for Breast Cancer
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. However, a reduction in estrogen levels 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 is an anti-estrogen drug that has historically been a mainstay of hormonal therapy. Tamoxifen 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.
- How Does Hormonal Therapy Work?
- What Are the Side Effects of Hormonal Therapy?
- How Are Hormonal Therapies Used in the Treatment of Early-stage Breast Cancers?
- How Are Hormonal Therapies Used in the Treatment of Metastatic or Recurrent Breast Cancer?
- Can Hormonal Therapy Reduce the Risk of Developing Breast Cancer?
- Are There Other Benefits Associated with hormonal Therapy?
- What New Strategies Are Being Developed to Improve the Hormonal Therapy?
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 drugs2,3,4 are approved for the treatment of postmenopausal women with breast cancer:
- Femara® (letrozole)
- Arimidex® (anastrozole)
- Aromasin® (exemestane)
Femara and Arimidex are nonsteroidal 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. A new precision cancer medicine known as a cyclin-dependent kinases (CDK) inhibitor interferes 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- advanced or metastatic breast cancer in combination with an anti-estrogen drug.
- Verzenio (abemaciclib)
- Kisqali (ribociclib)
- Ibrance (palbociclib)
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.6,7,8,9 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.
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® (exemestane). 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.
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, tamoxifen remains the mainstay of hormonal therapy for early-stage breast cancer.13 Tamoxifen 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 leuteinizing hormone releasing hormone (LHRH) agonists, is another approach to hormonal therapy that may be incorporated into the treatment of premenopausal breast cancer patients.
For postmenopausal women, use of an aromatase inhibitor (either alone or sequentially with tamoxifen) appears to produce better outcomes than tamoxifen alone. 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 or aromatase inhibitors could be used in place of tamoxifen as initial hormone therapy.16,17 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
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. Hormonal therapy for advanced breast cancer differs depending on whether it is being administered as:
- Initial treatment of metastatic breast cancer
- Hormonal therapy after prior tamoxifen
- Hormonal therapy after prior anti-aromatase drugs
Initial Treatment of Metastatic Breast Cancer
For premenopausal women, initial treatment of metastatic breast cancer historically used tamoxifen or an AI.19 More recent studies however have shown that the CDK inhibitor Kisqali in combination with tamoxifen or an AI plus goserelin improved time of survival without cancer progression to 23.8 months compared to 13.0 months for tamoxifen or an aromatase inhibitor plus goserelin.11
For postmenopausal women, initial treatment with an aromatase inhibitor appears to result in more anti-cancer response and/or delays in cancer progression than treatment with tamoxifen20, and the CDK inhibitor medications21 when combined with an AI are superior to treatment with an AI alone. For example; the CDK inhibitor Verzenio demonstrated a greater than 28-month median progression-free survival (PFS) in patients who received initial endocrine-based therapy for metastatic disease compared to 14.8 months for treatment with an AI alone.
Treatment of Patients with Advanced Breast Cancer That Have Failed Prior Hormonal Therapy
For individuals with metastatic breast cancer that has stopped responding to tamoxifen, or an AI clinical trials have demonstrated that 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 antiestrogen 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
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
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, raloxifene (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
1 Lake DE, Hudis C. Aromatase Inhibitors in Breast Cancer: An Update. Cancer Control. 2002;9:490-498.
2 Food and Drug Administration. FDA Oncology Tools Approval Summary for Femara® for Treatment of advanced breast cancer in postmenopausal women. Accessed March 29, 2002.
3 Food and Drug Administration. FDA Oncology Tools Approval Summary for Arimidex® for Treatment of advanced breast cancer in postmenopausal women with disease progression following Nolvadex® therapy. Accessed March 29, 2002.
4 Food and Drug Administration. FDA Oncology Tools Approval Summary for Aromasin® for Treatment of advance breast cancer in postmenopausal women whose disease has progressed following Nolvadex® therapy. Accessed March 29, 2002.
5 Patnaik A, Rosen LS, Tolaney SM, et al. Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors [published ahead of print May 23, 2016]. Cancer Discov. 2016;6:740-753.
6 Pritchard KI, Paterson AHG, Paul NA, Zee B, Fine S, Pater J. Increased thromboembolic complications with concurrent Nolvadex® and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. Journal of Clinical Oncology 1996;14:2731-2737.
7 Love RR, Cameron L, Connell BL, Leventhal H. Symptoms associated with Nolvadex® treatment in postmenopausal women. Arch Intern Med 1991;151:1842-1847.
