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 four kinds of targeted therapy to treat hormone receptor-positive breast cancer: AKT inhibitors, CDK 4/6 inhibitors, mTOR 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.

AKT inhibitors

AKT inhibitors target the AKT protein, which helps regulate cell growth, division, and survival. To do this, the AKT protein sends signals to PIK3CA and PTEN proteins within the PIK3-AKT pathway, a chain of molecules that acts as a communication network inside a cell. There is one FDA-approved AKT inhibitor, capivasertib (Truqap). Capivasertib stops AKT from working. Capivasertib is taken with fulvestrant (Faslodex).

Capivasertib is approved for people living with hormone receptor-positive, HER2-negative metastatic breast cancer that tests positive for AKT1, PIK3CA, or PTEN mutations, after the breast cancer grows or spreads while on an endocrine therapy.

Capivasertib is also approved for people who have a hormone receptor-positive, metastatic breast cancer diagnosis during or within 12 months of completing treatment for early-stage breast cancer. The cancer must test positive for AKT1, PIK3CA, or PTEN mutations.

In the phase III CAPItello-291 clinical trial, capivasertib plus fulvestrant lowered the risk of progression or death by 50% in people diagnosed with locally advanced or metastatic hormone receptor-positive breast cancer that had AKT pathway mutations when compared with fulvestrant alone. In the overall study population, the risk was lowered by 40%.

Capivasertib side effects include rash, diarrhea, increased blood sugar levels, nausea or vomiting, fatigue, high triglycerides, higher levels of creatinine, low blood cell counts, and mouth sores.

Learn more about this medicine and testing requirements on the capivasertib page.

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 hormone receptor-positive, HER2-negative breast cancer. The three CDK 4/6 inhibitors are:

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

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

For people diagnosed with hormone receptor-positive, HER2-negative early-stage breast cancer, there are two FDA-approved CDK 4/6 inhibitors:

• Abemaciclib, in combination with an aromatase inhibitor or tamoxifen, is approved for use after surgery to treat early-stage hormone receptor-positive, HER2-negative breast cancer that has traveled to the lymph nodes and has a high risk of recurrence.
• Ribociclib, in combination with an aromatase inhibitor, is approved for use after surgery to treat hormone receptor-positive, HER2-negative stage II and stage III early breast cancer that has a high risk of recurrence.

For people diagnosed with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer:

• All three CDK 4/6 inhibitors—abemaciclib, palbociclib, and ribociclib—are approved as a first treatment in combination with hormonal therapy.
• Several clinical trials have shown that these treatments can help people live without metastatic cancer progression for several months to a year longer than hormonal therapy alone.

CDK 4/6 inhibitors are taken as pills, typically once or twice a day.

In advanced or metastatic breast cancer, CDK 4/6 inhibitors can be given as a first treatment, or it can be given later.

As first-line therapy (a first treatment after diagnosis of advanced or metastatic breast cancer), any of these three medicines can be given along with an aromatase inhibitor or fulvestrant to women who have gone through menopause, or to men.

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 aromatase inhibitor or fulvestrant must also take a gonadotropin-releasing hormone (GnRH) agonist. GnRH agonists stop the ovaries from producing estrogen. Men are also usually advised to take a GnRH agonist to lower testosterone levels in the body.

What’s similar and different among the CDK 4/6 inhibitors

All three CDK 4/6 inhibitors are taken by mouth, as pills.

In early breast cancer:

• Abemaciclib is taken twice a day for two years.
• Ribociclib is taken once a day for 21 days, followed by a seven-day break, for three years.

In advanced and metastatic breast cancer:

• Abemaciclib is taken twice a day. In some people, abemaciclib can be used alone, without any hormonal therapy, for metastatic breast cancer.
• Ribociclib and palbociclib are taken once a day for 21-day cycles followed by a seven-day break.

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 you have been diagnosed with metastatic breast cancer that 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?
• In metastatic breast cancer, 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 HER2-positive cancer?

More specifically, some clinical trials are looking at:

• Using abemaciclib after breast cancer progresses on palbociclib
• Using either fulvestrant or fulvestrant plus ribociclib in people with metastatic breast cancer that 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 control cell growth. If breast cancer has a mutation in a gene called PIK3CA, PI3K can become overactive, causing cancer cells to grow. PI3K inhibitors are medicines that block this process. Two PI3K inhibitors are approved to treat hormone receptor-positive, HER2-negative, PIK3CA mutation-positive advanced or metastatic breast cancer:

• Alpelisib (Piqray)
• Inavolisib (Itovebi)

Antibody-drug conjugates

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

• Datopotamab deruxtecan (Datroway) is approved to treat metastatic breast cancer that is hormone receptor-positive and HER2-negative.
• 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.