Long-Term Use of Combined Hormone-Replacement Therapy Poses Significant Breast-Cancer Risk, Regardless of Regimen

SEATTLE — Jun. 24, 2003 — A study of hormone-replacement therapy focusing on long-term use among older women reveals that combination estrogen/progestin HRT poses a significant increase in breast-cancer risk, regardless of the pattern of progestin use, according to researchers at Fred Hutchinson Cancer Research Center.

Women over age 65 who take combined HRT for five to 15 years or for 15 or more years — whether they take progestin sequentially (estrogen daily plus progestin about 10 days a month to mimic natural hormonal fluctuations) or continuously (estrogen and progestin daily) — face a 100 percent increase in breast-cancer risk, report Christopher I. Li, M.D., Ph.D., and colleagues in the June 25 issue of the Journal of the American Medical Association.

"We found that long-term use of combined estrogen and progestin hormone replacement therapy not only doubles cancer risk, but that the magnitude of this risk increases with duration of use," said Li, an assistant member of Fred Hutchinson's Public Health Sciences Division and lead author of the JAMA paper.

While the health risks of continuous-combined HRT are well known — publicized widely last summer with the early closing of an arm of the Women's Health Initiative — the effect of sequential-combined HRT on breast-cancer risk until now has been largely undocumented, Li said.

"Few studies have assessed whether sequential progestin use is related to breast-cancer risk, although some studies have suggested that continuous use of progestin is more strongly associated with breast-cancer risk than sequential use. In this study we found that both regimens were associated with similar increases in breast-cancer risk. There does not seem to be any advantage to sequential progestin use compared to continuous progestin use with respect to reducing this risk," said Li, also a research assistant professor of epidemiology at the University of Washington School of Public Health and Community Medicine.

In addition to assessing the impact of combined HRT on overall breast-cancer risk, the researchers looked at its effect on the risk of specific types of breast cancer. Among their most significant findings:

  • Lobular breast cancer — the researchers found a 2.7-fold (170 percent) increased risk of invasive lobular breast cancer. Lobular carcinoma, the second most common histologic type of breast cancer, involves the lobules, or chambers in the breast that contain the milk-producing glands. Lobular cancer accounts for 10 percent to 15 percent of cases. The incidence of this type of breast cancer is on the rise nationally; rates have increased 65 percent during the past 12 years (as documented by Li and colleagues in a paper published in the March 19, 2003 issue of JAMA). "The increased use of combined HRT during the past several years may partly account for this rise in lobular breast-cancer rates in the United States," Li said.

  • Ductal breast cancer — the researchers found a 1.5-fold (50 percent) increased risk of invasive ductal carcinoma, which accounts for about 80 percent of all breast-cancer cases. This type of breast cancer involves the milk ducts that carry milk from the lobules and out the nipple.

  • Hormone-receptor-positive breast cancer — women who took combined HRT had double the risk (100 percent) of hormone-receptor-positive breast cancer (tumors that need estrogen or progesterone to grow). About two-thirds of all breast cancers are estrogen-receptor positive (ER positive) and progesterone-receptor positive (PR positive). Such tumors respond well to drugs such as tamoxifen that block the effect of estrogen.

Combined HRT did not, however, increase the risk for ER- or PR-negative breast tumors. Because such cancers can grow without estrogen and prostesterone, they are unresponsive to hormonal blockers (like tamoxifen) and more difficult to treat than hormone-receptor-positive tumors.

"Scientifically, our finding that the use of combined HRT only increased the risk of hormonally positive tumors points to the importance of progesterone in breast-cancer development," Li said. "It appears that HRT must contain progesterone to promote breast-cancer growth, and that it may act through stimulation of both estrogen and progesterone receptors, not just one or the other."

A potential clinical implication of these findings, Li said, is the need for developing chemotherapeutic agents that target progesterone receptors similar to how tamoxifen is used to treat ER-positive tumors by blocking the estrogen pathway.

In addition to assessing breast-cancer risk associated with various regimens of combined HRT, the researchers looked at the long-term impact of unopposed estrogen (estrogen-only) on breast-cancer risk.

Li and colleagues found that older women who took unopposed estrogen exclusively, even for 25 or more years, were at no greater risk of breast cancer than those who had never taken any form of hormone-replacement therapy. While this study confirms previous findings regarding the role of unopposed estrogen on breast-cancer risk, it is one of the first to evaluate very long-term use of unopposed estrogen.

More than 2,000 older women throughout western Washington (King, Pierce and Snohomish counties) participated in the study; half had a history of breast cancer and half did not. Those with a history of breast cancer were diagnosed between 1997 and 1999 and were identified through Fred Hutchinson's Cancer Surveillance System, a population-based registry of cancer incidence in western Washington.

"Focusing exclusively on older women who were diagnosed in more recent years resulted in a relatively high prevalence of HRT use for a long duration," Li said. "This provided us with greater statistical power to measure the link between long-term HRT use and the risks of breast cancer."

The study, funded by the National Cancer Institute, was designed to help researchers understand the causes of breast cancer among women ages 65 to 79 — a group that accounts for more than a third of newly diagnosed breast malignancies in the United States. In addition to hormone use, other factors studied included lifestyle, genetics, medication use, and medical and reproductive history.

Among the women with a history of combined HRT use, the majority — 70 percent — took both estrogen and progestin daily and 30 percent took progestin about 10 days a month in addition to daily estrogen.

About 39 percent of the study participants had a history of taking unopposed estrogen (estrogen only), and 31 percent of these women used unopposed estrogen for 25 years or longer. Because unopposed estrogen has been linked to a higher risk of endometrial cancer (cancer of the lining of the uterus), this form of HRT is recommended only for women who've had a hysterectomy.

"We were a little surprised to see such a high proportion of women using unopposed estrogen for such a long period of time, and then to see that duration of use had no effect on breast-cancer risk," Li said. "However, a more definitive answer regarding the role of unopposed estrogen on breast-cancer risk will not be available until the arm of the Women's Health Initiative evaluating use of unopposed estrogen is completed in a few years."

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Fred Hutchinson Cancer Research Center
The Fred Hutchinson Cancer Research Center, home of two Nobel Prize laureates, is an independent, nonprofit research institution dedicated to the development and advancement of biomedical technology to eliminate cancer and other potentially fatal diseases. Fred Hutchinson receives more funding from the National Institutes of Health than any other independent U.S. research center. Recognized internationally for its pioneering work in bone-marrow transplantation, the center's four scientific divisions collaborate to form a unique environment for conducting basic and applied science. Fred Hutchinson, in collaboration with its clinical and research partners, the University of Washington Academic Medical Center and Children's Hospital and Regional Medical Center, is the only National Cancer Institute-designated comprehensive cancer center in the Pacific Northwest and is one of 38 nationwide. For more information, visit the center's Web site at www.fhcrc.org.