Hormonal therapy involves reducing the level of estrogen in the body. 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 are stimulated to grow when exposed to estrogen. These cells have estrogen receptors on their surface. Estrogen circulating in the blood binds to these receptors and stimulates growth-related activities in the cell. 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.
Hormonal therapy appears to benefit all women with early stage breast cancer. The hormonal therapies that have been investigated in the treatment of early stage breast cancer are:
Tamoxifen
Anti-aromatase drugs
Furthermore, there is some evidence that patients who have been treated with tamoxifen for 2-5 years may benefit from switching to an anti-aromatase drug.[1],[2]
Tamoxifen for Early Stage Breast Cancer
The results of several clinical studies indicate that hormonal treatment with tamoxifen, either alone[3] or in combination with chemotherapy[4],[5],[6],[7] can reduce the rate of cancer recurrence and improve the duration of survival in women with ER-positive breast cancer. Patients with ER-status-unknown breast cancer may also benefit, but tamoxifen does not appear to be a beneficial treatment for patients with ER-negative breast cancer. However, ER-negative patients are at high risk of developing a cancer in their other breast and may want to learn more about prevention of breast cancer using hormonal treatment.[8]
It is currently recommended that patients receive tamoxifen for 5 years.
Anti-Aromatase Drugs for Early Stage Breast Cancer
Anti-aromatase drugs have been shown to provide a greater reduction in the risk of cancer recurrence and appear to produce fewer side effects than tamoxifen. The anti-aromatase drugs that are approved for the treatment of early stage breast cancer include Arimidex® (anastrazole) and Femara® (letrozole).
One of the most notable studies designed to evaluate the use of an anti-aromatase drug in the management of early stage breast cancer was the Arimidex, Tamoxifen Alone or in Combination (ATAC) clinical trial. In this clinical trial, over 9,000 post-menopausal women with ER-positive or unknown receptor status, early stage breast cancer were treated with either Arimidex, tamoxifen, or both drugs as adjuvant therapy for five years and the results were then directly compared. After 2.5 years of treatment, patients treated with the anti-aromatase drug Arimidex had a 17% decrease in the risk of cancer recurrence compared to patients treated with tamoxifen.[9]
After 4 years of treatment, ER-positive and ER status unknown patients treated with Arimidex® were more likely to be alive without cancer recurrence than patients treated with tamoxifen . In addition, the rate of breast cancer in the opposite breast was reduced by half in patients treated with Arimidex compared to patients treated with tamoxifen. Patients treated with tamoxifen were more likely to develop uterine cancer, vaginal bleeding, stroke, blood clots and hot flashes, while patients treated with Arimidex experienced more musculoskeletal problems and bone fractures.[10]
Should patients switch from tamoxifen to an anti-aromatase drug?
Because the anti-aromatase agents appear to be superior to tamoxifen, physicians have conducted clinical trials to determine whether patients on tamoxifen should switch to an anti-aromatase drug. Arimidex has been shown to provide benefit following tamoxifen in the treatment of patients with early stage breast cancer. Research is ongoing to directly compare these post-tamoxifen options and determine which treatment provides the best outcomes.
Switching from tamoxifen to Arimidex has also been shown to reduce cancer recurrence. One study evaluated over 400 postmenopausal women with ER-positive breast cancer who had already been treated with tamoxifen for at least 2 years. Patients either continued with tamoxifen for up to 5 years or switched to Arimidex for a comparable amount of time.[11] The patients who switched to Arimidex had 60% fewer cancer recurrences than patients who remained on tamoxifen.
How long should patients take hormonal therapy?
Tamoxifen has been the standard drug for hormonal therapy and is typically administered for 5 years. Research is ongoing to determine if patients can benefit from more than 5 years of hormonal therapy.
Femara has been shown to provide a reduced risk of death and cancer recurrence when used after 5 years of tamoxifen. Over 5,000 postmenopausal women who had completed 5 years of treatment with tamoxifen participated in a clinical trial evaluating Femara. Approximately half of these women received Femara and the other half received a placebo (inactive substance). Overall, treatment with Femara reduced the risk of cancer recurrence by 40%. Women with node-positive disease that were treated with Femara had a 39% reduced risk of death compared to patients who received placebo.
Approximately 5% of the patients treated with Femara experienced a reduced quality of life compared to those treated with placebo. This included decreased physical function (6%), increased pain (5%), and decreased vitality (5%). However, a large proportion of patients considered the side effects to be worth the reduced risk of a cancer recurrence. This trial was stopped prematurely due to the obvious benefits of treatment with Femara compared to placebo.[12]
What is the optimal sequence of therapy?
