Hormone Therapy For Breast Cancer

Proteins called the hormone receptors are present in hormone-sensitive breast cancer. They are activated on binding to hormones causing alteration in the expression of specific genes. These genetic alterations stimulate cell growth. (1) Hormone therapy is employed in the management of breast cancer to remove the hormone (estrogen) or block its action to stop the growth and multiplication of cancer cells. (2) It is employed for hormone-sensitive breast cancers. Hormonal therapy is usually considered after the surgical resection of the malignancy. However, in a few cases it may also be employed before surgery to shrink the size of the tumor. Hormonal therapy is generally recommended for duration of 5 years. (3)

• Reduces the size of the tumor before surgery
• Prevents the recurrence of the cancer, after surgical resection
• Decreases the incidence of cancer in other breast tissue
• Delays or completely stops the growth of cancer cells

Although effective, hormonal therapy may be associated with a few adverse effects which may vary from one drug to another. Some of the common adverse effects associated with hormonal therapy include hot flashes, menstrual disturbances, vaginal discharge or dryness, fatigue, nausea, headache, skin rash and muscle and joint pain. Hormonal therapy may also lead to more serious conditions such as stroke, venous thrombosis, endometrial or uterine cancer, heart disease, osteoporosis and fractures. Women on tamoxifen should avoid pregnancy while on the drug or until two months after its discontinuation as it may have an adverse effect on the fetus (teratogenic potential). (5)

Some of the common hormonal therapies used in the management of breast cancer are discussed below.

These drugs exert an anti-estrogenic effect on the estrogen receptors of the breast cancer cells. They temporarily block the binding of estrogen to these receptors. They are available in the form of oral pills.

In women with hormone sensitive breast cancer, post-surgery tamoxifen therapy for 5 years reduces the rate of recurrence by 50%. It can also be used for the management of metastatic breast cancer and in women who are at an increased risk of breast cancer (positive family history or other risk factors). Toremifene has an action similar to that of tamoxifene and is indicated in patients with metastatic breast cancer. However, these drugs may be associated with hot flashes, vaginal dryness or discharge, fatigue, and mood swings. Some patients with bony metastasis may experience a tumor flare associated with pain and swelling of the adjoining muscles and bone. This may usually subside but in some patients it may result in an increase in the blood calcium levels which requires treatment. In post-menopausal, women these drugs can increase the risk of endometrial cancer. They may also be associated with deep vein thrombosis and pulmonary embolism. In rare cases, tamoxifene has been found to be associated with stroke in post-menopausal women. Tamoxifene may cause the thinning of bones in pre-menopausal women while it increases the strength of the bones in post-menopausal women. Despite the associated adverse effects, these drugs are indicated in patients with breast cancer as the benefits far outweigh the risks. (6)

These drugs block estrogen production in post-menopausal women and have been approved for the management of early as well as advanced breast cancer. The commonly used AIs include letrozole (Femara®), anastrozole (Arimidex®), and exemestane (Aromasin®). They act by blocking the aromatase enzyme which is responsible for the production of estrogen from fat tissue. As they do not block the production of estrogen from the ovaries they are not very effective in women with functional ovaries. These drugs are also available in the form of oral pills.

Clinical studies have demonstrated that these drugs used alone or after tamoxifene therapy significantly reduce the recurrence of breast cancer when compared to tamoxifene monotherapy, for 5 years. Some of the common drug regimens for the AI include:

• Two to three years of Tamoxifen, followed by an AI to complete the 5 years course
• Tamoxifen followed by an AI for 5 years each
• AI monotherapy for 5 years

These drugs have been now recommended for the management of hormone-sensitive breast cancer in post-menopausal women. However, it is not clear if adjuvant therapy with one of these agents is superior to initiation of AI therapy after a course of tamoxifene therapy. The efficacy of treatment with these agents for duration beyond 5 years is also not clear.

Aromatase inhibitors are associated with fewer side effects. They are not associated with uterine cancers and do not generally cause blood clots. However, patients may experience muscle pain and joint stiffness with/without pain. This may generally resolve by changing to a different AI. In patients with joint pain due to AI, doctors recommend switching to tamoxifene therapy to complete 5 years of treatment. As AIs block estrogen production in post-menopausal women they may lead to osteoporosis and fractures. Hence patients on AIs should also be treated with bone strengthening drugs such as bisphosphonates and denosumab. (6) Ovarian ablation: This is commonly considered in pre-menopausal women with breast cancer to stop the production of estrogen form the ovaries. This is considered in the management of metastatic breast cancer and may enhance the efficacy of other hormone therapies.

Permanent ovarian ablation can be achieved by oophorectomy, which refers to the surgical removal of the ovaries. However, in most cases ovarian ablation is achieved with the help of luteinizing hormone-releasing hormone (LHRH) analogues such as goserelin (Zoladex®) or leuprolide (Lupron®). They hamper the transmission of signals to the ovaries, thereby stopping estrogen production. They be either be used alone or with tamoxifene in pre-menopausal patients. Clinical studies are being conduction to evaluate their efficacy in pre-menopausal women, in combination with AIs.

Chemotherapeutic agents may themselves damage the ovaries. The ovaries may resume normal functioning in a few months to a few years while in a few patients the ovaries may be permanently damaged leading to menopause. Although this may affect the fertility of the patient, this may be beneficial with respect to breast cancer. As these agents induce menopausal changes, they may be associated with hot flashes, night sweats, vaginal dryness, and mood swings. (6)

Fulvestrant also acts on the estrogen receptors. Rather than just blocking these receptors, it causes a transient elimination of the estrogen receptors. It is also effective in patients where the breast cancer stops responding to tamoxifene therapy. It is administered in the form of an injection, once in a month. It may cause nausea, hot flashes and fatigue. Currently the FDA has approved its use only in post-menopausal breast cancer patients not responding to tamoxifene or toremifene. (6)

This is a progesterone-like drug indicated in the management of advanced breast cancer, especially in women whose breast cancer does not respond to other hormonal therapies. One of the most common side effects associated with megestrol is weigh gain. However, high doses of megestrol are used in few patients with advanced cancer to reverse weight loss. Being an old drug, it is no longer commonly used. (6)

In patients with advanced breast cancer not responding to any of the commonly used hormonal therapies, male hormones (androgens) may be considered. These may be effective in a few cases but may be associated with masculine characteristics such as increased body hair and deepening of voice.

High doses of estrogen are another option for patients with advanced breast cancer not responding to any of the commonly used hormonal therapies. However, this may be associated with serious side effects such as deep vein thrombosis and pulmonary embolism.