Hormone Therapies
Breast and prostate cancers are unique among cancers in that they depend for their survival on the body’s hormones. The discovery that manipulating the endocrine system could affect the growth of cancer was made in 1896, when a Scottish surgeon named Sir George Beatson reported that several women with advanced breast cancer experienced dramatic shrinkage of their tumors after he removed their ovaries. By performing this surgery, Beatson had removed the major source of the hormone estrogen from the women’s bodies. Although estrogen had not yet been discovered, he knew that the ovaries could powerfully influence breast activity after observing that farmers removed the ovaries of cows after they gave birth, causing them to produce milk indefinitely. Fifty years later, other pioneering surgeons found that castration induced remissions of advanced prostate cancer; in these cases, production of the hormone testosterone was drastically reduced.
Researchers continue to focus on ways of manipulating the endocrine system in order to treat or prevent breast and prostate cancers. Surgery to remove the ovaries or testes remains an important weapon. In addition, an expanding array of drugs has become available. Some provide an alternative way of lowering estrogen or testosterone levels, whereas others prevent the hormones from acting once they reach a cancer.
THE BASIS OF HORMONE THERAPY
All hormone treatments ultimately work by blocking the signals generated inside cancer cells by estrogen or testosterone. Like a plant deprived of sunlight and water, hormone-dependent cancers cannot survive without their hormones. Therefore, the therapies that are commonly called “hormone treatments” are actually antihormone treatments.
How does estrogen initiate each menstrual cycle? How does testosterone induce facial hair? Why do these hormones stimulate breast and prostate cancers to grow? Whichever hormone function we consider, they all boil down to the actions of two pairs of molecules: estrogen plus the estrogen receptor (ER) on the female side and testosterone plus the androgen receptor (AR) on the male side. The ER and AR are collectively called hormone receptors.
The attachment of a hormone to its receptor inside a cell is like a baseball landing in a mitt.
In contrast to the growth receptors described before, hormone receptors exist inside cells, not on their surfaces. Once a hormone enters a cell and finds its receptor, the two go together to attach to DNA. This attachment turns on the DNA and results in the activation of a multitude of genes, accounting for the cell’s response to that hormone. For example, breast cells respond to rising levels of estrogen during puberty by maturing; breast cancers that contain the ER (75 percent of them) respond to estrogen by proliferating. Regardless of the type of cell affected, all of these hormonal changes are caused by estrogen binding to the ER. There are two main approaches to stopping the hormonal stimulation of cancer. The first is to reduce the levels of estrogen or testosterone by halting its production. In breast cancer, leuprolide (Lupron), goserelin (Zoladex), and similar medicines prevent the ovaries from making estrogen by blocking cues from the brain that regulate the ovaries. Anastrazole (Arimidex), exemestane (Aromasin), letrozole (Femara), and otheraromatase inhibitors prevent fat and other body tissues from making estrogen. In prostate cancer, Lupron and similar medicines prevent the testicles from manufacturing testosterone by blocking cues from the brain that tell them to do so. Ketoconazole prevents the adrenal glands from making testosterone.
The second approach is to prevent the hormone from attaching to its receptor. The following drugs bind to hormone receptors, blocking estrogen and testosterone from binding to them; as a result, these hormones cannot influence cell behavior. In breast cancer, tamoxifen (Nolvadex) binds to the estrogen receptor and blocks estrogen from binding to it. Fulvestrant (Faslodex) binds to the estrogen receptor and causes the cell to destroy the receptor so that estrogen has no target. In prostate cancer, flutamide (Eulexin), bicalutamide (Casodex), and nilutamide (Nilandron), called antiandrogens, attach to the androgen receptor and prevent testosterone from binding to it. The use of Lupron (or similar drugs) plus an antiandrogen is called “complete androgen blockade”: Lupron dramatically lowers (but not to zero) the amount of testosterone in the bloodstream, and the antiandrogen prevents any remaining testosterone from binding to its receptor. Without the hormonal signals that sustain them, breast and prostate cancer cells wither and die.
