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Dr. C.H. Weaver MD updated 5/2022

Estrogen is an essential female hormone that is produced by the ovaries and adrenal glands. It serves many critical functions in the body, including developing the female sex organs in puberty, preparing the breasts and uterus for pregnancy in adulthood, and maintaining cardiovascular and bone health. Without estrogen, the female body is unable to sustain pregnancy and is susceptible to heart disease and osteoporosis.

Estrogen can also cause some cancers to grow. The breasts, uterus and other female organs are composed of cells that contain estrogen receptors. When cells that have estrogen receptors become cancerous, exposure to estrogen increases the cancer’s growth. Cancer cells that have estrogen receptors are referred to as estrogen receptor-positive (ER+ positive) cancers.The growth of ER+positive breast cancer cells can be prevented or slowed by reducing the exposure to estrogen. This is the goal of hormonal therapy for breast cancer.

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A reduction in estrogen levels however, can also result in side effects because estrogen is necessary for important body functions, such as bone growth and cardiovascular health. Lower estrogen levels lead to decreased bone density and heart disease. Tamoxifen was the first anti-estrogen drug but it has largely been replace by aromatase inhibitors (AI) and Faslodex (fulvestrant), alone or combined with cyclin-dependent kinases (CDK) inhibitors because they are better at delaying cancer progression and prolonging survival in women who can benefit from anti-estrogen therapy.

How Does Hormonal Therapy Work?

In premenopausal women, the ovaries are the major source of estrogen. After menopause, when ovarian hormone production drops dramatically, some estrogen continues to be produced in tissues outside of the ovaries. In this process, androgens produced by the adrenal glands are converted into estrogen. An enzyme called aromatase is required for this conversion.1 The goal of hormonal therapy is to decrease the effect of estrogen on cancer cells. Reducing the effects of estrogen can be accomplished in the following ways:

  • by removing the ovaries, which produce the majority of estrogen in premenopausal women
  • by blocking the conversion of androgens to estrogens by inhibiting the aromatase enzyme, or
  • by blocking the estrogen receptors so that estrogen cannot bind and stimulate growth-related activity in breast and other cells.

Currently, the types (classes) of anti-estrogen drugs that are approved for the treatment of patients with breast cancer are called:

  • Aromatase inhibitors
  • Selective estrogen receptor modulators (SERMs)
  • Estrogen receptor antagonists

These three classes of drugs work by decreasing estrogen’s effects on the body, but they do so through different mechanisms.

Aromatase inhibitors: Aromatase inhibitors block the conversion of androgens to estrogen, and reduce estrogen levels in postmenopausal women. Currently, three anti-aromatase drugs2-4 are approved for the treatment of postmenopausal women with breast cancer:

Femara and Arimidex are non-steroidal aromatase inhibitors that bind reversibly to aromatase. Aromasin is a steroidal aromatase inhibitor that binds permanently to aromatase.

Selective Estrogen Receptor Modulators (SERM): SERMs block estrogen receptors within breast cells, thereby reducing estrogen-stimulated growth. Currently, tamoxifen is the most common SERM used for the hormonal treatment of breast cancer. However, tamoxifen is associated with side effects, including an increased risk of uterine cancer.

Estrogen Receptor Antagonist: Like SERMs, estrogen receptor antagonists work by preventing estrogen from stimulating the growth of estrogen receptor-positive cells. Faslodex® the first estrogen receptor antagonist, binds to and degrades estrogen receptors so that estrogen is no longer able to bind to the receptors and stimulate cellular growth.

Combination Therapy: A major hallmark of cancer cells is their ability to multiply rapidly. Precision cancer medicines known as cyclin-dependent kinases (CDK) inhibitors interfere with this process by blocking the activity of enzymes known as CDKs, particularly CDK 4 and CDK 6, that help to regulate cell division. Combining a CDK inhibitor with another anti-estrogen drug delays the time to cancer progression and prolongs survival.5 CDK inhibitors are indicated for the treatment of HR+, HER2- early stage and metastatic breast cancer in combination with an anti-estrogen drug. 

CDK Inhibitors in depth...

The monarchE clinical trial was designed to determine if the combination of the CDK inhibitor Verzenio with hormone therapy could improve outcomes in high risk early stage breast cancer compared to treatment with hormone therapy alone. The trial enrolled 5,637 patients with HR+, HER2- node-positive, high risk early stage breast cancer to treatment with Verzenio twice daily plus standard adjuvant endocrine therapy or standard adjuvant endocrine therapy alone. Verzino was administered for 2 years following completion of primary therapy that must have included surgery. High-risk disease was characterized by 4 or more positive axillary lymph nodes, or 1 to 3 positive lymph nodes in the setting of a tumor of at least 5 cm, grade 3 or centrally confirmed Ki-67 expression of at least 20% in untreated breast tissue.

