About Targeted Therapy for Breast Cancer

What to know about these therapies that can more precisely target cancer cells and their role in breast cancer treatment

Because of research, we’ve seen an overall 44 percent decline in deaths from breast cancer over the last three decades. That incredible progress has largely been driven by improvements in screening and a golden age of targeted therapies for breast cancer.

Targeted therapies—a form of precision medicine—have represented some of the most important breakthroughs in breast cancer research. Today, oncologists have numerous targeted therapies to treat patients including: endocrine therapy to target the estrogen receptor; Herceptin, which made HER2-positive breast cancer more treatable; and exciting newer classes of drugs like antibody-drug conjugates.

Read on to learn about currently available targeted therapies for breast cancer and what novel targeted therapies are on the horizon.

What is targeted therapy for breast cancer?

Targeted therapy for breast cancer refers to treatments or drugs that specifically target cancer cells while leaving normal cells mostly unscathed. To develop a new targeted therapy for breast cancer, researchers must first uncover the factors that drive normal cells to become breast cancer cells. These factors can be targets on or in the breast cancer cell, genetic mutations that cause normal cells to grow uncontrollably and form tumors, or even cellular pathways that get disturbed and change normal cells.

This information can be leveraged to engineer strategies to recognize these targets and stop them from promoting tumor growth. And if we can find a specific target, we can match patients with treatments that are more precise or personalized to their tumor.

Today, targeted therapies include several types of treatments including hormone therapies, anti-HER2 drugs, monoclonal antibodies, antibody-drug conjugates, and more.

About targeted therapy for breast cancer

The first thing to note is that targeted therapies are different from chemotherapies. Traditional chemotherapy works by killing cells that are growing quickly, which includes both cancerous cells and some normal cells. Targeted therapies slow or stop the growth of tumor cells by specifically zeroing in on the factor(s) that drive their transformation from normal cells, and in so doing, they can spare normal cells. That means targeted therapies are less toxic to healthy cells compared to chemotherapies.

Thanks to decades of research that provided viable targets for therapy development, today some people can avoid or decrease their time on chemotherapy. Some targetable factors include specific proteins that are overproduced, mutated proteins or genes, and novel proteins or genetic changes that are not found in normal cells.

Targeted therapies for breast cancer work by:

• Blocking or turning off signals that tell the cancer cell to grow and divide
• Triggering the immune system to recognize and kill the cancer cells
• Delivering drugs specifically to cancer cells

Targeted therapy for hormone receptor–positive breast cancer

The first targeted procedure for treating breast cancer was oophorectomy (removal of the ovaries), proposed by Albert Schinzinger in 1889 and first performed in 1896 by Sir George Thomas Beatson. It wasn’t until 1958, when Elwood Jensen discovered the estrogen receptor in cancer cells that scientists learned why oophorectomy was effective: the ovaries produce estrogen, a hormone that binds to the estrogen receptor and stimulates breast cancer cell growth. Targeted removal of the ovaries and a consequent decrease in estrogen could therefore improve survival rates for some breast cancers, namely estrogen receptor (ER)–positive breast cancer. Today, for premenopausal women, ovarian suppression drugs such as goserelin (Zoladex®) can stop the body from making estrogen, taking the place of oophorectomy. They are generally used in conjunction with other drugs.

The estrogen receptor’s discovery also opened the door for the development of endocrine therapies, the first targeted drugs to treat hormone receptor (HR)–positive breast cancer. Endocrine therapy, also called hormone therapy, describes several types of treatments: synthetic hormones, drugs that prevent the body from producing specific hormones, or drugs that prevent hormones from working properly.

The first of these targeted drugs for treatingER-positive breast cancer is tamoxifen, a selective estrogen receptor modulator (SERM) that blocks estrogen from reaching breast cancer cells—preventing excessive growth. An aromatase inhibitor, such as anastrozole, prevents estrogen production by inhibiting a key enzyme necessary for the process. Other newer drugs to treat this subtype are selective estrogen receptor degraders (SERDs), which work by binding to the estrogen receptor and causing a change in its structure that recruits cellular machinery to degrade or break it down. Fulvestrant (Faslodex®) was the first SERD approved to treat ER-positive breast cancer followed by elacestrant; others are being evaluated in clinic trials now.

