Hormonal therapies
Hormonal therapies, also known as hormone therapy or endocrine therapy, involve the use of synthetic hormones or hormone antagonists to treat certain cancers, particularly those that are hormone-sensitive. These treatments work by either blocking the action of hormones that promote cancer cell growth or reducing the production of these hormones in the body. Commonly associated with hormone-receptor-positive breast cancer, hormonal therapies are also utilized for prostate, endometrial, and adrenal cancers.
Key strategies include the use of selective estrogen receptor modulators (SERMs) like tamoxifen, which prevents estrogen from activating receptors in cancer cells, and aromatase inhibitors that lower estrogen production. While tamoxifen has historically been a standard treatment for breast cancer, aromatase inhibitors have emerged as more effective options for postmenopausal women.
Hormonal therapy may also come with various side effects, such as mood swings, weight gain, and an increased risk of certain cancers. Despite these potential risks, the benefits of hormonal therapy, particularly in reducing cancer recurrence, often outweigh the drawbacks for many patients. Understanding these therapies' mechanisms and implications is crucial for patients navigating cancer treatment options.
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Hormonal therapies
ALSO KNOWN AS: Hormone therapy, endocrine therapy, antiestrogen therapy
DEFINITION: Hormonal therapy is the use of exogenous hormones or hormone antagonists in the medical treatment of cancer. It removes hormones or prevents their growth and survival-promoting action in hormone-responsive cancer cells. Hormonal therapy should not be confused with hormone replacement therapy.
Cancers treated: Hormonal therapy most often refers to hormone-sensitive or hormone-receptor-positive breast cancer, but it also refers to several other types of cancers resulting from hormone-responsive tissues, including the prostate, endometrium, and adrenal cortex. Hormonal therapy may also be used to treat paraneoplastic syndromes, which arise from substances produced by tumors, or to alleviate certain chemotherapy-induced symptoms, such as (appetite loss).
Delivery routes: Oral
How these drugs work: Gonadal hormones, including estrogens and androgens, activate hormone receptors in hormone-responsive cells that, in turn, stimulate gene expression and may activate cell-signaling pathways to induce tumor growth. Hormone therapies prevent a specific hormone receptor from activating cell-signaling pathways that would induce tumor growth. There are two main effective strategies for starving hormone-responsive tumor cells. One strategy is to block a particular hormone’s ability to activate cell-signaling pathways, and the other approach is to introduce drugs that inhibit the production of the specific hormones responsible for tumor-cell growth.
In particular, 80 percent of breast cancer needs the hormone estrogen to grow. The metabolism of estrogen starts with the synthesis of cholesterol into androgens. Then, androgens, such as testosterone, are converted into estrogens via the aromatase enzyme. Primarily, estrogen is produced in the ovaries, but other tissues, including the liver, adrenal glands, and breasts, also produce estrogens. Although estrogen production in the ovaries ceases during menopause, the and other tissues continue to produce estrogen via the enzyme aromatase. Every year, approximately 23,000 postmenopausal women are diagnosed with estrogen-receptor-positive breast cancer.
One type of hormonal therapy for breast cancer patients prevents estrogen from binding to estrogen receptors to halt the growth of cancerous cells. This strategy has led to the development of tamoxifen (Nolvadex), which is a selective estrogen-response modulator (SERM) and an estrogen receptor antagonist. Tamoxifen used to be the gold standard of hormonal medicine for patients with hormone-receptor-positive breast cancer. It is used to treat breast cancer and in chemoprevention. Tamoxifen binds to estrogen receptors to prevent their activation, blocking a tumor’s ability to use estrogen. Raloxifene (Evista) is another SERM commonly used for chemoprevention of breast cancer in high-risk patients, and it also prevents osteoporosis, a common side effect of hormonal therapy. Toremifene (Fareston) and fulvestrant (Faslodex) are SERMs for treating metastatic breast cancer. Specifically, fulvestrant is an estrogen-receptor downregulator (ERD) that is an option for postmenopausal women with metastatic breast cancer that has stopped responding to antiestrogen therapy.