The 2-year survival without disease recurrence was 92.2% in patients receiving Verzenio compared to 89.3% for treatment with standard endocrine therapy alone. The risk of recurrence was reduced by 28.3%. The 2-year distant relapse-free survival rate was also improved with Verzenio to 93.8% compared with 90.8%.28

Verzenio is the first CDK4/6 inhibitor to show a significant improvement when combined with endocrine therapy in patients with hormone receptor positive ESBC.

The results of the monarchE study stands in contrast to two other studies of adjuvant CDK4/6 inhibitors plus ET in HR+/HER2- breast cancer. Neither the PALLAS or PENELOPE-B clinical trials found any benefit when adjuvant Ibrance (palbociclib) was added to standard ET.29-32

There are several factors that could explain the different results between these trials. Verzenio is a more potent inhibitor of CDK4 and CDK6 than ibrance.31 Moreover, verzenio is dosed continuously versus a 21-day on, 7-day off schedule for ibrance. The continuous dosing of might provide an advantage in the form of constant cell cycle inhibition. Longer follow-up is needed to determine if verzenio will have sustained long term benefits.32

Hormonal Therapy Treatment of Early-stage Breast Cancer

The use of hormonal therapy appears to benefit all women with hormone receptor-positive early-stage breast cancer. The primary benefit is a reduction in the risk of cancer recurrence. For premenopausal women hormone therapy is typically used for a period of five years. Suppression of ovarian hormone production, through surgical removal of the ovaries, radiation to the ovaries, or drugs such as leutenizing hormone releasing hormone (LHRH) agonists, is another approach to hormonal therapy that may be incorporated into the treatment of premenopausal breast cancer patients.13

For postmenopausal women, use of an aromatase inhibitor appears to produce better outcomes than tamoxifen. When considering how best to use aromatase inhibitors in the treatment of postmenopausal breast cancer, researchers have considered several possibilities:

  • Aromatase inhibitors could be used for extended hormonal therapy, after a woman has completed tamoxifen treatment.14
  • Women could be switched to aromatase inhibitors after a brief (two to three year) period of tamoxifen therapy.15
  • Aromatase inhibitors could be used in place of tamoxifen as initial hormone therapy.16,17
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While it’s still uncertain which of these approaches is best, each of them appears to produce better outcomes than use of tamoxifen alone.The benefits of hormonal therapy for women with estrogen receptor-positive breast cancer also apply to women with ductal carcinoma in situ (DCIS). Ductal carcinoma in situ (DCIS) is the earliest possible clinical diagnosis of breast cancer and is frequently diagnosed with screening mammography.18

How Long Should You Take Hormone Therapy?

The American Society of Clinical Oncology (ASCO) updated their guidelines for the use of adjuvant endocrine therapy for women with hormone receptor-positive breast cancer extending the duration of tamoxifen treatment beyond the five-year standard. Specifically, women in two large studies who used tamoxifen for a total of 10 years experienced “modest gains in survival” compared with those who used tamoxifen for five years. As well, women treated for 10 years had a lower risk of recurrence and of developing cancer in the other (previously unaffected) breast. 

Aromatase inhibitors have been shown to provide a somewhat higher disease-free survival rate than tamoxifen. A number of randomized trials have compared 5 years with 10 years and In general, these trials have shown no additional benefit from further endocrine therapy in the lymph node–negative population. The results in lymph node–positive patients have been mixed, with one trial showing some benefit and the other trials showing little or no benefit. 

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The GIM4 clinical trial studied the role of extended therapy with Femara (letrozole) after 2-3 years of tamoxifen for postmenopausal women with early stage breast cancer.36  A total of 2,056 patients were treated with either 2 to 3 years of Femara for a total of 5 years of treatment or 5 years of Femara for a total of 7 to 8 years of treatment. Twelve years from treatment initiation 62% of women treated for 5 years survived cancer free compared to 67% of those treated for 7-8 years. The 12-year overall survival was 84% for 5 years and 88% for 7-8 years of treatment. Two other trials have reported no benefit for 10 years compared to 7-8 years and are consistent with GIM4, suggesting that 7-8 years of endocrine may be the optimal duration of extended adjuvant therapy.37,38

As always, patients are encouraged to discuss all treatment options with their physician in order to make the best decision for optimal care.