Other targeted therapies for treating hormone receptor (HR)–positive/HER2-negative breast cancer are discussed below and include PARP inhibitors, CDK4/6 inhibitors, and PI3 kinase inhibitors. And the antibody-drug conjugate (ADC) sacituzumab govitecan (Trodelvy®) was also recently approved for treating this subtype.

Antibodies’ role in targeting breast cancer

Antibodies areproteins made by our immune system to protect us from foreign or infectious substances. Researchers have learned how to simulate this process in laboratory models and can create monoclonal antibodies (mAbs) that recognize one specific part of a target protein. Some monoclonal antibodies used to treat cancer are considered a type of targeted therapy for breast cancer because they work by attaching to a specific target on a cancer cell and disrupting its function. But other monoclonal antibodies act like immunotherapy because they help the immune system find and attack cancer cells more effectively.

Antibody drug conjugates (ADCs) are targeted therapies engineered to deliver drugs to cancer cells with substantially less toxicity to surrounding normal cells. ADCs are composed of three parts: an antibody, a drug or payload, and a dissolvable linker that connects the antibody to the drug. They are powerful tools that leverage the specificity of an antibody to strategically release a potent drug straight to the tumor. They include:  

• Ado-trastuzumab emtansine (T-DM1/Kadcyla®) is a construct of the antibody trastuzumab linked to the chemotherapy drug (payload) emtansine.
• Trastuzumab deruxtecan (T-DXd/Enhertu®) also contains trastuzumab but it is linked to a different drug called deruxtecan.
• Sacituzumab govitecan (SG/Trodelvy®) contains the antibody sacituzumab that targets the TROP2 protein linked to a SN-38 payload.

There are several ADCs in clinical trials, and other trials are testing the use of sequential ADCs in the clinic. In addition, researchers are optimizing different combinations of antibody and payload, and identifying novel antibody targets. 

Bispecific antibodies (bsAbs) are yet another targeted therapy for breast cancer but differ from mAbs in that they can recognize and bind two separate proteins or two distinct regions of the same protein. They are considered next-generation mAbs.

BsAbs have been created that can bind tumor cells and immune cells, serving as bridges between them. They facilitate targeted destruction of tumor cells by engaging immune cells such as T cells or natural killer cells, amplifying immune response against tumors, enhancing the ability of immune cells to remove the tumor with less toxicity to the surrounding normal cells, and improving clinical outcomes. Two bsAbs are currently in early clinical trials.

Targeted therapy for HER2-positive breast cancer

The first targeted therapy for HER2-positive breast cancer—the mAb trastuzumab (Herceptin®)—was developed in the 1990s following the discovery of HER2, a protein that promotes cell growth. The HER2 protein is a receptor found on the surface of normal cells that transfers growth signals from the surface into cells. In HER2-positive breast cancers, HER2 protein is overexpressed. More HER2 protein signals cells to keep growing, potentially leading to tumor formation.

Several targeted therapies have been developed against HER2: 

• Trastuzumab (Herceptin®) binds to the HER2 protein, where it is taken into the cancer cell and can disrupt HER2 protein’s growth-signaling function.
• Pertuzumab (Perjeta®) differs from trastuzumab in that it prevents HER2 from forming a dimer (two HER2 molecules bonded together). Dimerization is necessary for HER2 to transmit growth signals into the cell.
• Margetuximab (Margenza®) is different from the others in that it can bind to HER2 protein as well as nearby immune cells. It can dampen HER2 signaling as well as tag HER2-positive tumor cells for destruction by the body’s immune system.  
• The antibody-drug conjugates (detailed in the previous section) T-DM1/Kadcyla®and T-DXd/Enhertu® both target HER2 protein. T-DXd is also able to recognize very low levels of HER2.

Three drugs called tyrosine kinase inhibitors (TKIs) have been approved for HER2-positive breast cancer treatment and are described below: tucatinib (Tukysa®), lapatinib (Tykerb® or Tyverb®), and neratinib (Nerlynx®). Currently, there are also several BsAbs in development for treating HER-positive breast cancer.

