Hormonal Cancer Treatments

All cells respond to signals sent from other cells. One main way that cells communicate is hormones. Hormones can be either small proteins (like insulinA protein hormone secreted by the pancreas. Insulin controls glucose levels in the body by increasing uptake of glucose into cells of the body. Insulin also stimulates the formation of glycogen and alters fat and protein metabolism.) or they can be derived from steroids (like estrogenA steroid sex hormone. Estrogen's structure is closely related to cholesterol. Produced by the ovaries, estrogen has effects on the reproductive, cardiovascular and skeletal systems. Estrogen is also a growth factor for some types of cells, including breast cells. Inhibitors of estrogen function such as tamoxifen and arimidex are used to block the growth effects of estrogen. See also, estrogen receptor. and testosteroneTestosterone is the main male sex hormone and is responsible for the generation of the secondary sex characteristics. The hormone is produced in male testes and is normally found to a much lesser extent in females.). The signaling cell produces the hormoneA chemical produced by cells that alters the activity of other cells. The chemicals may be lipids, such as testosterone and estrogen or proteins like insulin. Hormones may act at locations far from their site of origin. Estrogen, for example, is produced primarily by cells in the ovaries but acts on cells in the breast and elsewhere. that floats over and binds to (or enters) the target cell to cause a change in behavior. Hormones can cause a cell to produce new proteins or to stop making products that were already being produced. One possible outcome of hormone signals is the growth and reproduction of the target cells.

Cancer cells, while abnormal, may retain the ability to respond to hormonal signals. The idea behind the majority of hormone-based cancer treatments is to starve the cancer cells of the hormonal signals that would otherwise stimulate them to divide. The drugs used in these treatments work by blocking the activity of the hormone in the target cell. Some newer treatments under investigation are designed to prevent the production of the hormone, cutting off the signal at the start. Some forms of breast, ovarian and prostate cancer are subject to hormonal treatments.

Hormonal treatments are often combined with surgery and/or radiationIn cancer biology: A cancer treatment in which high energy beams are used to kill cancer cells. Radiation can also cause genetic damage that can lead to cancer. As an example, skin cancer is believed to be greatly increased by exposure to ultraviolet (UV) radiation from the sun. and/or chemotherapyTreatment of cancer patients with anticancer drugs. Commonly called 'chemo'. These drugs work by attacking cell growth or division. Often these agents are used in combination to take advantage of their different modes of attack on cell division.. In these situations, the hormonal treatments are referred to as an 'adjuvant' treatment.

The hormonal treatments described below all work by interfering with hormonal signals but, as shown above, they may attack different parts of the signaling pathways to slow cancer growth. The different kinds of hormone inhibitors (also called 'antagonists') include:

• Selective Estrogen Receptor Modulators (SERMs): These agents work by interfering with the activity of the estrogen receptorA protein located within cells that binds estrogen. The protein:estrogen complex then binds to DNA to increase the transcription of certain genes, and therefore is a type of transcription factor. The estrogen receptor is the target of the anticancer drug tamoxifen. By binding to the estrogen receptor tamoxifen blocks the growth promoting effects of the hormone. May be abbreviated as ER.. Drugs that work this way include tamoxifen (Nolvadex®), raloxifene (Evista®) and toremifene (Fareston®)
• Aromatase Inhibitors: These drugs work by blocking the production of estrogen by the enzyme that makes it from its precursor. Drugs that work this way include anastrozole (Arimidex®), exemestane (Aromasin®) and letrozole (Femara®).
• Receptor Down-regulators: This class of drugs works by lowering the levels of the receptor for estrogen. Fulvestrant (Faslodex®) is a drug in this category.
• Selective Androgen Receptor Modulators (SARMs): These agents work by interfering with the activity of the androgen receptor. Drugs that work this way include flutamide (Eulexin®) and bicalutamide (Casodex®).
• Other Hormone Treatments: These drugs work to affect the production or activity of hormones in a manner that is not covered in the above categories. The way by which these drugs work may not be entirely clear.  An example of this type of drug is megastrol (Megace®).
• Glossary of Hormonal Treatment: An easy to use table of hormonal treatment drugs including trade name, generic name, and type. Contains links to additional information.
• Know the Flow: Hormonal Treatments: An interactive self-test about hormonal treatments for cancer.

Selective Estrogen Receptor Modulators (SERMs)

Many individuals with breast cancer have tumors driven to grow by the naturally occurring hormone, estrogen . One of estrogen's normal activities is to cause the proliferationRefers to cell division. The proliferation rate is an indicator of how quickly a tumor is growing. The proliferation rate may be represented as a percentage, showing what fraction of the cells are actively involved in the division process. of cells in the breast and uterus; each month new cell linings must be created for the milk glands (breast) and the endometrium (uterus). In some breast cancer patients this normal expression of estrogen contributes to the growth and division of the cancer cells. For these patients, treatment with selective estrogen receptor modulators (SERMs), also known as anti-estrogens, is appropriate.

