Combined HRT doubles breast-cancer risk

Science Article
July 3, 2003

PHS study finds long-term use of hormones estrogen and progestin a risk, regardless of regimen

Dr. Christopher Li found that breast-cancer risk increases regardless of whether a woman uses combined-hormone therapy sequentially or continuously. Photo by Gordon Todd

By KRISTEN WOODWARD

Older women who take combined-hormone-replacement therapy for five years or more double their risk of developing breast cancer, according to a new Public Health Sciences Division study.

Among study participants, who were 65 or older, long-term use of estrogen/progestin HRT increased cancer risk regardless of the pattern of progestin use.

The study, led by Dr. Christopher Li, appears in the June 25 issue of the Journal of the American Medical Association. Co-authors included PHS colleagues Dr. Kathleen Malone, Dr. Noel Weiss, Dr. Mei-Tzu Tang, Kara L. Cushing-Haugen and Dr. Janet Daling, and Dr. Peggy Porter of the PHS and Human Biology divisions.

"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," Li said.

The study looked at women who took combined HRT for five to 15 years or more, who either took progestin sequentially (estrogen daily plus progestin about 10 days a month to mimic natural hormonal fluctuations) or continuously (estrogen and progestin daily). 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.

Effects on specific cancers

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?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?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 progesterone, 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 the way tamoxifen treats ER-positive tumors by blocking the estrogen pathway.

Estrogen-only therapy

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

Li and colleagues found that older women who took unopposed estrogen exclusively, even long term, 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 from 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. Factors studied included lifestyle, genetics, medication use, and medical and reproductive history.

Among the women with a history of combined HRT use, 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.

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