Hormone Therapy for Breast Cancer: What It Is and Why It’s Used

Learn how breast cancer hormone therapy is used in treatment and prevention and how research is improving outcomes

Breast cancers are broadly classified according to whether tumors have or lack hormone receptors (HR) and HER2. A majority of breast cancers (75-80 percent) test positive for estrogen and/or progesterone receptors, making them HR-positive. One of the main treatments for HR-positive breast cancers is hormone therapy, which works by blocking or reducing hormones that can fuel breast cancer’s growth.

Here, we discuss different types of hormone therapies for breast cancer, how hormone therapy is used for breast cancer treatment, and new research to improve hormone therapy in the future.

What is hormone therapy for breast cancer?

Hormone therapy for breast cancer—also known as endocrine therapy—is a treatment for breast cancers that are sensitive to hormones. Hormones act as chemical messengers in the body, relaying signals to cells; only those with compatible receptors can respond to hormone signals. In the case of HR-positive breast cancer, signals from the hormones estrogen and progesterone influence cell growth and behavior, with estrogen in particular instructing breast cancer cells to grow.

Treatments that disrupt these hormones from signaling to breast cancer cells are collectively known as endocrine or hormone therapy for breast cancer.

HR-positive breast cancers can be further categorized as estrogen receptor (ER)–positive and progesterone receptor (PR)–positive based on diagnostic testing. The majority of breast cancers are ER-positive. About half are ER-positive and PR-positive. ER-negative and PR-positive is the least common. Endocrine therapy for ER-positive breast cancer was considered the first targeted therapy for breast cancer.

Breast cancers that have no hormone receptors are called HR-negative. Breast cancer hormone therapy isn’t effective for patients with HR-negative breast cancer.

How is hormone therapy used for breast cancer treatment?

Hormone therapy works by specifically disrupting estrogen’s ability to drive the growth of HR-positive cancers. Most hormone therapies for breast cancer reduce the levels of estrogen in the body or block estrogen from binding its receptors—both of which help slow the growth of HR-positive breast cancers.

Hormone therapy for breast cancer can be used at different stages of treatment. In early-stage breast cancer, hormone therapy may be given after surgery (called adjuvant therapy) to lower the risk of the cancer returning. In certain cases, hormone therapy may also be given before surgery (called neoadjuvant therapy) to shrink a tumor to make it easier to remove.

For metastatic breast cancer, hormone therapy may be used to slow the growth of metastases that have spread outside the breast to other parts of the body. Some patients with advanced breast cancer are treated with a combination of hormone therapy and targeted therapies such as CDK4/6 inhibitors. Recently, CDK4/6 ihnibitors have demonstrated efficacy in early breast cancer as well.

What are the different types of hormone therapies for breast cancer?

There are several different types of hormone therapies, outlined below. Doctors decide which breast cancer hormone therapy to recommend for a patient based on several factors including their risk of recurrence (when cancer comes back) and whether the patient is premenopausal or postmenopausal.

The four main types of breast cancer hormone therapy for breast cancer are:

• Selective estrogen receptor modulators (SERMs)
• Selective estrogen receptor degraders (SERDs)
• Aromatase inhibitors
• Ovarian suppression therapy

Selective estrogen receptor modulators (SERMs)

SERMs stop estrogen from binding to breast cancer cells, thereby blocking the signal from estrogen to cells. Interestingly, while SERMs have anti-estrogen effects in breast cells, they can mimic estrogen in other tissues, including in the uterus and bones. SERMs are taken in pill form. Common SERMs include tamoxifen and raloxifene.

Tamoxifen is one of the most-prescribed hormone therapies for breast cancer with several uses including:

• Treating both premenopausal and postmenopausal women with breast cancer, though it is most commonly used to treat women who have not yet gone through menopause
• Treating women at high risk of breast cancer to help lower their risk
• In women diagnosed with HR-positive ductal carcinoma in situ (DCIS) who have undergone breast-conserving surgery (lumpectomy), taking tamoxifen for five years lowers the chance of the DCIS returning in the same breast and lowers the chance of getting another DCIS or an invasive breast cancer in both breasts.
• For women with invasive breast cancer that is HR-positive who have undergone surgery, tamoxifen can help reduce the risk of the cancer coming back.
• For patients with HR-positive metastatic breast cancer, tamoxifen can help slow the growth of tumors in other parts of the body.

Selective estrogen receptor degraders (SERDs)

SERDs, like SERMs, act by attaching to estrogen receptors. But SERDs bind more tightly than SERMs and cause the receptors to break down or degrade.

SERDs are typically used in women who are postmenopausal and include:

• Fulvestrant (Faslodex®), the first SERD approved for breast cancer treatment, is given by injection. It is used for advanced HR-positive breast cancer in postmenopausal women.
• Elacestrant (Orserdu®), which is taken in pill form, was recently FDA approved for postmenopausal women and men with estrogen receptor (ER)–positive/HER2-negative advanced or metastatic breast cancer that has an ER mutation (ESR1m) and has progressed after at least one prior line of endocrine therapy.

Currently, SERDs are predominantly used in advanced/metastatic breast cancers but oral SERDs are being investigated in clinical trials in early-stage breast cancer before or after surgery.

