Progestin + Estrogen Multiplies Breast Ca Risk.
In a recent, large population-based case-control study, investigators analyzed data on 1,860 women who developed breast cancer during a 4 1/2-year period in Los Angeles County as well as 1,605 neighborhood controls. Use of estrogen replacement therapy for 5 years was associated with a modest 7% increase in breast cancer risk. In contrast, 5 years of combination hormone replacement therapy (HRT) increased breast cancer risk by 29%--more than fourfold greater than with estrogen replacement therapy alone (J. Natl. Cancer Inst. 92:328-32, 2000).
These cancers were disproportionately of the progesterone receptor-positive type, suggesting that women on combination HRT who develop breast cancer should have a relatively favorable prognosis, said study investigator Dr. Ross, professor and chairman of the department of preventive medicine and deputy director of the Norris Cancer Center at the University of Southern California, Los Angeles.
"We have to figure out a way to get progestins to the only organ that likes it postmenopausally, and that's the endometrium. The brain doesn't like it, the liver doesn't like it, the heart doesn't like it, and the breast sure as heck doesn't like it. The only organ that wants anything whatsoever to do with progestins is the endometrium," he said.
Ultimately, the answer will be to develop novel selective estrogen receptor modulators (SERMs) to serve as a sort of designer HRT. In the meantime, less-frequent administration of progestins is worth exploring.
"Instead of giving [SERMs] every month, perhaps give them every 3-4 months. ... This would be sufficient to slough off any cells that are undergoing malignant transformation and start over again. It's theoretically a good idea, and there's actually some preliminary supportive data out of the University of California, San Francisco, that this might in fact work to protect the endometrium."
The same phenomenon--a small increase in breast cancer risk associated with estrogen only and a far greater risk with estrogen plus progestin--was demonstrated in two other large recent studies: one by Catherine Schairer, Ph.D., of the National Cancer Institute and her associates involving more than 46,000 post menopausal women (JAMA 283:485-91, 2000) and a large Swedish epidemiologic study by Dr. Cecilia Magnusson and her associates at the Karolin ska Institute, Stockholm (Int. J. Cancer 81:339-44, 1999).
Moreover, in the National Heart, Lung, and Blood Institute's Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, women assigned to 0.625 mg of conjugated equine estrogen plus medroxyprogesterone acetate had much greater increases in mammographic densities--a well-established marker for increased breast cancer risk--than with estrogen alone (Ann. Intern. Med. 130[4, pt. 1]:262-69, 1999).
Dr. Ross found in his Los Angeles study that the breast cancer risk associated with sequential estrogen plus progestin therapy appeared to be greater than treating patients with continuous combined re placement therapy throughout the entire monthly cycle.
Other investigators have found no such difference in risk, and he considers this issue unresolved. A more important unresolved question involves the effect of progestins on cardiovascular risk.