Targeted therapy for hormone receptor-positive breast cancer

Hormone receptor-positive breast cancers grow in response to the hormones estrogen and progesterone. These cancers are often treated with hormonal therapy medicines.

Hormonal therapy medicines can work in two ways. They either stop the body from making estrogen or they block the effects of estrogen that drive cancer growth.

Targeted therapies are treatments that target specific proteins or markers on or within cancer cells that help those cells grow. There are many different kinds of targeted therapy. Hormonal therapy is actually a type of targeted therapy because it targets hormones that are active in cancer growth. Hormonal therapy has been used to treat breast cancer for many years. But doctors are now using newer kinds of targeted therapy to treat hormone receptor-positive breast cancer as well.

Over time, some breast cancers can build resistance to hormonal therapies. Studies have shown that some hormonal therapies are more effective when combined with other targeted therapies. Your doctor may recommend a combination therapy as first-line treatment or later on, if the cancer stops responding to hormonal therapy.

The FDA has approved three kinds of targeted therapy to treat hormone receptor-positive breast cancer: mTOR inhibitors, CDK 4/6 inhibitors, and PI3K inhibitors.

These targeted therapy medicines are mostly used to treat advanced or metastatic breast cancers; one CDK 4/6 inhibitor is also approved for early-stage breast cancer that has spread to the lymph nodes.

If you have hormone receptor-positive breast cancer and are interested in targeted therapies, ask your doctor whether these medicines are an option for you. If they are not, ask if you might be able to participate in a clinical trial .

Targeted therapies, hormonal therapies, and chemotherapy all cause different kinds of side effects. They can vary in type and level of disruption and seriousness. What happens to one person may not happen to you. Talk with your health care team about possible side effects to learn how you can prevent or lessen them, and check out our Side effects page for tips on how to cope.

CDK 4/6 inhibitors

CDK 4/6 inhibitors, also called cyclin-dependent kinase 4/6 inhibitors, target two specific kinases, CDK 4 and 6. These kinases, or proteins, signal cancer cells to grow and divide. Blocking these proteins in hormone receptor-positive breast cancer cells helps stop the cells from growing and spreading.

Three CDK 4/6 inhibitors are approved to treat metastatic breast cancer. Of the three, only abemaciclib is also approved for early-stage breast cancer. The three CDK 4/6 inhibitors are:

• Ribociclib (Kisqali)
• Palbociclib (Ibrance)
• Abemaciclib (Verzenio)

Who can take CDK 4/6 inhibitors and how they are used

CDK 4/6 inhibitors, used in combination with hormonal therapy, are now commonly recommended as the first treatment for people with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. That’s because several clinical trials have shown that all three medications can help people live longer without cancer growth—for several months to a year longer versus hormonal therapy alone. Many of these trials are ongoing.

Other clinical trials have shown that adding ribociclib and abemaciclib to hormonal therapy extends overall survival (how long people live with their cancer) versus taking hormonal therapy alone. Your doctor can help you decide what makes the most sense for your situation.

CDK 4/6 inhibitors are taken as pills, typically once or twice a day. There are different ways to use these medicines.

As first-line therapy (initial treatment for breast cancer):

• Any of these three medicines can be given along with hormonal therapy, such as aromatase inhibitor (AI) or fulvestrant (Faslodex), a selective estrogen receptor downregulator (SERD), also known as an estrogen receptor agonist (ERA), to women who have gone through menopause, or to men.
• Any of these three medicines can be used with an aromatase inhibitor and a luteinizing hormone-releasing hormone (LHRH) agonist for ovarian suppression in women who are still having regular periods (premenopausal) or are almost in menopause (perimenopausal).
• In some cases, men may be advised to take an LHRH agonist along with these medicines to suppress hormones in the body.

Abemaciclib is also approved for use in women with early-stage hormone receptor-positive, HER2-negative breast cancer that has traveled to the lymph nodes and has a high chance of coming back. In these situations, abemaciclib would be given after surgery along with tamoxifen or an AI. It is typically taken for 2 years as a pill, twice a day. In the study that led to this early-stage approval, some premenopausal participants also took ovarian suppression medications and some did not; you should talk with your doctor about your situation.

As second-line therapy:

• Palbociclib and abemaciclib, combined with fulvestrant, may be used for people whose cancer progressed on hormonal therapy and had one line of chemotherapy or no chemotherapy at all. Ribociclib also may be used in this way for postmenopausal women and men.
• Abemaciclib can also be used by itself in people who have previously been treated with hormonal therapy and chemotherapy.

Pre- and perimenopausal women taking a CDK 4/6 inhibitor plus an AI or fulvestrant must also take an LHRH agonist to stop the ovaries from producing estrogen. Men are also usually advised to take an LHRH agonist to lower testosterone levels in the body.

What’s similar and different among the CDK4/6 inhibitors

All three CDK 4/6 inhibitors are taken by mouth, as pills. The main difference is that ribociclib and palbociclib are taken for 21 days followed by a 7-day break, while abemaciclib is taken continuously. As noted, only abemaciclib can be used for early-stage breast cancer, and in some people, it can be used alone without any hormonal therapy for metastatic breast cancer.

These medicines are not recommended for women who are pregnant or may become pregnant. They also may cause fertility problems in men. CDK 4/6 inhibitors should not be taken with strong doses of medications that affect the enzyme known as CYP3A, as well as grapefruit or grapefruit juice.

CDK 4/6 inhibitors have similar side effects, the most common being neutropenia and leukopenia (decreases in white blood cell counts). These can increase the risk of illness and infection.

