that focuses on the chromosomes that make up each cell’s genetic makeup to provide a more comprehensive picture of a cancer diagnosis.

FISH identifies the amplification of HER-2-positive breast cancer cells.

Symptoms of HER2 breast cancer

The most typical sign of breast cancer is a lump that feels different from the surrounding tissue.

The following are additional signs of HER2-positive breast cancer:

• A modification to the breast form
• Having breast or nipple pain
• Secretions from the nipple (not breast milk)
• Nipple or breast skin color or thickness
• Skin rashes or dimples
• Breast enlargement

During a self-examination, you could have detected a change in your breasts. Or perhaps mammography you had revealed a tumor.

Causes of HER2 breast cancer

The specific causes of breast cancer are unknown to doctors. According to experts, a mix of factors, such as genetics, environment, and lifestyle, may be to blame.

A defective copy of the HER2 gene cannot be inherited from a parent and cannot be passed onto offspring.

What are HER-2 targeted therapies for the treatment of breast cancer:

The main drug that is being used to treat HER-2-positive breast cancer is Trastuzumab. It is combined with endocrine therapy and chemotherapy.

There are 4 biosimilars of Trastuzumab that have been approved by the FDA. These include:

• Herzuma
• Ogivri
• Ontruzant
• Trazimera

A subcutaneous formulation has also been approved recently by the name of Herceptin Hylecta which is a combination of Trastuzumab and Hyaluronidase. It is administered as a slow subcutaneous injection rather than given intravenously.

Other HER-2 targeted therapies include:

• Monoclonal antibodies:

  • Pertuzumab

• Tyrosine kinase inhibitors:

  • Neratinib
  • Turacitinib

• Antibody-Drug Conjugate:

  • ado-trastuzumab emtansine,
  • trastuzumab deruxtecan

The latest approved combination drug is Phesgo (Pertuzumab/Trastuzumab/Hyaluronidase).

In patients who are not tolerating Trastuzumab or are resistant to it, Lapatinib (Tykerb) is used. Lapatinib targets both HER-2 and EGFR.

Lapatinib is orally available. It is a small molecule tyrosine kinase inhibitor that crosses the blood-brain barrier and can be used to treat HER-2-positive breast cancer with brain metastasis.

In Conclusion:

HER-2-positive breast cancer is an aggressive form of breast cancer. Trastuzumab is a drug that targets HER-2 proteins and is commonly implicated in the treatment of HER-2-positive cancers.

As more targeted therapies are being investigated, the treatment of HER-2-positive aggressive breast cancer has dramatically changed.

The survival rates have increased by more than 50%. The table below summarizes the drugs that target HER-2-positive breast cancers [Ref]: