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Tamoxifen: A Treatment With A New Role
Tamoxifen (brand name Nolvadex) is the best-known hormonal treatment and the most prescribed anti-cancer drug in the world. Hormonal therapy is the use of drugs capable of preventing the spread of cancer by depriving malignant cells of hormones that prompt their growth. In some cases, hormonal therapy can reduce cancer recurrences after initial treatment with surgery and radiation. In others, it can decrease the growth of advanced cancer. In contrast to conventional chemotherapy, which is designed to kill cancer cells, hormonal therapy usually is relatively nontoxic. Hair doesn't fall out, and most patients don't get the nausea that often accompanies chemotherapy.
Used for over 20 years to treat women with advanced breast cancer, tamoxifen also is commonly prescribed to prevent recurrences among women with early breast cancer. And tamoxifen actually can prevent breast cancer among healthy women who are considered at high risk for breast cancer.
How Hormonal Therapy Works
Several other hormonal drugs are used to treat advanced breast cancer or cases that have recurred despite treatment with tamoxifen. Hormonal drugs that turn off production of the male hormone testosterone are used to treat prostate cancer, usually when the disease is advanced. However, studies are underway to determine whether hormonal agents are useful in treating newly diagnosed prostate cancer or whether they actually can prevent the disease.
Doctors have long known that depriving breast-cancer cells of the female hormone estrogen can reduce the chances of a recurrence. At one time, it was common practice to remove the ovaries in order to eliminate the major source of estrogen. Today, before recommending treatment with hormonal drugs, doctors first must determine whether or not breast-cancer cells are sensitive to estrogen. Laboratory studies of cells from a breast-cancer tumor can reveal the presence of estrogen receptors, tiny structures usually likened to locks that can be opened only with a single molecule, in this case estrogen. When estrogen receptors are present, tamoxifen can jam the "locks," thus preventing the hormone from entering the cells. In general, breast cancer among women who are past menopause is estrogen-receptor positive, while premenopausal breast cancer tends to be estrogen-receptor negative. Although the ovaries no longer produce estrogen after menopause, a weaker version of the hormone generated by the adrenal glands and fat tissues continues to circulate and is capable of stimulating the growth of estrogen-receptor positive breast-cancer cells.
Tamoxifen has proved remarkably effective against breast cancer, reducing the recurrence rate by about one-third and preventing development of new cancers in the opposite breasts of about half the women treated. The usual dose is two 10-mg tamoxifen pills per day for five years after surgery.
Tamoxifen's most common side effects are hot flashes and vaginal discharge. Some women also report bleeding and irritation of the skin around the vagina. Elsewhere in the body tamoxifen can have both positive and negative effects. On the plus side, it seems to have estrogenlike effects, bonding with bone-building cells to help protect against osteoporosis.
On the negative side, tamoxifen acts like estrogen in the uterus by stimulating the overgrowth of the endometrium, or uterine lining. This is less of a problem among premenopausal women whose bodies still produce progesterone, the hormone that regularly prompts the uterus to shed its lining as menstrual flow. And, of course, it presents no danger to women of any age who have had hysterectomies. But endometrial overgrowth or hyperplasia can lead to potentially life-threatening uterine cancer among postmenopausal women. The National Cancer Institute estimates that the disease will develop among only 1/10th of 1 percent of women taking tamoxifen for five years. If endometrial cancer does occur, it usually is curable. The principal symptom of uterine cancer is abnormal bleeding. If diagnosed and treated promptly, most cases can be cured with hysterectomy. Tamoxifen can also increase the risk of blood clots in the veins.
Preventing Breast Cancer With Tamoxifen
The first major breakthrough in breast-cancer prevention occurred in 1998 when the National Cancer Institute (NCI) announced results of a six-year study showing that tamoxifen reduced the incidence of breast cancer by 45 percent among healthy but high-risk women. This study, the Breast Cancer Prevention Trial, was halted 14 months ahead of schedule because results were so much better than expected. At the outset, investigators had predicted optimistically that tamoxifen might reduce the incidence of breast cancer by 30 percent.
A total of 13,388 healthy women considered at high risk for breast cancer were recruited. Among those taking tamoxifen, only 85 developed breast cancer compared to 154 of those on the placebo or dummy pill. Three of those who took tamoxifen died of breast cancer while five among the placebo group died.
As expected, some of the participants developed serious, potentially life-threatening side effects. There were 33 cases of endometrial cancer in the tamoxifen group, compared with 14 in the placebo group. Seventeen women developed pulmonary embolisms (blood clots in the lung) in the tamoxifen group versus six in the placebo group. There were 30 cases of blood clots in major veins (deep-vein thrombosis) in the tamoxifen groups and only 19 cases in the placebo group.
Because these problems developed exclusively among postmenopausal women, critics have questioned whether the benefits of breast-cancer protection are worth the risks to these women. NCI officials calculate that tamoxifen could prevent 17 cases of breast cancer among every 1,000 women older than age 50, but would cause 12 cases of endometrial cancer and 10 serious blood clots per 1,000 women.
In order to qualify for the study, a woman had to be 60 years old or have a breast-cancer risk equivalent to that of a 60-year-old, an age at which 17 out of every 1,000 women can be expected to develop breast cancer within five years. Women between the ages of 35 and 59 were eligible to participate if their risks matched or exceeded those of a 60-year-old. Researchers weighed the following factors to determine whether younger women were at high risk:
- Family history the number of first-degree relatives (mother, sisters, daughters) diagnosed with breast cancer
- Whether a woman had delivered children and her age of her first delivery
- The number of breast biopsies, particularly those that revealed atypical hyperplasia, a crowding of atypical, but noncancerous, cells in the breast's milk ducts
- Age at her first menstrual period
- A history of lobular carcinoma in situ, a noninvasive type of breast cancer
In addition to studying the impact of tamoxifen on the incidence of breast cancer, the investigators also evaluated its effects on the bones and the heart. They found that only 47 women taking the drug had fractures of the hip, wrist and spine, compared with 71 in the placebo group. However, there were no differences in the number of heart attacks between the two groups.
Although the findings are historic and ultimately may prove life-saving for many women, NCI officials cautioned that results will need further analysis before individual women can decide whether or not to take the drug preventively. Among the unanswered questions are:
- How long to take tamoxifen for prevention
- Whether or not the drug will benefit women who carry mutations in the breast-cancer genes, BRCA1 and BRCA2, that predispose to the disease
- How it will affect women who take estrogen as hormone replacement after menopause. None of the women in the study were on hormone-replacement therapy (HRT) or were taking birth-control pills. However, women could join the study three months after giving up HRT or going off the pill.
Last updated September 17, 2010
Used for over 20 years to treat women with advanced breast cancer, tamoxifen is also commonly prescribed to prevent recurrences among women with early breast cancer.
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