Aromatase inhibitors (AIs)

AIs stop most estrogen production in the entire body. In women whose ovaries aren’t making estrogen (i.e., following menopause), the hormone is still made in body fat by a process involving the enzyme aromatase. AIs prevent this enzyme from making estrogen, reducing estrogen levels in the body and slowing the growth of cancer cells that require estrogen to grow.

AIs such as anastrozole (Arimidex®) and letrozole (Femara®) are taken as daily pills and are usually used in postmenopausal women. If AIs are given to premenopausal women, steps must be taken to prevent the ovaries from producing estrogen.

Ovarian suppression therapy

This hormone therapy for breast cancer uses drugs or surgery to prevent the ovaries from making estrogen. Since the ovaries are the primary source of estrogen in premenopausal women, ovarian suppression along with tamoxifen or an AI, may be recommended for those with high-risk ER-positive breast cancer.

Common ovarian suppression medications include goserelin (Zoladex®) and leuprolide (Lupron®), which are both luteinizing hormone–releasing hormone (LHRH) agonists that work by disrupting signals from the brain that direct ovaries to produce estrogen. Eliminating ovarian function can also be done surgically by removing the ovaries (oophorectomy) or by treatment with radiation.

What are the side effects of hormone therapy for breast cancer?

Because non-cancerous cells also use estrogen, hormonal therapy that blocks access to estrogen can also interfere with normal cell functions, resulting in side effects. Common side effects of hormone therapy for breast cancer include hot flashes, night sweats, changes to your menstrual cycle if you are pre-menopausal, vaginal dryness, joint pain, mood changes, and fatigue.

A specific side effect of AIs is osteoporosis and bone weakening. Doctors usually request that patients have a bone density test called a DEXA scan ahead of AI treatment so that they can monitor your bone density going foward.

Tamoxifen and raloxifene have a few rare but potentially serious side effects, including an increased risk of developing blood clots in the legs (deep vein thrombosis) or lungs (pulmonary embolism), and, in the case of tamoxifen, an increased risk of uterine cancer.

How long do you stay on hormone therapy after breast cancer?

Women often start hormone therapy for breast cancer after surgery to help reduce their risk of recurrence and stay on it for at least five years. The exact duration of treatment is tailored to each individual patient, considering factors like specific breast cancer type and recurrence risk. Treatment for longer than five years may be offered if tests determine that a breast cancer has a higher chance of returning. For metastatic breast cancer, hormone therapy may be a lifelong treatment.

Hormone therapy can also be used to prevent breast cancer. The seminal Breast Cancer Prevention Trial found that when postmenopausal women at an increased risk of breast cancer took tamoxifen for five years, their risk of developing invasive ER-positive breast cancer was approximately halved.

Research to improve hormone therapy for breast cancer

One of the biggest issues in treatment for HR-positive breast cancer is hormone therapy resistance—when breast cancer stops responding to this treatment. This resistance often results from acquired ESR1 mutations that can lead to receptor activation, independent of the presence of estrogen. Researchers are seeking ways to overcome resistance to improve outcomes.

Since SERDs can bind and cause a change in the estrogen receptor’s shape and induce its degradation, they have the potential to overcome resistance. In fact, because oral SERDs have demonstrated positive results in clinical trials, the oral SERD elacestrant is now approved for patients with ESR1mutations. Other oral SERDs are being studied for treatment alone or in combination with CDK4/6 inhibitors, and research is ongoing to develop new SERDs with improved efficacy.

In addition, technological advances are being leveraged to develop novel therapies such as proteolysis-targeting chimeras (PROTACs). Vepdegestrant, a PROTAC estrogen receptor degrader, is the first oral PROTAC to enter clinical trials. These drugs work by binding two distinct regions: one on the protein to be degraded and the other on an enzyme that triggers a cell’s own machinery to actively and efficiently degrade the estrogen receptor. Thus, PROTACs offer another potential way to overcome acquired resistance to current hormone therapies for breast cancer.

Innovative degrader therapies such as oral SERDs and PROTACs are set to improve current options for hormone therapy for breast cancer. In addition to novel endocrine agents in development, researchers are also exploring combination therapies, possible sequencing strategies for existing therapies, and other ways to optimize treatment for HR-positive breast cancer.

Active areas of research have the potential to dramatically improve outcomes for patients:

• Adding a CDK4/6 inhibitor to standard breast cancer hormone therapy. A promising recent clinical trial demonstrated that the combination reduces the risk of breast cancer recurrence in stage 2 or 3 HR-positive breast cancer.
• Inhibiting the PI3K pathway
• Combining hormone therapy with other known or novel targeted therapies
• Identifying new biomarkers that can help predict specific mechanisms of resistance in an individual patient
• Monitoring treatment response by measuring circulating tumor DNA levels in the blood via liquid biopsy to adjust treatment in real-time—and before progression

BCRF investigators are at the forefront of this research to improve and expand hormone therapy for breast cancer. They continue to build on their findings and leverage innovative technologies, all with the goal of advancing the field and providing new options to patients with HR-positive breast cancer.