The timing or sequence of therapy may be important. A large clinical study has addressed the question of whether radiation therapy should be given before or after chemotherapy following treatment with breast-conserving surgery. Following breast-conserving surgery, half the patients in this study were treated with chemotherapy followed by radiation and half were treated with radiation followed by chemotherapy. The patients treated with chemotherapy followed by radiation were more likely to live 5 years or more after treatment than patients treated with radiation followed by chemotherapy. Patients treated with chemotherapy first survived longer because they were less likely to experience systemic recurrence of their cancer. Patients treated with radiation first, however, were less likely to experience a local recurrence of their cancer.[13]
It is much easier to treat local recurrence of cancer than systemic recurrence of cancer and this may explain why the patients treated with chemotherapy followed by radiation had improved survival compared to patients treated with radiation followed by chemotherapy. An additional explanation is that delivering radiation therapy before chemotherapy treatment of systemic disease may adversely affect the doctor’s ability to deliver the chemotherapy treatment. Although the sequence of treatments is undergoing continued evaluation, the current data suggest that standard treatment of early stage breast cancer outside the context of a clinical study should include definitive surgery first, followed by systemic chemotherapy, and lastly, radiation. Hormone therapy can begin during or following radiation therapy.
Stage III Breast Cancer
Systemic Therapy: Chemotherapy, Targeted Therapy, and Hormonal Therapy
Chemotherapy
Targeted Therapy
Strategies to Improve Treatment
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References
[1] Goss P, Ingle J, Martino S, et al. Updated analysis of the NCIC CTC MA.17 randomized placebo (P) controlled trial of letrozole (L) after five years of tamoxifen in postmenopausal women with early stage breast cancer. Proceedings from the 40th annual meeting of the American Society of Clinical Oncology. New Orleans LA. 2004; Abstract #847.
[2] Goss, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. Proceedings from the 2003 San Antonio Breast Cancer Symposium. 2003.
[3] Muss HB. Role of adjuvant endocrine therapy in early-stage breast cancer. Seminars in Oncology. 2001;28:313-321.
[4] Early Breast Cancer Trialists’ Collaborative Group: Ovarian ablation in early breast cancer: Overview of the randomised trials. Lancet. 1996;348: 1189-1196.
[5] Fisher B, Redmond C, Legault-Poisson S, et al. Postoperative chemotherapy and Nolvadex® compared with Nolvadex® alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to Nolvadex®: Results from the National Surgical Adjuvant Breast and Bowel Project B-16. Classic Papers and Current Comments. 1996;1:71-84.
[6] International Breast Cancer Study Group. Effectiveness of adjuvant chemotherapy in combination with Nolvadex® for node-positive postmenopausal breast cancer patients. J Clin Oncol. 1997;15:1385-1394.
[7] Fisher B, Dignam J, DeCillis A, et al. The worth of chemotherapy and Nolvadex® (TAM) over TAM alone in node-negative patients with estrogen-receptor (ER) positive invasive breast cancer (BC): first results from NSABP B-20. Proceedings of American Society of Clinical Oncology. 1997;16:Abstract #1.
[8] Li CI, Malone KE, Weiss NS. Nolvadex® therapy for primary breast cancer and risk of contralateral breast cancer. Journal of the National Cancer Institute. 2001;13:963-965.
[9] Baum M, on behalf of the ATAC Trialists’ Group. The ATAC (Arimidex, Nolvadex, alone or in combination) adjuvant breast cancer trial in post-menopausal women. 24th annual San Antonio Breast Cancer Symposium. 2001.
[10] The ATAC (Arimidex, tamoxifen alone or in combination) trialists’ group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer. Cancer. 2003;98 (9):1802-1810.
[11] Boccardo F, Rubagotti A, Amoroso D, et al. Anastrozole appears to be superior to tamoxifen in women already receiving adjuvant tamoxifen treatment. Proceedings from the 2003 San Antonio Breast Cancer Symposium, 2003;Abstract #3.
[12] Goss P, Ingle J, Martino S, et al. Updated analysis of the NCIC CTC MA.17 randomized placebo (P) controlled trial of letrozole (L) after five years of tamoxifen in postmenopausal women with early stage breast cancer. Proceedings from the 40th annual meeting of the American Society of Clinical Oncology “Best of oncology symposium”, New Orleans, LA. 2004; Abstract #847.
[13] Recht A, Come SE, Henderson IC, et al. The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. N Engl J Med. 1996;334:1356-1361.