8 Nolvadex®-associated eye toxicity. Bethesda, Md.: National Cancer Institute, January 27, 1997.
9 Fisher B, Costantino JP, Redmond CK, Fisher ER, Wickerham DL, Cronin WM. Endometrial cancer in Nolvadex®-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. Journal of the National Cancer Institute 1994;86:527-537.
10 Burstein HJ. Aromatase inhibitor-associated arthralgia syndrome. Breast. 2007 Jun;16(3)223-34.
11 Laroche M, Seniow M, Roche H, Ruyssen-Witrand A. Arthralgia Associated with Autoimmune Abnormalities under Aromatase Inhibitor Therapy: Outcome after Cessation of Treatment. Journal of Rheumatology. 43;10; 1945-1946. doi: 10.3899/jrheum.160254
12 Coleman R, Banks L, Girgis S, et al. Skeletal effects of exemestane on bone mineral density, bone biomarkers, and fracture incidence in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES): a randomised controlled study. Lancet Oncology . 2007;8:119-27.
13 Davidson NE, Osborne CK. Adjuvant Endocrine Therapy for Early-stage Breast Cancer. In: Govindan R, ed. American Society of Clinical Oncology 2007 Educational Book. Alexandria, VA: American Society of Clinical Oncology; 2007:96-99.
14 Goss P, Ingle J, Martino S, et al. Randomized Trial of Letrozole Following Tamoxifen as Extended Adjuvant Therapy in Receptor-Positive Breast Cancer: Updated Findings from NCIC CTG MA.17. Journal of the National Cancer Institute. 2005; 97: 1262-1271.
15 Coombes RC, Paridaens R, Jassem J et al. First Mature Analysis of the Intergroup Exemestane Study: a Randomized Trial in Disease-free, Postmenopausal Patients with Early Breast Cancer Randomized to Continue Tamoxifen or to Switch to Exemestane Following an Initial 2-3 Years of Adjuvant Tamoxifen. Presented at the 2006 ASCO Annual Meeting. Abstract #LBA527.
16 Howell A, Cuzick J, Baum M et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) Trial after Completion of 5 Years’ Adjuvant Treatment for Breast Cancer. The Lancet. 2005;365:60-2.
17 The Breast International Group (BIG) 1-98 Collaborative Group. A Comparison of Letrozole and Tamoxifen in Postmenopausal Women with Early Breast Cancer. New England Journal of Medicine. 2005;353:2747-57.
18 Fisher B, Dignam J, Wolmark N et al. Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet. 1999;353:1993-2000.
19 Klijn JGM, Blamey RW, Boccardo F, Tominaga T, Duchateau L, Sylvester R. Combined tamoxifen and leuteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer. Journal of Clinical Oncology. 2001;19:343-353.
20 Tripathy D, Sohn J, Im S, et al. First-line ribociclib or placebo combined with goserelin and tamoxifen or a non-steroidal aromatase inhibitor in premenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer: results from the randomized Phase III MONALEESA-7 trial. Presented at the San Antonio Breast Cancer Symposium (SABCS), December 6, 2017, San Antonio, Texas (abstract#S2-05).
21 Altundag K, Ibrahim NK. Aromatase Inhibitors and Breast Cancer: An Overview. The Oncologist. 2006;11:553-562.
22 Turner NC, Ro J, André F, et al. Palbociclib in Hormone-Receptor–Positive Advanced Breast Cancer. New England Journal of Medicine. June 1, 2015DOI: 10.1056/NEJMoa1505270.
23 Vogel VG, Costantino JP, Wickerham DL et al. Effects of Tamoxifen vs Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes. Journal of the American Medical Association. 2006;295:(doi:10.1001/jama.295.23.joc60074).
24 Barrett-Connor E, Mosca L, Collins P, et al. Effects of Raloxifene on Cardiovascular Events and Breast Cancer in Postmenopausal Women. New EnglandJournal of Medicine. 2006; 355: 125-137.
25 Rutqvist LE, Mattsson A. Cardiac and thromboembolic morbidity among postmenopausal women with early-stage breast cancer in a randomized trial of adjuvant Nolvadex®. Journal of the National Cancer Institute 1993;85:1398-1406.
26 Vogel VG, Costantino JP, Wickerham DL et al. Effects of Tamoxifen vs Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes. Journal of the American Medical Association. 2006; 295:2727-41.