Endocrine-Hormone Therapy for Advanced-Metastatic Breast Cancer

Anti-estrogen endocrine or hormone therapy can be used to prevent estrogen sensitive ER + cancers from growing.

Charles H. Weaver, MD
14–21 minutes
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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 endocrine (hormonal) therapy for breast cancer.

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 Tamoxifen was the first anti-estrogen drug, but it has largely been replaced by aromatase inhibitors (AI) and Faslodex (fulvestrant) used alone or in combination with cyclin-dependent kinases (CDK) inhibitors and other precision cancer medicines because they are better at delaying cancer progression and prolonging survival.

How Does Endocrine 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 (AI) 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.

CDK Inhibitors

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 can be added to AI’s for the treatment of HR+, HER2- early stage and metastatic breast cancer in combination with an anti-estrogen drug.

CDK Inhibitors in depth…

Can Genomic Assays Help with Treatment Decision Making?

Genomic testing looks at a cancer cells DNA. Genomic testing can provide information to better understand an individual’s cancer and how best to manage it – which drugs might or might not work. The table below summarizes the frequency that various genomic alterations occur in breast cancer. Currently therapies that target PIK3CA, PTEN, ERB, ESR, and AKT are available. 

It’s important to further understand that some of these mutations are “acquired” after treatment.

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 and AKT mutations are more likely to respond to Truqap (capivasertib). Individuals being treated with endocrine 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.2
  • 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 Faslodex had a median PFS of 11.9 months compared with 5.7 months in those who remained on an aromatase inhibitor.35

Second line Endocrine Therapy

Second line endocrine therapies work best when they can target specific genomic alterations. Patients with ER + HER negative recurrent breast cancer can derive additional benefit from treatment with the following.

  • PIK3CA and ATK can be targeted with Truqap in combination with Faslodex.36
  • PTEN also appears to benefit from Truqap in combination with Faslodex.36
  • ESR1 is a resistance mutation “acquired” after treatment with an AI can be targeted with the precision medicine Orserdu (elecestrant).37

What about HER2 “low” disease?

Clinical trials are currently ongoing to determine if women with ER + HER2 negative cancers might benefit from treatment targeting HER2. Recent studies suggest that HER2 low expressing cancers benefit from treatment targeting HER2.

Are There Other Benefits Associated with Endocrine 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 Endocrine Therapy?

Endocrine therapy 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. Bone loss or osteopenia is a significant complication of endocrine therapy that can be prevented with bisphosphonate drugs.

Tamoxifen: 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

Connect With Others for Support and information

CancerConnect was the first social network created for people with cancer. Founded by oncologists to support breast cancer patients and their caregivers, over 40 million individuals have accessed CancerConnect programs since 1997. Cancer Connect is used by leading cancer centers like Dana Farber, Roswell Park and The James at Ohio State to support their patients. Join the conversation, ask questions, share your experience, and learn how the best cancer centers are treating breast cancer from others. Share your experience, ask a question, or start a conversation by posting on CancerConnect.

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