Can Genomic Assays Help with Treatment Decision Making?

Genomic assays can provide a clue as to which drugs might or might not work. For example, if someone has a mutation in the estrogen receptor (ER) gene ESR1, aromatase inhibitors probably will not work. Emerging evidence also suggests that patients with the PIK3CA mutation are more likely to respond to the phosphoinositide 3-kinase inhibitor Piqray (alpelisib). Individuals being treated with hormone therapy for breast cancer should discuss the role of blood based genomic monitoring to detect resistant mutations and early cancer progression. 

Hormonal Therapy Treatment of Metastatic or Recurrent Breast Cancer

When breast cancer occurs outside of the breast in the bones, lungs, liver or other organs, it is referred to as metastatic. Patients with breast cancer may also experience a recurrence of cancer after initial treatment with hormonal therapy. Patients with newly diagnosed metastatic breast cancer benefit from initial treatment with hormonal therapy and those with recurrent cancer may benefit from switching to a different hormonal therapy.

Recommendations set forth by a convening Expert Panel specifically for women with HR-positive, metastatic breast cancer included the following.27

  • Patients whose cancer cells express any level of HR-positivity should be offered endocrine therapy as initial therapy.
  • Sequential endocrine therapy (using one endocrine agent until the patient’s cancer progresses, then switching to a different endocrine agent until the cancer progresses again, etc.) is the preferred treatment of choice.
  • Among postmenopausal women, aromatase inhibitors (AIs) are the initial treatment of choice, with or without the addition of the CDK inhibitor Ibrance®.20-23 CDK inhibitor medications when combined with an AI however are superior to treatment with an AI alone.21 For example; the CDK inhibitor Verzenio demonstrated a greater than 28-month median progression-free survival in patients who received initial endocrine-based therapy for metastatic disease compared to 14.8 months for treatment with an AI alone.
  • If the patient’s cancer starts to progress on AIs, Faslodex® (fulvestrant) or combination therapy with a CDK inhibitor and an AI can further prolong survival. For example the CDK inhibitor Ibrance when combined with Faslodex nearly doubles the duration of survival when compared to an AI alone.22  The anti-estrogen drug Faslodex has been approved for the treatment of postmenopausal, estrogen receptor-positive metastatic breast cancer that has progressed following other anti-estrogen therapy.23
  • Among premenopausal women, ovarian suppression or ablation should be included in the treatment strategy. The CDK inhibitor Kisqali in combination with tamoxifen or an AI plus goserelin improve time of survival without cancer progression to 23.8 months compared to 13 months for tamoxifen or an aromatase inhibitor plus goserelin.11
  • Patients whose cancer is HER2-positive, agents targeted against HER2 in addition to endocrine therapy is recommended if patients are not able to tolerate chemotherapy.

Early Switch to Faslodex Benefits Patients with Estrogen Receptor Mutations

Switching from an aromatase inhibitor to Faslodex after detection of estrogen receptor mutations can delay recurrence in patients with hormone-receptor positive breast cancer being treated with Ibrance. Breast cancer can become resistant to aromatase inhibitor treatment through mutations in ESR1, the gene that encodes estrogen receptor alpha. The PADA-1 clinical trial evaluated the clinical benefit associated with a switch to Faslodex upon detection of a rising ESR1 mutation in blood in 1,017 patients with hormone receptor-positive, HER2-negative patients who were being treated with first-line aromatase inhibitor plus Ibrance. Patients provided blood samples for ESR1 mutation screening every two months. Among patients receiving an aromatase inhibitor plus palbociclib, those whose blood samples displayed a rising ESR1 mutation before disease progression and subsequently switched to fulvestrant had a median PFS of 11.9 months compared with 5.7 months in those who remained on an aromatase inhibitor.35

Can Hormonal Therapy Reduce the Risk of Developing Breast Cancer?

Drugs that block the effects of estrogen have been shown to reduce the risk of breast cancer in women at high risk of the disease. Two drugs that have been approved for breast cancer risk reduction in certain groups of women are tamoxifen and Evista® (raloxifene). Tamoxifen is approved for breast cancer risk reduction in women who are at high risk of the disease (including high-risk premenopausal women). Evista – originally approved for the prevention and treatment of osteoporosis — is approved for breast cancer risk reduction in postmenopausal women with osteoporosis or postmenopausal women at high risk of breast cancer.