Immunotherapy

Immunotherapy leverages the power of the immune system to recognize, bind, and mark tumor cells for destruction. This strategy has been brought to the clinic to treat breast cancer, and more are being developed and tested in the laboratory every day.  

Immune check point inhibitors don’t kill cancer cells directly. Instead, they target specific proteins on immune cells called immune checkpoint proteins. PD-1 receptor is one and acts as a set of brakes to stop immune cells from attacking other cells in the body. It does this by attaching to PD-L1, a protein on normal cells. This interaction between PD-1 (on the immune cell) and PD-L1 (on the normal cell) helps the immune system tell the difference between normal and foreign cells.

But some cancer cells have large amounts of PD-L1 which can bind to PD-1 on immune cells,  enabling cancer cells to avoid being noticed. MAbs that target either PD-1 or PD-L1 can block this interaction and expose cancer cells to the immune system. Pembrolizumab (Keytruda®) is an mAb used in breast cancer treatment to target the PD-1 receptor protein on immune cells so that tumor cells can’t hide from the immune system.

Other immune checkpoint inhibitors target the checkpoint proteins CTLA-4 and LAG-3. These are typically used in combination with a PD-1 or PD-L1 inhibitor to treat several types of cancer.

Building on our increased understanding of the immune system and growing expertise in gene therapy, researchers are working to bring vaccines to patients to treat and potentially prevent breast cancer. While several are in development, others are currently being tested in breast cancer clinical trials, including:

• STEMVAC: This targets proteins that are expressed on breast cancer cells and boosts the immune system to recognize and destroy them.
• ADVAC (anti-inflammatory vaccine): targets proteins that highly expressed in inflammatory fat, which has been shown to promote significant metabolic stress and imbalance on immune cells thereby promoting cancer formation. This is one of the first vaccines designed to lower a person’s risk of developing breast cancer.
• MUC1-specific vaccine: This targets the tumor antigen MUC1 that is overexpressed on cancer cells including early, precancerous cells. It is being tested in the prevention space to hinder development of breast cancer in patients diagnosed with pre-cancerous ductal carcinoma in situ (DCIS). Read more
• INO-5401: A DNA-based vaccine specific for the human telomerase reverse transcriptase (hTERT), which is overexpressed in most cancers. This is the first prevention vaccine tested in BRCA mutation carriers, a high-risk population.

Other targeted therapies for breast cancer

Just like normal cells, tumor cells undergo a growth cycle. In the case of tumors, this process becomes uncontrollable. But researchers have found several avenues to disrupt tumor cell growth by targeting portions of the growth cycle.

During a cell’s growth cycle, DNA damage can occur, and efficient DNA repair is necessary for normal cell growth. Poly (ADP-ribose) polymerase (PARP) mediates the repair of damaged DNA and serves a vital function in the cell growth cycle. A hallmark of cancer is that DNA can’t be repaired efficiently because cancer cells are rapidly dividing. Cells that have defective DNA repair capabilities such as BRCA1– and BRCA2-mutated cells are more reliant on PARP to repair DNA, and this makes PARP an attractive therapy target. PARP inhibitors were developed to exacerbate the DNA repair defect in BRCA1/2 mutated cells, thereby promoting cancer cell death. Oloparib (Lynparza®) and talazoparib (Talzenna®) target and trap PARP proteins on DNA to block the proteins’ normal function, disrupting cell division and leading to cell death in rapidly dividing cancer cells.

Cell growth is cyclical and cyclin-dependent kinases 4 and 6 (CDK4/6) are proteins found in healthy and cancerous cells that control this cycle. But they can also become overactive and cause uncontrollable cell growth. CDK4/6 inhibitors were developed to interrupt these proteins to slow or even stop the cancer cells from growing. Three CDK4/6 inhibitors have been FDA approved for treating HR-positive/HER2-negative metastatic breast cancer: palbociclib (Ibrance®), ribociclib (KisqaliT®), and abemaciclib (Verzenio®). Recently, ribociclib has also been approved for early-stage breast cancer.

