POINTS TO CONSIDER REGARDING ESTROGEN REPLACEMENT THERAPY IN POST MENOPAUSAL WOMEN WHO HAVE NOT HAD BREAST CANCER AND WHO HAVE NO KNOWN FAMILIAL PREDISPOSITION TO BREAST CANCER

Benefits of estrogen: Estrogen is the major female hormone produced in the ovary during a woman’s reproductive years. The beneficial physiologic effects of estrogen are numerous. Menopause is associated with the loss of production of estrogen; therefore, estrogen replacement therapy (ERT) is often recommended as a "natural hormone replacement" in post menopausal women because of menopausal symptoms such as hot flashes, vaginal dryness, depression and mood swings, and because of important effects on maintaining calcium in bones and controlling cholesterol. In fact, studies have shown that ERT results in a 30-60% reduction in deaths from cardiovascular disease and a 30-60% reduction in deaths from complications associated with hip fractures (due to osteoporosis) in post menopausal women. Recent studies suggest that ERT is associated with a decreased risk of polyps and colon cancer, and a decreased risk of developing Alzheimer’s disease. Although careful scientific studies have not been conducted, it is generally accepted that use of ERT is associated with a better "quality of life" for many women.

Concerns regarding the relationship between estrogen and breast cancer:

There is biological evidence which suggests that estrogen is critical to the promotion and growth of breast cancer cells. For instance, breast cancer is rare in men, who lack ovaries and do not produce significant amounts of estrogen. It is difficult to grow breast cancer cells in tissue culture or in animals without stimulating them with estrogen. Treatment with estrogen-like drugs which have anti-estrogen effects on breast tissue (such as tamoxifen or toremifen), or removal of the ovaries or chemical inhibition of ovulation (chemotherapy) in premenopausal women, usually causes regression of metastatic breast cancer cells which have receptors for estrogen. There is also evidence suggesting that the longer duration of exposure to estrogen is an important risk factor for breast cancer. For example, events which decrease estrogen production and/or exposure are associated with a slight decrease in the risk of developing breast cancer. Examples include late menarche, early or premature menopause, multiple pregnancies, breast feeding, and any activity or medication which is associated with failure to ovulate and the associated decreased estrogen production. Conversely, early menarche, late menopause, and regular ovulation without pregnancies are associated with slight increased risk of breast cancer relative to other women. It should be emphasized that none of this estrogen-related risk is anywhere near as significant as a family history of breast cancer. Despite the association with estrogen exposure, only about 2% of women will have had breast cancer by age 50, and a woman who reaches age 85 has only a 10% chance of developing breast cancer.

Available data regarding estrogen replacement therapy and the risk of breast cancer:

There is medical concern that ERT in postmenopausal women may be associated with an increased risk of developing breast cancer compared to women who do not take estrogen after menopause. The best data available comes from a recent metanalysis of 51 epidemiology studies from 21 countries involving 52,705 women with breast cancer and 108,411 women without breast cancer. This analysis suggested that prolonged use of ERT does increase the risk of breast cancer, but not by much. In fact the data suggests that if one took 2000 women age 50, and gave half a placebo and half ERT, after 5 years there would be 27 breast cancers in the placebo group compared to 28 in the ERT group; after 10 years there would be 38 breast cancers in the placebo group compared to 41 in the ERT group; and after 15 years there would be 50 cancers in the placebo group compared to 57 in the ERT group. In other words, after 15 years of ERT, a woman would have about 1% higher risk (from 5%-6%) of having breast cancer than if she had never taken ERT. Epidemiology studies looking at the association of ERT with death from breast cancer actually have suggested a decreased risk of dying, probably because of closer medical monitoring while on estrogen.

Estrogen and uterine cancer:

For many years it has been known that ERT increases the risk of uterine cancer. However, when combined with progestins, this risk appears to be neutralized. Thus, with appropriate combined hormone replacement therapy and gynecologic monitoring, there is no increased risk of endometrial cancer.

Other estrogen-like drugs:

Tamoxifen is a drug which acts like estrogen on some tissues, but has "anti-estrogen" effects on breast tissue. For many years it has been used in the treatment of hormone-receptor-positive breast cancer. Earlier trials showed that tamoxifen decreased the risk of a new cancer in the opposite breast in women who already had breast cancer. A recent trial in 13,000 women at "high-risk" for breast cancer showed that tamoxifen helped prevent breast cancer in those women as well. After five years of follow-up there were half as many new cases of breast cancer (85 vs. 154) in women who took tamoxifen compared to women who took a placebo (inactive drug). In addition the tamoxifen group had half has many bone fractures (9 vs. 20) as a complication of osteoporosis, and half as many cardiovascular events (14 vs. 33) such as heart attacks and strokes. However, the tamoxifen group had twice as many blood clot problems (47 vs. 25), and was associated with more cases of uterine cancer. Tamoxifen did not seem to reduce the risk of hormone-receptor-negative breast cancer and it does not relieve hot flashes and some of the other symptoms associated with menopause.

Raloxifene is one of a new class of drugs called "selective estrogen receptor modulators" or "SERMS." In 1998 it was approved for the treatment of osteoporosis based on a randomized trial in 7,705 women less than age 80 who already had osteoporosis. Half got Raloxifene and half received a placebo. After three years there had been 22 breast cancer cases in the placebo group vs. 13 in the Raloxifene group, with four cases of uterine cancer in each group. Other drugs like this are being developed, and like tamoxifen, may have many of the advantages of estrogen but actually decrease the risk of being diagnosed with hormone-receptor-positive breast cancer.

Conclusion:

The benefits of ERT appear to outweigh the minimal increased risk of breast cancer for most postmenopausal women. However, each women should ascertain her own unique set of potential risks and benefits with the help of her physician, to determine if ERT would be appropriate. For women who have an increased risk of breast cancer, tamoxifen or some of the newer SERUMS should be considered.

This information was developed by Robert O. Dillman, M.D., Medical Director, Hoag Cancer Center, in conjunction with Sandra Finestone, Psy.D., Cancer Patient Services Coordinator, and Maureen McWeeney, MPH, Oncology Services Coordinator of the Hoag Cancer Center.

Inquiries: Hoag Cancer Center,
(949) 7-CANCER (722-6237).