To directly compare Evista to tamoxifen in the prevention of breast cancer in high-risk women, researchers conducted a clinical trial known to as the STAR trial (The NSABP Study of Tamoxifen and Raloxifene [STAR] P-2 Trial).24 The study found that Evista is as effective as tamoxifen in reducing the risk of invasive breast cancer in high-risk postmenopausal women, but may be less effective in reducing the risk of noninvasive breast cancers such as ductal carcinoma in situ (DCIS). Evista carried a lower risk of blood clots and cataracts than tamoxifen, but is not without side effects. Evista has been found to increase the risk of blood clots and fatal strokes in women with coronary heart disease or at risk for coronary heart disease.25

Are There Other Benefits Associated with Hormonal Therapy?

Hormonal treatment may offer additional benefits beyond the treatment of cancer. Although tamoxifen acts against the effects of estrogen in breast tissue, it acts like estrogen in certain other body systems. Tamoxifen may help to lower blood cholesterol and reduce the rate of bone loss (osteoporosis). Two clinical studies have reported that women treated with tamoxifen had a lower risk of cardiac disease than women not treated with tamoxifen.26 In addition, Evista®, another selective estrogen receptor modulator (SERM), is FDA-approved for the prevention and treatment of osteoporosis and appears to reduce the risk of breast cancer.27

What Are the Side Effects of Hormonal Therapy?

Tamoxifen: Tamoxifen is associated with some side effects similar to symptoms of menopause, which include hot flashes, irregular menstrual periods and vaginal discharge or bleeding. Not all women will experience these symptoms. More serious side effects can also occur as a result of long-term use of tamoxifen. There is a small increase in the number of blood clots in individuals taking tamoxifen. Individuals taking tamoxifen have a slightly increased risk of developing cataracts. In addition, tamoxifen appears to increase a woman’s risk of developing uterine cancer by about 2-3 times that of the general population.5-9 This risk of uterine cancer is similar to that for women taking postmenopausal estrogen replacement therapy. Since the majority of uterine cancers can be detected at an early stage when they are highly curable, the overall benefit of anti-estrogen treatment in breast cancer patients probably outweighs the risk of uterine cancer. All women who have a uterus and are receiving anti-estrogen therapy should undergo regular gynecologic examinations. The most common side effects caused by tamoxifen are

  • Hot flashes
  • Vaginal dryness
  • Discharge or Irritation
  • Decreased interest in sex.

These side effects are not usually serious, but they can be bothersome. Other side effects that are rare but are more dangerous include:

  • Overgrowth of the lining of the uterus (endometrial hyperplasia).
  • Cancer of the lining of the uterus (Endometrial cancer).
  • An increased risk of blood clots (in the legs (deep vein thrombosis and the lungs (pulmonary embolism).
  • A small increased chance of stroke.
  • Ovarian cysts
  • An increased risk of eye cataracts - Five or more years of tamoxifen use increases cataract risk and at higher doses and for longer periods of time, may lead to retinopathy. Breast cancer patients should have a baseline eye exam within the first year of treatment including an examination of the macula and testing of central and color vision.

Aromatase inhibitors: Possible side effects of AIs include joint pain and decreased bone density. In fact, as many as half of women on AI therapy experience joint pain, and 20% become non-compliant with their AI therapy because of side effects. The origin of AI-associated joint pain is unclear. There are no effective supportive care therapies to mitigate AI-associated joint pain and premature discontinuation of AI therapy may adversely affect breast cancer outcomes. Overall two-thirds of the women with AI-associated joint pain appear to have resolution or improvement of their symptoms once AI therapy was discontinued. For women whose joint pain is significantly affecting quality of life, it is important to discuss quality of life factors, side effects and benefits of staying on therapy with their physician in order to make an informed treatment decision.10,11

In a study known as the Intergroup Exemestane Study, postmenopausal women who had received two-to-three years of tamoxifen were assigned either to continue on tamoxifen or to switch to the aromatase inhibitor Aromasin. Women who switched to Aromasin had improved survival, but also experienced a minor loss of bone mineral density in the lumbar spine.12 Women who are treated with aromatase inhibitors may wish to talk with their doctor about bone health.

Sexual Function: Both Tamoxifen and aromatase inhibitors can have a negative impact on sexual functioning and diminish sexual enjoyment Sexual dysfunction should be addressed early and proactively in patients undergoing endocrine therapy.33

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