The use of oral contraceptives during the last 3 decades may have contributed to a dramatic decline in the incidence of endometrial and ovarian cancers, but a decline in breast cancer rates has not been seen. Now, a contraceptive strategy to prevent all three cancers is being tested at the City of Hope National Medical Center in Duarte, Calif.
The City of Hope researchers, headed by Jeffrey N. Weitzel, M.D., director of the Department of Clinical Cancer Genetics, are recruiting a small group of high-risk premenopausal women, most with BRCA1 mutations, for a phase I trial. Five centers nationwide are involved in the 12-month study whose primary endpoint is reduction of mammographic density. Reducing breast density should make the detection of asymptomatic cancers easier.
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The strategy is to block a woman's hormone production and then add back estrogen and progestogen to a level seen in postmenopausal women on estrogen replacement therapy. The actual protocol calls for a daily nasal spray containing deslorelin, a gonadotropin-releasing hormone agonist (GnRHA) that blocks ovulation and reduces serum estradiol and progesterone to postmenopausal levels. Daily low doses of estradiol and testosterone are added back (by either nasal spray or patch) to reduce the symptoms of menopause, preserve bone density, maintain favorable serum cholesterol, and increase libido. In addition, progestin is taken orally every 3 months to protect against endometrial cancer.
"I think it's a very important alternative method of contraception particularly because it addresses the issue of breast cancer risk," said Brian E. Henderson, Ph.D., of the University of Southern California's Norris Comprehensive Cancer Center in Los Angeles. "We have to find hormone-related alternatives to reducing breast cancer risk. . . . That's the only way we're going to really [have an] impact on breast cancer. There's no other realistic manipulation."
Existing contraceptives are a combination of synthetic estrogens and progestins the high hormone levels fool the pituitary into thinking that a women is pregnant so she doesn't ovulate.
These added hormones lower endometrial and ovarian cancer risks. But the effects of contraceptives on breast cancer risk are less clear. "There is evidence of a modest increase in breast cancer risk in women under age 45 of about 3.1% per year of contraceptive use," reported Malcolm Pike, Ph.D., USC professor and chairman of the Department of Preventive Medicine and the pioneer of the GnRHA approach to contraception. "The few studies in women over age 45 find no change in risk," he said.
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The GnRHA regimen preserves the benefits of existing contraceptives by blocking ovulation to lower ovarian risk and adding back both hormones to lower endometrial risk. To lower breast cancer risk, hormones are added back at a level about sixfold lower than the levels to which women the same age would normally be exposed. Pike estimates that women on the regimen for 5 years would lower their breast cancer risk by about 30%, ovarian cancer risk by about 40%, and endometrial cancer risk by about 20%.
Indirect Evidence
There is already indirect evidence that this strategy might work. In a 1994 report of a phase I study, Pike and Darcy V. Spicer, M.D., also of USC, found that women ages 25 to 40 with a high risk for breast cancer taking a combination of an agonist with added back estrogen and progesterone at levels used for estrogen replacement therapy, showed a significant reduction in mammographic density.
Spicer reported that other effects included a beneficial rise in high-density lipoprotein cholesterol and the loss of mood swings associated with premenstrual syndrome. He also noted that the few occurrences of hot flashes or vaginal dryness were eliminated by increasing the conjugated estrogen dose.
USC's Donna Shoupe, M.D., who was an investigator for two previous trials using this hormonal regimen one for treating PMS and the other for high-risk younger women is optimistic about the proposed agonist therapy. "I'm pretty sure it's going to work," she said, "but the fine tuning of it is the hard part."
Need for Caution
Weizel agrees. But he said there is a need for caution with the agonist regimen. The main concern is that researchers do not know the long-term effects of GnHRA. Other agonists, like Lupron®, have been used for years, but only for short-term use to treat endometriosis and fibroids, for example. Nor do clinicians have data on the long-term consequences of testosterone. And of course, the calculations made by Pike for lowering risks are just that, estimates. A large, controlled phase III trial is needed for those answers.
"And if the calculations prove true that a woman's breast cancer risk can be dropped by 47% if used for 10 years moderate risk women might be more receptive to this regimen because it has such a modest risk profile and these women feel better," Weitzel added. "But first, we have to prove that it's safe and has some benefit."
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