The drugs work by causing changes in the shape of estrogen receptors (ERThe endoplasmic reticulum. A large subcellular network of membranes within the cell. The ER membrane, an extension of the outer nuclear membrane, has two structurally and functionally distinct regions: Rough ER (RER) and Smooth ER (SER). The RER ( the portion closer to the nucleus) has a 'rough' appearance due to ribosomes attached to the surface of the membrane. Ribosomes attached to the ER are producing proteins that are to be released from the cell. Smooth ER (SER) appears smooth and is devoid of ribosomes. SER functions include the detoxification of drugs, the production of steroid hormones and the formation of membrane components. Molecules produced by the RER and SER can be packaged into vesicles and sent to other locations in the cell or to the outside of the cell.), preventing the action of the hormone. The drugs only affect a subset of the cells capable of responding to estrogen but the precise mechanism of this selectivity is not yet known. It is this selective action that has earned the drugs their name. The blockage of estrogen in the target cells causes changes in geneA stretch of DNA that leads to the production of an RNA. The RNA is produced during the process of transcription. This RNA can be used to guide the formation of a protein via translation or can be used directly in the cell. expression and alters the behavior of the cells, preventing cell division.1

In 1992, tamoxifen became the first SERM to be used for the treatment of breast cancer. While it does decrease estrogenic effects in the breast, it unfortunately has a pro-estrogenic activity in the uterus, causing a rise in uterine cancer for tamoxifen-treated breast cancer patients.2

Recently, next generation SERMs such as raloxifene have been investigated for their potential as breast cancer treatments. This drug appears to have anti-estrogenic effects in both breast and uterine tissues. Two six-month studies conducted in 1999 show that raloxifene does not stimulate endometrialRefers to the endometrium, the inner lining of the uterus. The endometrium is a common site of cancer. growth. Studies of 969 post-menopausal women taking raloxifene showed that treatment with the drug did not lead to a significant increase in endometrial thickness as compared to women taking a placebo.3

The results of the STAR trial showed that raloxifene was equal to tamoxifen for the prevention of invasive breast cancer in post-menopausal women and had somewhat improved side effects.4, 5, 6

In 2007, the U.S. Food and Drug Administration approved raloxifene hydrochloride tablets (EVISTA, Eli Lilly and Company) to reduce the risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive breast cancer.7, 8, 9

Watch an animation showing how these drugs work.

Tamoxifen (Nolvadex®)
Raloxifene (Evista®)
Toremifene (Fareston)

Inhibitors and Down Regulators

Additional hormonal treatments have been developed which can act as alternatives to treatment with SERMs (tamoxifen/raloxifene) or be utilized if SERMs are ineffective. Tamoxifen and raloxifene are both designed to interfere with the action of estrogen once it has entered a target cell. There are several other points of attack that may be taken to prevent signalling via estrogen. The most direct approach is to prevent the production of the estrogen by blocking the enzyme that is responsible for its formation, aromatase.

A second approach is to remove the target of the estrogen (the estrogen receptor). Both of these approaches to therapy have been developed for the treatment of breast cancer. Because these hormone treatments block estrogen production or function, they can have negative side effects on pregnancy. Therefore, they are used to treat postmenopausal women.10

Watch animations of the estrogen receptor and the action of the drug tamoxifen.

Aromatase Inhibitors
After menopause, women produce a consistent low level of estrogen that is derived from androgen precursors. These precursors are converted to estrogen through the actions of the enzyme aromatase. By blocking the action of this enzyme, aromatase inhibitors prevent the formation of estrogen. There are two types of aromatase inhibitors that have been approved as treatment for postmenopausal women with estrogen-receptor positive metastaticThe term for a cancer that has spread beyond its point of origin. Metastatic disease is responsible for the majority of cancer deaths. breast cancer: steroidal inhibitors such as exemestane (Aromasin®) and non-steriodal inhibitors that competitively bind to aromatase (anastrozole and letrozole).10

Anastrozole
Exemestane
Letrozole

An advantage of these drugs is that they do not apear to have the side effect of increasing the risk of endometrial cancer.10

Because they interfere with that activity of the sex hormone estrogen, aromatase inhibitors do have additional side effect of impacting sexual function and satisfaction.11

Estrogen Receptor Down-regulators
By decreasing the concentration of estrogen receptors and their activity, the effects of estrogen can be negated.

Fulvestrant

Selective Androgen Receptor Modulators (SARMs)

Testosterone and dihydroxytestosterone (DHT) are two hormones (androgens) produced in the testes and adrenal glands. Among other activities, these hormones bind to specific receptors in the cells of the prostate. A normal function of this binding is to regulate the growth of the prostate cells, however, in cancer cells this regulation is compromised. The androgens bind to the receptors in cancer cells and contribute to their growth and division.

Anti-androgen molecules have been created, that can enter cells and prevent the binding of testosterone to the receptor proteins. This occurs via the preferential binding of the drug molecule to the androgen receptors. The binding of the drug prevents the androgens from binding and therefore reduces their pro-growth activities.12

Bicalutamide(Casodex®)
Flutamide (Eulexin®)
Nilutamide (Nilandron®, Anandron®)

The drugs are frequently used in combination with surgery to cause the maximal reduction in androgen levels.13PUBMED] Additional drugs are also being studied for their ability to reduce androgen levels in prostate cancer patients and to overcome the drug resistance seen in some patients. 14, 15

Additional Hormone Treatments

Additional agents have been developed to interefere with the hormonal control of cell division. These agents may mimic naturally occuring hormones or may work through novel or unknown mechanisms. Examples of this type of drug include:

Megestrol (Megace): this drug interferes with the production and/or activity of estrogen. 16

Know the Flow: Hormonal Treatments

Know the Flow is an educational game for you to test your knowledge. To play:

• Drag the appropriate choices from the column on the right and place them in order in the boxes on the left. Note that you will only use five of the six choices to complete the game.
• When done, click on 'Check' to see how many you got correct.
• For incorrect answers, click on 'Description' to review information about the processes.
• To try again, choose 'Reset' and start over.