MNT Investigates: Anti-HER2 drugs and the fight against metastatic breast cancer

In In The News by Barbara Jacoby

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From: medicalnewstoday.com

HER2-positive breast cancer occurs when cancer cells have excessive amounts of a growth-promoting protein called human epidermal growth factor receptor 2 (HER2). The protein causes the tumor cells to grow and multiply, making these breast cancers aggressive and fast-spreading.

About 1 in 5 women with breast cancer have HER2-positive breast cancers.

Anti-HER2 drugs are therapies developed to target HER2 proteins and block their function through different mechanisms. Because they target HER2 proteins specifically, they are considered a form of targeted therapy.

This article explores the role of these medications in treating metastatic breast cancer (MBC) and how they may impact future treatments.

Available anti-HER2 drugs

There are two classes of anti-HER2 drugs currently available: monoclonal antibodies and kinase inhibitors.

Monoclonal antibodies

Monoclonal antibodies are laboratory-made molecules designed to mimic the immune system’s ability to attack harmful cells.

For the treatment of HER2-positive breast cancer, monoclonal antibodies attach themselves to HER2 proteins on the cancer cells, stopping the cells from growing and multiplying.

Some monoclonal antibodies are “naked,” which means that they enter the bloodstream alone. Others are antibody-drug conjugates, which means that they are a combination of a monoclonal antibody and another drug.

“All of these drugs are very effective in different ways at targeting the HER2 marker on tumor cells and preventing replication of tumor cells,” Dr. Jessica Sullivan, a medical oncologist specializing in breast cancer at the California Cancer Associates for Research & Excellence, told Medical News Today.

Naked monoclonal antibodies include:

  • Trastuzumab (Herceptin): This drug binds to the outer surface of HER2 proteins and inhibits their ability to receive growth signals. Doctors often give it alongside chemotherapy, but they can also give it on its own. A doctor will administer this drug either through a vein or into the thigh.
  • Margetuximab (Margenza): Margetuximab also attaches itself to the HER2-expressing tumor cells and inhibits their ability to receive growth signals. It also helps immune cells better bind to HER2-positive breast cancer cells, improving their capacity to destroy the cancer cells. Doctors typically give it in combination with chemotherapyTrusted Source to treat metastatic HER2-positive breast cancer when two or more other anti-HER2 therapies have not been effective. A person will receive it intravenously.
  • Pertuzumab (Perjeta): Pertuzumab attaches itself to HER2-positive tumor cells and blocks the downstream signals that stimulate growth. It has approval for use in combination with trastuzumab. Pertuzumab binds to a different HER2 portion than trastuzumab, so when a doctor gives it in combination with trastuzumab, it blocks HER2 growth signaling more strongly. A doctor will administer it intravenously.

There are two components to antibody-drug conjugates. “The first component is the antibody, which is specific for the HER2 protein expressed on the surface of the tumor cells,” Dr. Patrick J. Ward, Ph.D., a medical oncologist and the co-director of Oncology Hematology Care’s (OHC) Research Department, explained.

“The second component is chemotherapy, which is conjugated to the antibody. Functionally, what happens is that the antibody binds to the HER2 protein and is internalized into the tumor cell. Once this happens, the chemotherapy is released within the tumor cell. This provides exquisite specificity for drug delivery while at the same time vastly minimizing toxicity.”

Available antibody-drug conjugates include fam-trastuzumab deruxtecan (Enhertu) and ado-trastuzumab emtansine (Kadcyla)

Enhertu consists of a monoclonal antibody and a topoisomerase I inhibitor, which is a type of chemotherapy drug. Doctors typically use this drug to treat breast cancer that is not removable with surgery or MBC that has previously been unresponsive to at least two other anti-HER2 drugs. A person will receive Enhertu through an intravenous infusion.

Kadcyla incorporates the HER2-targeted actions of trastuzumab with a chemotherapy drug called emtansine. Together, they inhibit cell division and activate cell death. A person will receive Kadcyla intravenously.

Kinase inhibitors

HER2 belongs to a family of enzymes called kinases, which help regulate the signaling, division, and growth of cells in the body. Kinase inhibitors block the actions of kinases such as HER2.

The three approved kinase inhibitors for the treatment of HER2-positive MBC are:

  • lapatinib (Tykerb)
  • neratinib (Nerlynx)
  • tucatinib (Tukysa)

Doctors typically use these alongside a chemotherapy drug. People take them as oral medications daily.

Side effects of anti-HER2 treatments

Some anti-HER2 drugs can lead to serious side effects, such as heart damage. The risk of heart problems is higher when doctors combine anti-HER2 drugs with certain chemotherapy drugs.

Kinase inhibitors specifically can cause severe diarrhea, hand-foot syndrome, and liver problems.

Also, Enhertu can sometimes cause interstitial lung disease, pneumonitis, and a decreased neutrophil count.

The future of anti-HER2 treatments

Research is ongoing to determine the effectiveness of other treatments or combination treatments for HER2-positive MBC.

“What we are likely to see are combinations. Combinations of anti-HER2 therapy with other agents that target other aspects of the HER2 pathway within the tumor cell or parallel pathways within the tumor cell,” Dr. Ward, who is also the principal investigator for breast cancer clinical trials at OHC, told MNT.

“And combinations of anti-HER2 therapy with immunotherapy, too. We will probably also see progress in identifying, exploring, and finding ways to circumvent resistance mechanisms.”

To make this future a reality, researchers will have to overcome a number of challenges, such as serious side effects and therapy resistance, during drug development.

“Most of us are still learning about the side effects from newer agents and how best to manage them. Some combinations of therapies may be useful in vitro but cause a side effect profile that is not reasonable in humans,” Dr. Sullivan said.

People can consider joining a clinical trial to help researchers discover new treatments by visiting ClinicalTrials.gov or talking with a doctor.

”Clinical trials are the only way for us to gain information on tolerability, dosing, progression-free survival, [and] overall survival,“ Dr. Sullivan said.

The takeaway

Anti-HER2 drug approvals have changed the landscape of MBC treatment. The first anti-HER2 drug, Herceptin, received approval in 1998 to treat HER2-positive breast cancer. Since then, many more anti-HER2 drugs have joined the list of approved treatments.

“In the past couple of years, the treatment options have expanded further, and there are others in the pipeline. [People with HER2-positive cancer] are living longer and enjoying longer progression-free survival,” said Dr. Sullivan.