Targeted Therapy: Breakthrough Treatments for Metastatic Breast Cancer

“Amazing changes have happened in options for treatment for metastatic disease.”

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Metastatic breast cancer is the most advanced stage of breast cancer (also known as stage IV), which means the cancer has spread beyond the breast to other distant parts of the body. While metastatic breast cancer can’t be cured and is more difficult to treat than early-stage breast cancer, there are many treatment options for metastatic breast cancer available, such as chemotherapy, hormonal therapy, and targeted therapy.

These treatment advances are changing the prognosis and outcomes for metastatic breast cancer patients.

“Metastatic breast cancer used to be considered a death sentence and that’s absolutely not true anymore,” says Amy Tiersten, MD, a hematologist and oncologist at the Mount Sinai Hospital in New York City. “Amazing changes have happened in options for treatment for metastatic disease.”

How Targeted Therapies for Metastatic Breast Cancer Work

Researchers have discovered certain characteristics that help cancer cells (or other cells near them) grow and thrive. This has led to the development of drugs that “target” these differences from normal cells, a class known as targeted therapy.

Targeted therapies are generally less likely than chemotherapy to harm normal, healthy cells. Many targeted drugs go after the cancer cells’ inner workings—what makes them different from normal, healthy cells—while leaving most healthy cells alone. These drugs tend to have side effects different from standard chemo drugs. Depending on the type of breast cancer, however, doctors may use targeted therapies along with chemotherapy for maximum effectiveness.

“The age of targeted therapies is really about understanding what pathways make a cancer cell proliferate more than a normal cell,” says Dr. Tiersten. “The medications that have been developed to target those specific pathways [are] absolutely incredible.”

Understanding Breast Cancer Receptors

When you look at breast cancer cells under a microscope, there are currently three possible receptors that you may find sitting on the surface: an estrogen receptor, progesterone receptor, or a growth-promoting protein called HER2/neu.

About two out of three breast cancers are hormone receptor-positive (ER-positive or PR-positive), which means their cells have estrogen or progesterone receptors. For about one in five women with breast cancer, the cancer cells have too much of HER2/neu (also called HER2) on their surface. These cancers, known as HER2-positive breast cancers, tend to grow and spread more aggressively.

“You can have some of those receptors in combination [or] one of the receptors, [but] having any of the receptors is a good thing,” says Dr. Tiersten. “Think of it as the receptor being a target, and we have targeted weapons, specific to those receptors.”

Breast cancer cells that don’t have any of these receptors are called triple-negative breast cancer.

For breast cancer cells that have receptors, doctors will recommend a targeted therapy drug depending on the type—estrogen receptor, progesterone receptor, or HER2/neu—to help stop that cell from growing.

Treating Hormone Receptor-Positive Breast Cancer with Hormone and Targeted Therapy

Hormone receptor-positive (ER-positive or PR-positive) breast cancer cells grow in response to estrogen and progesterone; they’re dependent upon these hormones for cell growth and cell division. If the cancer is hormone receptor-positive, the first course of treatment is hormone therapy using antiestrogen medications.

Antiestrogen medications (hormone therapy): “Antiestrogen medications deprive [these cells] of that estrogen and thereby starve them of what they used to grow and replicate,” says Dr. Tiersten. For hormone receptor-positive breast cancer cells, the antiestrogen hormone therapies aim to either:

  • Block estrogen production. Drugs called aromatase inhibitors block the activity of an enzyme called aromatase, which the body uses to make estrogen. Examples of aromatase inhibitors approved by the FDA for metastatic breast cancer are anastrozole (Arimidex®) and letrozole (Femara®), both of which temporarily deactivates aromatase.
  • Block estrogen’s effects. Selective estrogen receptor modulators (SERMs) bind to estrogen receptors to prevent estrogen from binding. SERMs approved by the FDA for treatment of metastatic breast cancer are tamoxifen (Nolvadex®) and toremifene (Fareston®). Tamoxifen has been used for more than 30 years to treat hormone receptor positive breast cancer. “Tamoxifen is one of the most well-known, gold standard [antiestrogen medications],” says Dr. Tiersten.

For women with hormone receptor-positive cancer, using targeted therapies along with hormone therapy is often helpful. Certain targeted therapy drugs can make hormone therapy even more effective, although these targeted drugs might also add to the side effects.

CDK4/6 inhibitors: CDK4 and CDK6 are enzymes that are important in cell division. CDK4/6 inhibitors are a newer class of drugs designed to interrupt the growth of cancer cells. The CDK4/6 inhibitors abemaciclib (Verzenio®), palbociclib (Ibrance®) and ribociclib (Kisqali®) are FDA-approved for breast cancer treatment. Each drug can be used in combination with antiestrogen therapy to treat hormone receptor-positive metastatic breast cancers. Abemaciclib may also be used alone without antiestrogen therapy.

mTOR inhibitors: Everolimus is a drug that targets what’s called the mTOR pathway, which is an important pathway in terms of growth and proliferation,” says Dr. Tiersten. “They’ve primarily been studied in combination with antiestrogen medications and they appear to increase the chance of response and duration of response to anti-estrogen medications,” says  Dr. Tiersten. “They may reverse the emerging resistance that patients can develop to anti estrogen medications.” The medication Afinitor® is FDA-approved for metastatic breast cancer.

Treating HER2-Positive Breast Cancer with Targeted Therapy

For HER2-positive breast cancer cells, there are incredibly effective drugs that target the HER2/neu receptor, says Dr. Tiersten.

Anti-HER2 medications: These include trastuzumab (Herceptin®) or pertuzumab (Perjeta®), which are antibodies to the HER2/neu protein. Trastuzumab attaches to the HER2/neu protein, which slows or stops its growth. Trastuzumab (Herceptin®) has been used in combination with docetaxel, a traditional chemotherapy drug, to treat women with metastatic breast cancer that overexpresses the protein HER2/neu. Pertuzumab blocks the ability of HER2-positive breast cancer cells to receive signals that tell the cells to grow.

T-DM1: A new category of anti-HER2 medications is called T-DM1 or ado-trastuzumab emtansine. In combination with chemo, T-DM1 treats HER2-positive, locally advanced-stage or metastatic breast cancer that’s previously been treated with Herceptin and a taxane chemotherapy. T-DM1 blocks HER2-positive breast cancer cells from having the ability to receive signals telling the cells to grow. “It’s a very interesting design of a drug because it’s a very potent chemotherapy, but it attaches it to the Herceptin molecule, so it makes the chemo also very targeted and spares more normal tissue,” says Dr. Tiersten. The FDA has approved the drug Kadcyla® for the treatment of HER2-positive metastatic breast cancer.

Treating Triple-Negative Breast Cancer

Triple-negative breast cancer means that none of the common receptors—estrogen, progesterone, or HER2 / neu—are present on the breast cancer cells. For triple-negative breast cancer, the mainstay of treatment is chemotherapy, since there are no receptors on the breast cancer cell to target.

“However, there are tons of clinical trials looking at the role of newer biologic or targeted therapy to augment the effectiveness of chemotherapy or even use in lieu of chemotherapy for triple negative breast cancers,” says Dr. Tiersten.