Like other hormone antagonists, tamoxifen is a weak agonist or weak estrogen. As a result, in patients who develop resistance to estrogen agonists, the best alternative treatments are aromatase inhibitors, which prevent the production of estrogens. As a result, estrogen levels drop, which induces apoptosis (cell death), thus halting the growth of hormone-responsive cancer cells. Several international clinical trials have shown evidence that the aromatase inhibitors Arimidex (anastrozole), Aromasin (exemestane), and Femara (letrozole) work more effectively than tamoxifen in postmenopausal women in treating breast cancer. Therefore, aromatase inhibitors have become the standard of care for postmenopausal women with hormone-receptor-positive breast cancer. For premenopausal women, however, tamoxifen remains the choice of hormonal treatment.
Typically, tamoxifen is used as adjuvant therapy following primary treatment for early-stage breast cancer. In the case of breast cancers in postmenopausal women, the first line of breast cancer treatment tends to be the use of aromatase inhibitors, such as letrozole and anastrozole. Exemestane is superior to megestrol in the treatment of tamoxifen-refractory breast cancer. Aminoglutethimide is a nonselective inhibitor that blocks aromatase and other enzymes that promote steroid hormone synthesis. Since it is nonselective to estrogen, it is not preferred to treat breast cancer. However, it may also be prescribed for the treatment of hyperadrenocortical syndromes, such as Cushing syndrome and carcinoma.
One of the most common cancers among men in the United States is prostate cancer. Antiandrogens (antitestosterone-like drugs), such as flutamide, bicalutamide, nilutamide, and cyproterone acetate, block the growth- and survival-promoting effects of testosterone and dihydrotestosterone in prostate cancer cells. Luteinizing hormone-releasing hormone (LHRH) agonists, like leuprolide (Lupron) and goserelin (Zoladex), stunt the pituitary gland's production of luteinizing hormones.
Another form of hormonal therapy is orchidectomy and ovariectomy (oophorectomy), which are surgical removal of male or female endocrine organs, respectively. In particular, removal of the Fallopian tubes and ovaries reduces the risk for or prevents breast and ovarian cancer in women at high risk because of mutations in the BRCA1 or BRCA2 gene. As an alternative to surgical castration, gonadotropin-releasing hormone (GnRH) analogs, such as leuprolide and goserelin, are used for chemical castration. GnRH suppresses the production of estrogen and progesterone in the ovaries and the production of testosterone by the testes.
While most hormonal therapies block hormone-induced signals to cancer cells, in some therapies, the hormone supplementation has a cytotoxic effect on tumor cells. Progestins (progesterone-like drugs), androgens, and estrogens are among these hormones.
Side effects: The side effects of hormonal therapy vary among treatments. Side effects may be brief, mild, and manageable, or they may be serious. In women, side effects of hormonal therapy that are common to all treatments are mood swings, depression, weight gain, hot flashes, vaginal dryness, early start of menopause, and, in metastatic cancer, burning pain in the bones. Tamoxifen promotes a less than 1 percent increased risk of uterine cancer, blood clots, cataracts, stroke, and fertility issues. Hormone therapy with tamoxifen or estrogens may increase the chance of developing endometrial cancer; therefore, women taking tamoxifen should have a pelvic examination every year to look for any signs of cancer. In particular, abnormal vaginal bleeding (other than menstrual bleeding) while taking estrogen-like medication should be reported to a doctor as soon as possible. The benefits of tamoxifen, however, far outweigh the potential risks. Aromatase inhibitors may induce osteoporosis and cause upset stomach and sweating, and they can increase cholesterol levels and the risk of blood clotting. Unlike other aromatase inhibitors, exemestane does not appear to have osteoporosis-promoting side effects. Similar to aromatase inhibitors, ERDs may weaken bones and cause upset stomach. In addition, ERDs may also cause swelling at the injection site. Ovariectomy weakens the bones and results in infertility.
Research shows that tamoxifen used for early-stage breast cancer reduces the risk of recurrence of the primary cancer and the risk of developing new cancers in the other breast. Most patients take tamoxifen for five to ten years, but some take it longer. Many women develop resistance to hormonal therapy over time, leading to cancer recurrence. After tamoxifen treatment, breast cancer recurs in about one-quarter of patients after five years. In large-scale clinical trials, steroidal and nonsteroidal aromatase inhibitors are superior to tamoxifen in extending survival in postmenopausal women with metastatic disease and in preventing recurrence when used as primary adjuvant therapy.
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