Other shared side effects can include fatigue, nausea and vomiting, mouth sores, hair loss, diarrhea, and headache.

Abemaciclib causes diarrhea more frequently than the other two drugs, and in some people, it can be severe and lead to dehydration. This medicine also can cause uncommon but serious side effects such as:

• Inflammation of the lungs
• Liver problems
• Blood clots in the veins or in the arteries of the lungs

Ribociclib also can lead to uncommon but potentially serious side effects such as:

• Inflammation of the lungs
• Severe skin reactions
• QT interval prolongation, a heart rhythm problem that can lead to a fast or irregular heartbeat
• Liver problems

Your doctor will monitor you for side effects and tell you what symptoms to watch for. If you experience a severe side effect, the dosage of the medication can be reduced as needed. In fact, the prescribing information for each medication has specific instructions about how to reduce the dosage to lessen side effects. Your doctor also can recommend strategies for preventing infection and managing diarrhea.

Choosing a CDK 4/6 inhibitor

Your doctor can help you decide which CDK 4/6 inhibitor to take, based on the features of the cancer, your menopausal status, and which treatments you have already had, if any. Other factors in that decision may include:

• Side effects: Your medical history or personal preferences may lead you and your doctors to avoid a certain CDK 4/6 inhibitor based on side effects—such as the potential for severe diarrhea, or liver or heart rhythm problems.
• Ease of access/health insurance coverage: Insurance coverage for CDK 4/6 inhibitors can vary depending on the plan you have. In addition, if your doctors need to reduce the dose because of side effects, certain CDK 4/6 inhibitors require a new prescription, versus simply taking one fewer pill. This may influence your decision.
• Your doctor’s preference: If your team tends to use one of these medicines more than others in a specific situation or certain groups of patients, this may affect their recommendations.

Because these medicines have shown similar effectiveness for controlling breast cancer in clinical trials so far, you and your doctors can make the choice that is right for you.

Switching between CDK 4/6 inhibitors

If you experience difficult side effects that do not improve when the dose of a CDK 4/6 inhibitor is lowered, your doctors may recommend switching to a different one.

If breast cancer progresses while on CDK 4/6 inhibitor therapy, there is not enough evidence yet to suggest that a different CDK 4/6-containing regimen will be effective. However, your doctor still may recommend trying a different CDK 4/6 inhibitor. Other options may include:

• Using fulvestrant alone, or combining it with another targeted therapy called alpelisib (Piqray), if the cancer has a PIK3CA mutation (apelisib is a PI3K inhibitor)
• Using the mTOR inhibitor everolimus (Afinitor) with exemestane (Aromasin), a hormonal therapy medicine

The choice often depends on whether or not the cancer responded well to hormonal therapy in the past. Your doctor can help you decide based on your individual situation.

Generally, doctors will use targeted therapies before recommending chemotherapy, unless the cancer is causing difficult symptoms—such as pain or trouble breathing—related to where it has moved within the body.

Research on CDK 4/6 inhibitors

Researchers continue to study how best to use CDK 4/6 inhibitors. Some key questions they are trying to answer include:

• Are there certain tumor biomarkers (such as specific gene mutations) that make a cancer more likely to respond to a CDK 4/6 inhibitor?
• Should a CDK 4/6 inhibitor be continued if the cancer progresses, or should it be switched?
• Do CDK 4/6 inhibitors work well in combination with other therapies besides hormonal therapy?
• Can these medicines be used in early-stage hormone receptor-positive, HER2-negative breast cancer, or in HER2-positive cancer?

More specifically, some clinical trials are looking at:

• Treating hormone receptor-positive, HER2-negative early breast cancer with ribociclib after surgery
• Using abemaciclib after breast cancer progresses on palbociclib
• Using either fulvestrant or fulvestrant plus ribociclib in patients whose cancer progresses on palbociclib or ribociclib plus an aromatase inhibitor
• Combining an investigational CDK 4/6 inhibitor, dalpiciclib, with an aromatase inhibitor and comparing its effectiveness to chemotherapy alone
• Combining paclitaxel with palbociclib in people with different subtypes of breast cancer who have not had a CDK 4/6 inhibitor before

The use of these medicines is likely to be updated as new clinical trial results become available in the coming years. To learn more about accessing these options, explore the resources in Clinical trials.

mTor inhibitors

mTOR, or mammalian target of rapamycin, is a type of protein called a kinase. Kinase helps control cell growth.

In some cancers, mTOR-activated proteins work abnormally and encourage cancer cells to grow and spread. mTOR also directs nutrients to the cancer cells, helping to support them.

mTOR inhibitors are a newer type of targeted therapy. They work to slow or stop mTOR’s role in the growth of cancer cells. The mTOR inhibitor approved to treat metastatic breast cancer is:

• Everolimus (Afinitor)

PI3K inhibitors

PI3K, also called phosphatidylinositol-3 kinase, is a family of enzymes that sends signals that affect cell growth. One medicine of this kind is approved to treat hormone receptor-positive, HER2-negative metastatic breast cancer that has a specific mutation, PIK3CA, in postmenopausal women and in men:

• Alpelisib (Piqray)

Antibody-drug conjugates

Antibody-drug conjugates (ADCs) are treatments that pair a chemotherapy medicine with a targeted therapy. There is one ADC approved to treat hormone receptor-positive breast cancer:

• Sacituzumab govitecan (Trodelvy) is approved to treat metastatic breast cancer that is hormone receptor-positive and HER2-negative. It is also approved to treat metastatic breast cancer that is triple-negative.