Cells have developed complex methods to relay messages internally and externally, relying on signaling pathways to accomplish important cell functions. A pathway is considered a cascade of reactions involving multiple factors, each having a job to do. One reaction involves tyrosine kinases, part of a family of enzymes. Since the HER2 protein contains a tyrosine kinase domain that is involved in cell growth, this paved the way for the development of tyrosine kinase inhibitors (TKIs). These small molecule inhibitors bind to the tyrosine kinase domain of HER2 and halt activation of the cell signaling pathway.

PI3K/AKT/mTOR is a signaling pathway that, when activated, can result in sustained cell growth and tumor formation. In HR-positive/HER2-negative breast cancer cases, a few key genetic aberrations were discovered in this pathway that led to the development of PI3K/AKT/mTOR inhibitors to stop their effect: the PI3K inhibitor alpelisib (Piqray®) and the first-in-class AKT inhibitor capivasertib (Truqap™). Endocrine therapy is the standard-of-care for HR-positive/HER2-negative breast cancer, but these tumors often develop resistance to it. PI3K and AKT inhibitors are effective, targeted therapies that provide strategies to overcome resistance.

Targeted therapy for triple-negative breast cancer

Triple-negative breast cancers (TNBCs) cannot be treated with endocrine or HER2-targeted therapies because they lack ER and the HER2 protein. Therefore, chemotherapy is still the standard of care. However, researchers are working to identify targetable factors to give patients with TNBC more treatment options. Studies looking at the molecular components of TNBC have identified key elements in TNBCs that can be therapy targets:

• BRCA1/2-mutated TNBCs have DNA repair deficiency which can be targeted with PARP inhibitors
• Expression of the Trop2 protein in TNBC led to its targeting with the ADC sacituzumab govetican (Trodelvy®)

Other targets have been found in TNBC such as cell cycle alterations that may be targeted with CDKinhibitors and alterations in the PI3K/AKT/mTOR pathway may be targeted with PI3K/AKT/mTOR inhibitors. Studies are ongoing to test these drugs as well as drug combinations that may effective at targeting TNBCs.

What to expect while on targeted therapy for breast cancer

Targeted therapy is an important type of cancer treatment, and researchers will develop more targeted drugs as they learn more about specific changes in breast cancer cells. But so far, only a few types of breast cancers are routinely treated using only these drugs. Most people receiving targeted therapy for breast cancer also need surgery, chemotherapy, or radiation therapy.

Some targeted therapies are given intravenously (IV) right into the bloodstream. IV infusion typically lasts from a few minutes to a few hours. IV push is when the drugs are given quickly, over a few minutes. Other targeted therapies can be taken by mouth as pills, capsules, or liquids, just like other medicines. If taken at home, it’s very important to make sure you know exactly how and when you should take it.

Be sure to ask questions about which side effects are most common with your treatment, how long they might last, how bad they might be, and when you should call the doctor’s office about them. Your doctor may give you instructions to follow or medicines to help prevent some side effects before they happen. It’s important to keep in mind:

• Drug actions and where they work affect the side effects they cause.
• Not every person gets every side effect, and some people get few or none.
• The severity of side effects can vary greatly from drug to drug and from person to person.
• Rare and unusual side effects can happen; some can be serious.
• Report all changes and side effects as soon as possible to your cancer care team.

Research to advance targeted therapy for breast cancer

Targeted therapy for breast cancer is sometimes called precision medicine or personalized medicine. This is because they are made to exactly target specific changes or substances in cancer cells, and these targets can be different even when people have the same type of cancer. That’s why researchers are focused on identifying targets and devising strategies around them. They are also developing and testing new targeted technologies including:

• Modifying a patient’s own T-cells to target cancer cells more effectively via CAR T-cells
• PROTACs, a new type of drug, designed to induce the degradation of a specific protein
• Tri-specific antibodies that are engineered to recognize three targets
• CDK2 inhibitors that are currently being tested in clinical trials

These are just a few of the targeted therapies that are on the horizon.

Researchers are also rigorously refining and testing existing targeted therapies, exploring new combinations, and working to optimize dosing strategies to balance efficacy with possible side effects and a patient’s quality of life. Research has brought us a long way since oophorectomy was the targeted treatment. But the journey to bring more targeted therapies to breast cancer patients continues.